U.S. patent application number 12/172684 was filed with the patent office on 2009-01-15 for fused heterocyclic compound.
This patent application is currently assigned to TAKEDA PHARMACEUTICAL COMPANY LIMITED. Invention is credited to Hiroshi BANNO, Tomoyasu ISHIKAWA, Masaki SETO, Takahiko TANIGUCHI.
Application Number | 20090018335 12/172684 |
Document ID | / |
Family ID | 35462874 |
Filed Date | 2009-01-15 |
United States Patent
Application |
20090018335 |
Kind Code |
A1 |
ISHIKAWA; Tomoyasu ; et
al. |
January 15, 2009 |
FUSED HETEROCYCLIC COMPOUND
Abstract
The present invention relates to a compound represented by the
formula: ##STR00001## wherein W is C(R.sup.1) or N, each A is an
optionally substituted aryl group or a heteroaryl group, X.sup.1 is
--NR.sup.3--Y.sup.1--, --O--, --S--, --SO--, --SO.sub.2-- or
--CHR.sup.3-- wherein R.sup.3 is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3 is optionally
bonded to A to form an optionally substituted ring structure,
R.sup.1 is a hydrogen atom or an optionally substituted group
bonded via a carbon atom, a nitrogen atom or an oxygen atom,
R.sup.2 is a hydrogen atom or optionally substituted group bonded
via a carbon atom or a sulfur atom, or R.sup.1 and R.sup.2, or
R.sup.2 and R.sup.3 are optionally bonded to form an optionally
substituted ring structure, or a salt thereof, and a tyrosine
kinase inhibitor or an agent for the prophylaxis or treatment of
cancer, which contains this compound or a prodrug thereof.
Inventors: |
ISHIKAWA; Tomoyasu;
(Osaka-shi, JP) ; TANIGUCHI; Takahiko; (Osaka-shi,
JP) ; BANNO; Hiroshi; (Osaka-shi, JP) ; SETO;
Masaki; (Osaka-shi, JP) |
Correspondence
Address: |
HAMRE, SCHUMANN, MUELLER & LARSON, P.C.
P.O. BOX 2902
MINNEAPOLIS
MN
55402-0902
US
|
Assignee: |
TAKEDA PHARMACEUTICAL COMPANY
LIMITED
Osaka
JP
|
Family ID: |
35462874 |
Appl. No.: |
12/172684 |
Filed: |
July 14, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10592812 |
Sep 14, 2006 |
|
|
|
PCT/JP2005/010451 |
Jun 1, 2005 |
|
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12172684 |
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Current U.S.
Class: |
544/236 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 43/00 20180101; A61P 1/18 20180101; A61P 13/12 20180101; C07D
487/04 20130101; A61P 9/00 20180101; A61P 11/00 20180101; C07D
487/16 20130101; A61P 35/02 20180101; A61P 31/18 20180101; A61P
13/08 20180101; A61P 15/00 20180101; A61P 9/10 20180101; A61P 35/04
20180101 |
Class at
Publication: |
544/236 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 2, 2004 |
JP |
2004-165050 |
Mar 2, 2005 |
JP |
2005-058231 |
Claims
1-29. (canceled)
30.
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyr-
rolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol or a salt thereof.
31. A pharmaceutical agent comprising the compound of claim 30 or a
salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Division of application Ser. No.
10/592,812, filed Sep. 14, 2006, which is a U.S. National Stage of
PCT/JP2005/010451, filed Jun. 1, 2005, which applications are
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to a fused pyrimidine compound
having a growth factor receptor tyrosine kinase inhibitory
activity, which is useful for the prophylaxis or treatment of
cancer, a production method thereof and use thereof.
BACKGROUND ART
[0003] The gene of cell growth factor and growth factor receptor is
called a protooncogene and plays a key role in the pathology of
human tumor. The epithelial cell growth factor receptor family
(erbB) includes EGFR, HER2, HER3 and HER4, which are type I
receptor type tyrosine kinases. These erbB family express in
various cell groups, and are deeply involved in the control of the
growth and differentiation of cells and the control of suppression
of cell death (apoptosis suppression). For example, high expression
of EGFR and HER2, and homeostatic activation of receptors are
empirically known to transform cells.
[0004] It is also known that high expression and simultaneous
expression of each of these receptors are poor prognostic factors
in various cancer patients.
[0005] These receptors are bound with many peptide ligands such as
EGF, TGF.alpha. and the like, and binding of the ligand promotes
homo- or heterodimerization of the receptors. This induces increase
of kinase activity from self-phosphorylation or
transphosphorylation of the receptors, and causes activation of
downstream signaling pathway (MAPK, Akt) via a protein bound with a
particular phosphorylated tyrosine residue. This is the mechanism
of the receptor activity of the above-mentioned cell growth,
differentiation, cell death suppression and the like, which is
considered to be responsible for the high expression of receptor in
cancer and malignant degeneration of cancer due to topical increase
in the ligand concentration.
[0006] Many cancers are associated with the high expression of EGFR
or HER2. For example, breast cancer (20-30%), ovarian cancer
(20-40%), non-small cell lung cancer (30-60%), colorectal cancer
(40-80%), prostate cancer (10-60%), bladder cancer (30-60%), kidney
cancer (20-40%) and the like can be mentioned. Moreover, receptor
expression and prognosis are correlated, and receptor expression is
a poor prognostic factor in breast cancer, non-small cell lung
cancer and the like.
[0007] In recent years, clinical use of a humanized anti-HER2
antibody (Trastuzumab) against HER2 highly expressing breast
cancer, clinical trial of anti-EGFR antibody and clinical trials of
several low molecular weight receptor enzyme inhibitors have
demonstrated a potential of these drugs against HER2 or EGFR for
therapeutic drugs for cancer. While these drugs show a tumor growth
inhibitory action in clinical and non-clinical trials, they are
known to induce inhibition of receptor enzyme activity and
suppression of downstream signaling pathway. Therefore, a compound
inhibiting EGFR or HER2 kinase, or inhibiting activation of EGFR or
HER2 kinase is effective as a therapeutic drug for cancer.
[0008] As a compound that inhibits receptor type tyrosine kinases
represented by HER2/EGFR kinase, fused heterocyclic compounds
(e.g., WO97/13771, WO98/02437, WO00/44728), quinazoline derivatives
(e.g., WO02/02552, WO01/98277, WO03/049740, WO03/050108),
thienopyrimidine derivatives (e.g., WO03/053446), aromatic azole
derivatives (e.g., WO98/03648, WO01/77107, WO03/031442) and the
like are known; however, there is no HER2 kinase inhibitory
substance to the present that has been marketed as a therapeutic
drug for cancer.
[0009] As to pyrrolo[3,2-d]pyrimidine derivatives, the following
compounds are known as compounds having a cell growth inhibitory
activity (Khim.-Farm. Zh., 1982, 16, 1338-1343; Collect. Czech.
Chem. Commun., 2003, 68, 779-791).
##STR00002##
[0010] As a compound having a receptor type tyrosine kinase
activity, the following pyrrolo[3,2-d]pyrimidine derivative is
known (WO96/40142, WO98/23613).
##STR00003##
[0011] Furthermore, as to pyrazolo[4,3-d]pyrimidine derivatives,
3,5,7-trisubstituted pyrazolo[4,3-d]pyrimidine derivatives are
known as compounds having a CDK inhibitory action, a cell growth
inhibitory action and/or an apoptosis inducing action
(EP-A-1348707), and 3-isopropylpyrazolo[4,3-d]pyrimidine
derivatives are known as compounds having a CDK1/cyclin B
inhibitory activity (Bioorganic & Medicinal Chemistry Letters,
2003, 13, 2989-2992). Furthermore, synthesis of
3-methylpyrazolo[4,3-d]pyrimidine derivatives has been reported
(The Journal of Organic Chemistry, 1956, 21, 833-836).
DISCLOSURE OF THE INVENTION
[0012] The present invention aims at providing a compound having a
superior tyrosine kinase inhibitory action, which is low toxic and
highly satisfactory as a pharmaceutical product.
[0013] The present inventors have conducted intensive studies and
found that a compound represented by the following formula (I) and
a salt thereof (sometimes to be referred to as compound (I) in the
present specification) have a superior tyrosine kinase inhibitory
action. Further studies have resulted in the completion of the
present invention.
[0014] Accordingly, the present invention provides
[1] a compound represented by the formula:
##STR00004##
wherein W is C(R.sup.1) or N, A is an optionally substituted aryl
group or an optionally substituted heteroaryl group,
X.sup.1 is --NR.sup.3--Y.sup.1--, --O--, --S--, --SO--,
--SO.sub.2-- or --CHR.sup.3--
[0015] wherein R.sup.3 is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3 is optionally
bonded to a carbon atom or a hetero atom on the aryl group or the
heteroaryl group represented by A to form an optionally substituted
ring structure, and Y.sup.1 is a single bond or an optionally
substituted C.sub.1-4 alkylene or an optionally substituted
--O--(C.sub.1-4 alkylene)-, R.sup.1 is a hydrogen atom or an
optionally substituted group bonded via a carbon atom, a nitrogen
atom or an oxygen atom, and R.sup.2 is a hydrogen atom or an
optionally substituted group bonded via a carbon atom or a sulfur
atom, or R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3 are optionally
bonded to form an optionally substituted ring structure, provided
that the compounds represented by the formulas
##STR00005##
are excluded, or a salt thereof, [2] a prodrug of the compound of
the above-mentioned [1], [3] the compound of the above-mentioned
[1], wherein W is C(R.sup.1), [4] the compound of the
above-mentioned [3], wherein A is an aryl group substituted by a
group of the formula --Y.sup.2--B and optionally further
substituted, wherein Y.sup.2 is a single bond, --O--,
--O--(C.sub.1-3 alkylene)-, --NH-- or --S--, and B is an aryl
group, a heterocyclic group, a C.sub.3-8 cycloalkyl group, a
carbamoyl group, a ureido group, a C.sub.6-18 aryl-carbonyl group
or a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, each of which
is optionally substituted, [5] the compound of the above-mentioned
[3], wherein R.sup.1 is a group of the formula --X.sup.2--R.sup.4
wherein X.sup.2 is a single bond, --NH-- or --O--, and R.sup.4 is a
hydrogen atom, a cyano group, or a C.sub.1-8 alkyl group, a
C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a carbamoyl
group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.3-8 cycloalkyl
group, a C.sub.6-18 aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl
group, a C.sub.6-18 aryl-carbonyl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl-carbonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted, [6] the compound of the above-mentioned
[3], wherein R.sup.2 is a hydrogen atom or a C.sub.1-8 alkyl group,
a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a carbamoyl
group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl
group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a
C.sub.6-18 aryl-C.sub.1-14 alkyl group, a C.sub.6-18 aryl-carbonyl
group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a
C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted, [7] the compound of the above-mentioned
[3], wherein X.sup.1 is --NR.sup.3-- wherein R.sup.3 is a hydrogen
atom or an optionally substituted aliphatic hydrocarbon group, [8]
the compound of the above-mentioned [3], wherein A is an aryl group
substituted by a group of the formula --Y.sup.2--B and optionally
further substituted, wherein Y.sup.2 is a single bond, --O--,
--O--(C.sub.1-3 alkylene)-, --NH-- or --S--, and B is an aryl
group, a heterocyclic group, a C.sub.3-8 cycloalkyl group, a
carbamoyl group, a ureido group, a C.sub.6-18 aryl-carbonyl group
or a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, each of which
is optionally substituted; R.sup.1 is a group of the formula
--X.sup.2--R.sup.4 wherein X.sup.2 is a single bond, --NH-- or
--O--, and R.sup.4 is a hydrogen atom, a cyano group, or a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a carbamoyl group, a C.sub.1-8 alkyl-carbonyl group,
a C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a heterocyclic
group, a heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl
group or a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of
which is optionally substituted; R.sup.2 is a hydrogen atom or a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a carbamoyl group, a C.sub.1-8 alkyl-carbonyl group,
a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a
C.sub.6-18 aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a
C.sub.6-18 aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4
alkyl-carbonyl group, a C.sub.6-18 aryl-sulfonyl group, a
heterocyclic group, a heterocycle-C.sub.1-4 alkyl group, a
heterocycle-carbonyl group or a heterocycle-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted; and
X.sup.1 is --NR.sup.3-- wherein R.sup.3 is a hydrogen atom or an
optionally substituted aliphatic hydrocarbon group, [9] the
compound of the above-mentioned [1], wherein W is N, [10] the
compound of the above-mentioned [9], wherein A is an aryl group
substituted by a group of the formula --Y.sup.2--B and optionally
further substituted, wherein Y.sup.2 is a single bond, --O--,
--O--(C.sub.1-3 alkylene)-, --NH-- or --S--, and B is an aryl
group, a heterocyclic group, a C.sub.3-8 cycloalkyl group, a
carbamoyl group, a ureido group, a C.sub.6-18 aryl-carbonyl group
or a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, each of which
is optionally substituted, [11] the compound of the above-mentioned
[9], wherein R.sup.2 is a hydrogen atom or a C.sub.1-8 alkyl group,
a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a carbamoyl
group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl
group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl
group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a
C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted, [12] the compound of the above-mentioned
[9], wherein X.sup.1 is --NR.sup.3-- wherein R.sup.3 is a hydrogen
atom or an optionally substituted aliphatic hydrocarbon group, [13]
the compound of the above-mentioned [9], wherein X.sup.1 is
--NR.sup.3-- wherein R.sup.3 is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group; A is an aryl group
substituted by a group of the formula --Y.sup.2--B and optionally
further substituted, wherein Y.sup.2 is a single bond, --O--,
--O--(C.sub.1-3 alkylene)-, --NH-- or --S--, and B is an aryl
group, a heterocyclic group, a C.sub.3-8 cycloalkyl group, a
carbamoyl group, a ureido group, a C.sub.6-18 aryl-carbonyl group
or a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, each of which
is optionally substituted; R.sup.2 is a hydrogen atom or a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a carbamoyl group, a C.sub.1-8 alkyl-carbonyl group,
a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a
C.sub.6-18 aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a
C.sub.6-18 aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4
alkyl-carbonyl group, a C.sub.6-18 aryl-sulfonyl group, a
heterocyclic group, a heterocycle-C.sub.1-4 alkyl group, a
heterocycle-carbonyl group or a heterocycle-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted, [14]
the compound of the above-mentioned [9], wherein X.sup.1 is
--NR.sup.3--; A is an aryl group substituted by a group of the
formula --Y.sup.2--B and optionally further substituted, wherein
Y.sup.2 is a single bond, --O--, --O--(C.sub.1-3 alkylene)-, --NH--
or --S--, and B is an aryl group, a heterocyclic group, a C.sub.3-8
cycloalkyl group, a carbamoyl group, a ureido group, a C.sub.6-18
aryl-carbonyl group or a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, each of which is optionally substituted; and R.sup.2 and
R.sup.3 are bonded to form an optionally substituted ring
structure, [15] a compound represented by the formula:
##STR00006##
wherein R.sup.1a is a hydrogen atom or an optionally substituted
group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
R.sup.2a is an optionally substituted group bonded via a carbon
atom or a sulfur atom, or R.sup.1a and R.sup.2a, or R.sup.2a and
R.sup.3a are optionally bonded to form an optionally substituted
ring structure, R.sup.3a is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3a is optionally
bonded to a carbon atom of the adjacent phenyl group to form an
optionally substituted ring structure, B.sup.a is an optionally
substituted benzene ring, and C.sup.a is an optionally substituted
--C.sub.6-18 aryl group, or a salt thereof, [16] a compound
represented by the formula:
##STR00007##
wherein R.sup.1b is a hydrogen atom or an optionally substituted
group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
R.sup.2b is an optionally substituted group bonded via a carbon
atom or a sulfur atom, or R.sup.1b and R.sup.2b, or R.sup.2b and
R.sup.3b are optionally bonded to form an optionally substituted
ring structure, R.sup.3b is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3b is optionally
bonded to a carbon atom of the adjacent phenyl group to form an
optionally substituted ring structure, B.sup.b is an optionally
substituted benzene ring, C.sup.b is an optionally substituted
C.sub.6-18 aryl group, and Z.sup.b is an optionally substituted
C.sub.1-3 alkylene group, or a salt thereof, [17] a compound
represented by the formula:
##STR00008##
wherein R.sup.1c is a hydrogen atom or an optionally substituted
group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
R.sup.2c is an optionally substituted group bonded via a carbon
atom or a sulfur atom, or R.sup.1c and R.sup.2c, or R.sup.2c and
R.sup.3c are optionally bonded to form an optionally substituted
ring structure, R.sup.3c is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3c is optionally
bonded to a carbon atom of the adjacent phenyl group to form an
optionally substituted ring structure, B.sup.c is an optionally
substituted benzene ring, and C.sup.c is an optionally substituted
heterocyclic group, or a salt thereof, [18] a compound represented
by the formula:
##STR00009##
wherein R.sup.1d is a hydrogen atom or an optionally substituted
group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
R.sup.2d is an optionally substituted group bonded via a carbon
atom or a sulfur atom, or R.sup.1d and R.sup.2d, or R.sup.2d and
R.sup.3d are optionally bonded to form an optionally substituted
ring structure, R.sup.3d is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3d is optionally
bonded to a carbon atom of the adjacent phenyl group to form an
optionally substituted ring structure, B.sup.d is an optionally
substituted benzene ring, C.sup.d is an optionally substituted
heterocyclic group, and Z.sup.d is an optionally substituted
C.sub.1-3 alkylene group, or a salt thereof, [19] a compound
represented by the formula:
##STR00010##
wherein R.sup.2e is an optionally substituted group bonded via a
carbon atom or a sulfur atom, or R.sup.2e and R.sup.3e are
optionally bonded to form an optionally substituted ring structure,
R.sup.3e is a hydrogen atom or an optionally substituted aliphatic
hydrocarbon group, or R.sup.3e is optionally bonded to a carbon
atom of the adjacent phenyl group to form an optionally substituted
ring structure, B.sup.e is an optionally substituted benzene ring,
and C.sup.e is an optionally substituted C.sub.6-18 aryl group, or
a salt thereof, [20] a compound represented by the formula:
##STR00011##
wherein R.sup.2f is an optionally substituted group bonded via a
carbon atom or a sulfur atom, or R.sup.2f and R.sup.3f are
optionally bonded to form an optionally substituted ring structure,
R.sup.3f is a hydrogen atom or an optionally substituted aliphatic
hydrocarbon group, or R.sup.3f is optionally bonded to a carbon
atom of the adjacent phenyl group to form an optionally substituted
ring structure, B.sup.f is an optionally substituted benzene ring,
C.sup.f is an optionally substituted C.sub.6-18 aryl group, and
Z.sup.f is an optionally substituted C.sub.1-3 alkylene group, or a
salt thereof, [21] a compound represented by the formula:
##STR00012##
wherein R.sup.2g is an optionally substituted group bonded via a
carbon atom or a sulfur atom, or R.sup.2g and R.sup.1g are
optionally bonded to form an optionally substituted ring structure,
R.sup.3g is a hydrogen atom or an optionally substituted aliphatic
hydrocarbon group, or R.sup.3g is optionally bonded to a carbon
atom of the adjacent phenyl group to form an optionally substituted
ring structure, B.sup.g is an optionally substituted benzene ring,
and C.sup.g is an optionally substituted heterocyclic group, or a
salt thereof, [22] (i)
2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]-
pyrimidin-5-yl]ethoxy}ethanol, (ii)
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethoxy}ethanol, (iii)
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide, (iv)
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide, (v)
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-methyl-2-(methylsulfonyl)propanamide,
(vi)
5-{2-[2-(tert-butylsulfonyl)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluorometh-
yl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine, (vii)
2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phen-
yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide, (viii)
N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyri-
midin-5-yl)ethyl]-2-(methylsulfonyl)acetamide, or (ix)
N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide, or a
salt of any of them, [23] a method of producing a compound
represented by the formula:
##STR00013##
wherein each symbol is as defined in the above-mentioned [1], or a
salt thereof, which comprises reacting a compound represented by
the formula:
##STR00014##
wherein L is a leaving group, and other symbols are as defined in
the above-mentioned [1], or a salt thereof with a compound
represented by the formula:
G-X.sup.1-A (III)
wherein G is a hydrogen atom or a metal atom, and other symbols are
as defined in the above-mentioned [1], or a salt thereof, [24] a
pharmaceutical agent comprising a compound represented by the
formula:
##STR00015##
wherein W is C(R.sup.1) or N, A is an optionally substituted aryl
group or an optionally substituted heteroaryl group,
X.sup.1 is --NR.sup.3--Y.sup.1--, --O--, --S--, --SO--,
--SO.sub.2-- or --CHR.sup.3--
[0016] wherein R.sup.3 is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3 is optionally
bonded to a carbon atom or a hetero atom on the aryl group or the
heteroaryl group represented by A to form an optionally substituted
ring structure, and Y.sup.1 is a single bond or an optionally
substituted C.sub.1-4 alkylene or an optionally substituted
--O--(C.sub.1-4 alkylene)-, R.sup.1 is a hydrogen atom or an
optionally substituted group bonded via a carbon atom, a nitrogen
atom or an oxygen atom, and R.sup.2 is a hydrogen atom or an
optionally substituted group bonded via a carbon atom or a sulfur
atom, or R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3 are optionally
bonded to form an optionally substituted ring structure, provided
that the compounds represented by the formulas
##STR00016##
are excluded, or a salt thereof, or a prodrug thereof, [25] the
pharmaceutical agent of the above-mentioned [24] which is a
tyrosine kinase inhibitor, [26] the pharmaceutical agent of the
above-mentioned [24] which is an agent for the prophylaxis or
treatment of cancer, [27] the pharmaceutical agent of the
above-mentioned [26] wherein the cancer is breast cancer, prostate
cancer, lung cancer, pancreatic cancer or kidney cancer, [28] a
method for the prophylaxis or treatment of cancer in a mammal,
which comprises administering, to said mammal, an effective amount
of a compound represented by the formula:
##STR00017##
wherein W is C(R.sup.1) or N, A is an optionally substituted aryl
group or an optionally substituted heteroaryl group,
X.sup.1 is --NR.sup.3--Y.sup.1--, --O--, --S--, --SO--,
--SO.sub.2-- or --CHR.sup.3--
[0017] wherein R.sup.3 is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3 is optionally
bonded to a carbon atom or a hetero atom on the aryl group or the
heteroaryl group represented by A to form an optionally substituted
ring structure, and Y.sup.1 is a single bond or an optionally
substituted C.sub.1-4 alkylene or an optionally substituted
--O--(C.sub.1-4 alkylene)-, R.sup.1 is a hydrogen atom or an
optionally substituted group bonded via a carbon atom, a nitrogen
atom or an oxygen atom, and R.sup.2 is a hydrogen atom or an
optionally substituted group bonded via a carbon atom or a sulfur
atom, or R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3 are optionally
bonded to form an optionally substituted ring structure, provided
that the compounds represented by the formulas
##STR00018##
are excluded, or a salt thereof, or a prodrug thereof, [29] use of
a compound represented by the formula:
##STR00019##
wherein W is C(R.sup.1) or N, A is an optionally substituted aryl
group or an optionally substituted heteroaryl group,
X.sup.1 is --NR.sup.3--Y.sup.1--, --O--, --S--, --SO--,
--SO.sub.2-- or --CHR.sup.3--
[0018] wherein R.sup.3 is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3 is optionally
bonded to a carbon atom or a hetero atom on the aryl group or the
heteroaryl group represented by A to form an optionally substituted
ring structure, and Y.sup.1 is a single bond or an optionally
substituted C.sub.1-4 alkylene or an optionally substituted
--O--(C.sub.1-4 alkylene)-, R.sup.1 is a hydrogen atom or an
optionally substituted group bonded via a carbon atom, a nitrogen
atom or an oxygen atom, and R.sup.2 is a hydrogen atom or an
optionally substituted group bonded via a carbon atom or a sulfur
atom, or R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3 are optionally
bonded to form an optionally substituted ring structure, provided
that the compounds represented by the formulas
##STR00020##
are excluded, or a salt thereof, or a prodrug thereof, for the
production of an agent for the prophylaxis or treatment of cancer,
and the like.
[0019] Furthermore, the present invention provides
[30] the compound of the above-mentioned [15], wherein R.sup.2, is
(i) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8
alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18
aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18
aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, a C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from the
group (substituent group T) consisting of (a) halogen, (b) oxo, (c)
optionally halogenated C.sub.1-4 alkyl, (d) --(CH.sub.2).sub.m-Q,
(e) --(CH.sub.2).sub.m-Z.sup.1- (optionally halogenated C.sub.1-4
alkyl), (f) --(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7, --OCONH.sub.2 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--, --C(OH)R--,
--C(.dbd.N--OR.sup.8)--, --S--, --SO--, --SO.sub.2--,
--N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--,
--CO--OC--, --O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR (CH.sub.2).sub.m and (CH.sub.2).sub.n are optionally
substituted by 1 to 5 substituents selected from halogen,
optionally halogenated C.sub.1-4 alkyl and hydroxy, and when m or n
is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2) is optionally replaced by
--CH.dbd.CH-- or --C.ident.C--, R.sup.6 and R.sup.7 are the same or
different and each is a hydrogen atom or a C.sub.1-4 alkyl group,
or R.sup.6 and R.sup.7 are bonded to form, together with a nitrogen
atom, a 3- to 8-membered saturated or unsaturated aliphatic
heterocyclic group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.9 is a C.sub.1-4 alkyl group, or (ii) a carbamoyl
group optionally having 1 or 2 C.sub.1-8 alkyl group(s) optionally
substituted by substituent(s) selected from substituent group T,
wherein said carbamoyl group has two substituents, which optionally
form, together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or unsaturated aliphatic heterocyclic group optionally
substituted by substituent(s) selected from substituent group T,
[31] the compound of the above-mentioned [15], wherein B.sup.a is a
benzene ring optionally substituted by 1 to 4 substituents selected
from halogen, C.sub.1-4 alkyl, hydroxy-C.sub.1-4 alkyl and
C.sub.1-4 alkyloxy; C.sup.a is a phenyl group optionally
substituted by 1 to 5 substituents selected from (i) halogen, (ii)
optionally halogenated C.sub.1-4 alkyl, (iii) hydroxy-C.sub.1-4
alkyl, (iv) heterocycle-C.sub.1-4 alkyl (preferably, 5- to
8-membered heterocycle-C.sub.1-4 alkyl, said 5- to 8-membered
heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom,
an oxygen atom and an optionally oxidized sulfur atom, such as
imidazolyl, triazolyl and the like), (v) optionally halogenated
C.sub.1-4 alkyloxy, (vi) C.sub.1-4 alkyl-carbonyl, (vii) cyano,
(viii) carbamoyl optionally substituted by C.sub.1-8 alkyl, and
(ix) C.sub.1-4 alkoxy-carbonyl;
R.sup.1a is
[0020] (i) a hydrogen atom, (ii) a cyano group, or (iii) a
C.sub.1-4 alkyl group or a C.sub.2-4 alkenyl group, each of which
is optionally substituted by
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7 wherein n is an
integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, R.sup.8 is
a hydrogen atom or a C.sub.1-4 alkyl group, and when n is not less
than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--; and R.sup.2a is a C.sub.1-8
alkyl group, a C.sub.2-8 alkenyl group or a C.sub.2-8 alkynyl
group, each of which is optionally substituted by substituent(s)
selected from (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally
halogenated C.sub.1-4 alkyloxy, (e) --O--(CH.sub.2).sub.n--OH, (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (h) --O--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (i) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18
aryl, (j) --O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH,
(k) --O--(CH.sub.2).sub.n--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2)--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (m) --O--(CH.sub.2)--NR.sup.8--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (n)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4 alkyl,
(q) --NR.sup.6R.sup.7,
[0021] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl),
(u) --NR.sup.8--CO--(CH.sub.2)--OH,
(v) --NR.sup.8--CO--(CH.sub.2)--CN,
[0022] (w) --NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, (x)
--NR.sup.8--CO--(CH.sub.2)--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2)--SO-- (optionally halogenated C.sub.1-4
alkyl), (z) --NR.sup.8--CO--(CH.sub.2)--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2)--SO.sub.2--C.sub.3-8 cycloalkyl, (bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc) --NR.sup.8--CO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (dd)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl,
(ii) --S--(CH.sub.2)--OH,
[0023] (jj) --SO--(CH.sub.2).sub.n--OH, (kk)
--SO.sub.2--(CH.sub.2).sub.n--OH, and (ll) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--O--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like)
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
(CH.sub.2).sub.n are optionally substituted by halogenated
C.sub.1-4 alkyl or hydroxy, and when n is not less than 2, a subset
--CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH--; R.sup.3a is a hydrogen atom or a C.sub.1-6 alkyl
group; or R.sup.1a and R.sup.2a are optionally bonded to form
##STR00021##
R.sup.2a and R.sup.3a are optionally bonded to form C.sub.2-4
alkylene optionally substituted by an imino group, particularly
preferably, R.sup.2a is a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group or a C.sub.2-8 alkynyl group (particularly, a
C.sub.1-8 alkyl group), each of which is optionally substituted by
substituent(s) selected from (a) hydroxy, (b) carboxy, (c) cyano,
(d) optionally halogenated C.sub.1-4 alkyloxy, (e)
--O--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is optionally
substituted by hydroxy), (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g) --O--(CH.sub.2)--O--
(optionally halogenated C.sub.1-4 alkyl), (h)
--O--(CH.sub.2)--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (i) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (j)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2)--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1--
4 alkyl, (m) --O--(CH.sub.2)--NR.sup.8--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (n)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), [0024] (p) --CO--NR.sup.8--O--C.sub.1-4
alkyl,
(q) --NR.sup.6R.sup.7,
[0025] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-14 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2)--OH (wherein (CH.sub.2).sub.n is
optionally substituted by optionally halogenated C.sub.1-4 alkyl or
hydroxy), (v) --NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2)--NR.sup.6R.sup.7 (when n is not less
than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--), (x)
--NR.sup.8--CO--(CH.sub.2)--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (z) --NR.sup.8--CO--(CH.sub.2)--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl) (wherein (CH.sub.2) is
optionally substituted by C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc)
--NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(dd) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl, (ii)
--S--(CH.sub.2).sub.n--OH, (jj) --SO--(CH.sub.2).sub.n--OH, (kk)
--SO.sub.2--(CH.sub.2).sub.n--OH, and (ll) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--O--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, [32]
the compound of the above-mentioned [15], wherein B.sup.a is a
benzene ring optionally substituted by 1 to 4 substituents selected
from halogen and optionally halogenated C.sub.1-4 alkyl; C.sup.a is
a phenyl group substituted by 1 to 5 substituents selected from (i)
halogen, (ii) optionally halogenated C.sub.1-4 alkyl, (iii)
hydroxy-C.sub.1-4 alkyl, (iv) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl and the like), (v) optionally halogenated
C.sub.1-4 alkyloxy, (vi) cyano, and (vii) carbamoyl optionally
substituted by C.sub.1-8 alkyl; R.sup.1a is a hydrogen atom;
R.sup.2a is a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group or a
C.sub.2-8 alkynyl group, each of which is substituted by
substituent(s) selected from (a) hydroxy, (b) optionally
halogenated C.sub.1-4 alkyloxy, (c) --O--(CH.sub.2).sub.n--OH, (d)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (e)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (f)
--O--(CH.sub.2).sub.n--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (g) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (h)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (i)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (j) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (k)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl),
(l) --NR.sup.6R.sup.7,
[0026] (m) --NR.sup.8--(CH.sub.2).sub.n--OH, (n)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (o)
--NR.sup.8--CO(CH.sub.2).sub.n--OH, (p)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (q)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (r) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (s)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(t) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (u)--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (v)
--NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(w) --S--(CH.sub.2).sub.n--OH, (x) --SO--(CH.sub.2).sub.n--OH, (y)
--SO.sub.2--(CH.sub.2).sub.n--OH, and (z) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--NH--C.sub.1-4 alkyl, --CONH.sub.2,
--SO.sub.2--C.sub.1-4 alkyl, --SO.sub.2--NH--C.sub.1-4 alkyl,
--SO.sub.2NH.sub.2 and the like), wherein n is an integer of 1 to
4, R.sup.6 and R.sup.7 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, R.sup.8 is a hydrogen
atom or a C.sub.1-4 alkyl group, and (CH.sub.2).sub.n is optionally
substituted by C.sub.1-4 alkyl or hydroxy; R.sup.3a is a hydrogen
atom or a C.sub.1-6 alkyl group; or R.sup.1a and R.sup.2a are
optionally bonded to form
##STR00022##
R.sup.2a and R.sup.3a are optionally bonded to form C.sub.2-4
alkylene, particularly preferably, R.sup.2a is a C.sub.1-18 alkyl
group, a C.sub.2-8 alkenyl group or a C.sub.2-8 alkynyl group
(particularly, a C.sub.1-18 alkyl group), each of which is
substituted by substituent(s) selected from (a) hydroxy, (b)
optionally halogenated C.sub.1-4 alkyloxy, (c)
--O--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is optionally
substituted by hydroxy), (d)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (e)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (f)
--O--(CH.sub.2).sub.n--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (g) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (h)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (i)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (j) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (k)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl),
(l) --NR.sup.6R.sup.7,
[0027] (m) --NR.sup.8--(CH.sub.2).sub.n--OH, (n)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (o)
--NR.sup.8CO--(CH.sub.2).sub.n--OH (wherein CH.sub.2).sub.n is
optionally substituted by C.sub.1-4 alkyl), (p)
--NR.sup.8--CO--(CH.sub.2).sub.n, --O--C.sub.1-4 alkyl, (q)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (r) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl) (wherein (CH.sub.2).sub.n
is optionally substituted by C.sub.1-4 alkyl), (s)
--NR.sup.8--CO--(CH.sub.2)--SO.sub.2--C.sub.3-8 cycloalkyl, (t)
--NR.sup.8--CO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl, (u)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(v) --NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (w) --S--(CH.sub.2).sub.n--OH, (x)
--SO--(CH.sub.2).sub.n--OH, (y) --SO.sub.2--(CH.sub.2).sub.n--OH,
and (z) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
[33] the compound of the above-mentioned [31], wherein R.sup.2a is
(i) a C.sub.5-8 alkyl group substituted by hydroxy, (ii) a
C.sub.1-8 alkyl group substituted by substituent(s) selected from
(a) halogenated C.sub.1-4 alkyloxy, (b) --O--(CH.sub.2).sub.n--OH,
(c) --O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (d)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (e) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (f)
--O--(CH.sub.2).sub.n--SO.sub.2--C.sub.618 aryl, (g)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl) (h) --CO--NR--(CH.sub.2).sub.n--OH, (i)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (j)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (k)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (l)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (m)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (n) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(p) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (q)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(r) --NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (s) --S--(CH.sub.2).sub.n--OH, (t)
--SO--(CH.sub.2).sub.n--OH, (u) --SO.sub.2--(CH.sub.2).sub.n--OH,
and (v) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, and (CH.sub.2).sub.n is optionally
substituted by C.sub.1-4 alkyl or hydroxy, (iii) a C.sub.2-8
alkenyl group optionally substituted by hydroxy, or (iv) a
C.sub.2-8 alkynyl group optionally substituted by hydroxy,
particularly preferably, R.sup.2a is (i) a C.sub.5-8 alkyl group
substituted by hydroxy, (ii) a C.sub.1-8 alkyl group substituted by
substituent(s) selected from (a) halogenated C.sub.1-4 alkyloxy,
(b) --O--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by hydroxy), (c)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (d) --O--(CH.sub.2)--O--
(optionally halogenated C.sub.1-4 alkyl), (e)
--O--(CH.sub.2)--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (f) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (g)
--O--(CH.sub.2)N--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (h) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (i)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (j)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (k)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by C.sub.1-4 alkyl), (l)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (m)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (n) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (wherein (CH.sub.2).sub.n
is optionally substituted by C.sub.1-4 alkyl), (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(p) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (q)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(r) --NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (s) --S--(CH.sub.2).sub.n--OH, (t)
--SO--(CH.sub.2).sub.n--OH, (u) --SO.sub.2--(CH.sub.2).sub.n--OH,
and (v) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom
or a C.sub.1-4 alkyl group, (iii) a C.sub.2-8 alkenyl group
optionally substituted by hydroxy, or (iv) a C.sub.2-8 alkynyl
group optionally substituted by hydroxy, [34] the compound of the
above-mentioned [16], wherein R.sup.2b is (i) a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a
C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from the
group (substituent group T) consisting of (a) halogen, (b) oxo, (c)
optionally halogenated C.sub.1-4 alkyl, (d) --(CH.sub.2).sub.m-Q,
(e) --(CH.sub.2)-Z.sup.1- (optionally halogenated C.sub.1-4 alkyl),
(f) --(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7, --OCONH.sub.2 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH-- or --C.ident.C--, R.sup.6 and R.sup.7 are the same or
different and each is a hydrogen atom or a C.sub.1-4 alkyl group,
or R.sup.6 and R.sup.7 are bonded to form, together with a nitrogen
atom, a 3- to 8-membered saturated or unsaturated aliphatic
heterocyclic group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.9 is a C.sub.1-4 alkyl group, or (ii) a carbamoyl
group optionally having 1 or 2 C.sub.1-8 alkyl group(s) optionally
substituted by substituent(s) selected from substituent group T,
wherein the carbamoyl group has two substituents, and they
optionally form, together with the adjacent nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group
optionally substituted by substituent(s) selected from substituent
group T, [35] the compound of the above-mentioned [16] wherein
B.sup.b is a benzene ring optionally substituted by halogen;
C.sup.b is a phenyl group optionally substituted by 1 to 5
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl and cyano; R.sup.1b is (i) a hydrogen atom, or (ii)
a C.sub.2-4 alkenyl group optionally substituted by hydroxy;
R.sup.2b is
[0028] (i) a C.sub.1-8 alkyl group optionally substituted by
substituent(s) selected from (a) halogen, (b) hydroxy, (c)
C.sub.1-4 alkyloxy, (d) --O--(CH.sub.2).sub.n--OH, (e)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl,
(f) --CO--NR.sup.8--(CH.sub.2)--OH,
(g) --NR.sup.6R.sup.7, and
[0029] (h) --NR.sup.8--(CH.sub.2).sub.n--OH, wherein n is an
integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.8
is a hydrogen atom or a C.sub.1-4 alkyl group, (ii) a C.sub.6-18
aryl-C.sub.1-4 alkyl group optionally substituted by substituent(s)
selected from (a) C.sub.1-4 alkyl optionally having hydroxy, (b)
carboxy, (c) C.sub.1-4 alkoxy-carbonyl, (d) 5- to 8-membered
heterocycle-carbonyl having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and a sulfur atom, which optionally
has substituent(s) selected from hydroxy and C.sub.1-4 alkyl, and
(e) C.sub.1-4 alkyl-carbamoyl optionally having substituent(s)
selected from hydroxy and carbamoyl, (iii) a C.sub.6-18
aryl-carbonyl group optionally substituted by C.sub.1-4 alkoxy,
(iv) a C.sub.6-18 aryl-sulfonyl group optionally substituted by
C.sub.1-4 alkoxy, or (v) a 5- to 8-membered heterocycle-C.sub.1-14
alkyl group having 1 to 3 hetero atoms selected from a nitrogen
atom, an oxygen atom and a sulfur atom, which is optionally
substituted by substituent(s) selected from (a) carboxy, and (b)
C.sub.1-4 alkoxy-carbonyl; R.sup.3b is a hydrogen atom or a
C.sub.1-6 alkyl group; or R.sup.2b and R.sup.3b are optionally
bonded to form C.sub.2-4 alkylene; and Z.sup.b is a C.sub.1-3
alkylene group, [36] the compound of the above-mentioned [16],
wherein B.sup.b is a benzene ring optionally substituted by
halogen; C.sup.b is a phenyl group optionally substituted by 1 to 5
substituents selected from halogen and optionally halogenated
C.sub.1-4 alkyl; R.sup.1b is a hydrogen atom; R.sup.2b is a
C.sub.1-8 alkyl group optionally substituted by substituent(s)
selected from (a) hydroxy,
(b) --O--(CH.sub.2)--OH,
[0030] (c) --O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH,
(e) --NR.sup.6R.sup.7, and
[0031] (f) --NR.sup.8--(CH.sub.2).sub.n--OH, wherein n is an
integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.8
is a hydrogen atom or a C.sub.1-4 alkyl group; R.sup.3b is a
hydrogen atom or a C.sub.1-6 alkyl group; and Z.sup.b is a
C.sub.1-3 alkylene group, [37] the compound of the above-mentioned
[36], wherein B.sup.b is a benzene ring optionally substituted by
halogen; C.sup.b is a phenyl group optionally substituted by 1 to 5
substituents selected from halogen and optionally halogenated
C.sub.1-4 alkyl; R.sup.1b is a hydrogen atom; R.sup.2b is a
C.sub.1-8 alkyl group substituted by substituent(s) selected from
(a) --O--(CH.sub.2).sub.n--OH, (b)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, and (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, wherein n is an integer of 1
to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group;
R.sup.3b is a hydrogen atom or a C.sub.1-6 alkyl group; and Z.sup.b
is a methylene group, [38] the compound of the above-mentioned
[17], wherein R.sup.2c is (i) a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.2-8 alkynyl group, a C.sub.1-8
alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from the
group (substituent group T) consisting of (a) halogen, (b) oxo, (c)
optionally halogenated C.sub.1-4 alkyl, (d) --(CH.sub.2).sub.m-Q,
(e) --(CH.sub.2).sub.m-Z.sup.1- (optionally halogenated C.sub.1-4
alkyl), (f) --(CH.sub.2).sub.m-Z.sup.1-C.sub.3-- cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l) --(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-
(CH.sub.2).sub.n-Z.sup.1-C.sub.1-4 alkyl wherein m is an integer of
0 to 4, n is an integer of 1 to 4, Q is hydroxy, carboxy, cyano,
nitro, --NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH--, R.sup.6 and R.sup.7 are the same or different and
each is a hydrogen atom or a C.sub.1-4 alkyl group, or R.sup.6 and
R.sup.7 are bonded to form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group,
R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.9
is a C.sub.1-4 alkyl group, or (ii) a carbamoyl group optionally
having 1 or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or unsaturated aliphatic heterocyclic group optionally
substituted by substituent(s) selected from substituent group T,
[39] the compound of the above-mentioned [17], wherein Bc is a
benzene ring optionally substituted by 1 to 4 substituents selected
from halogen and optionally halogenated C.sub.1-4 alkyl; C.sup.c is
a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom
(e.g., pyridyl, pyrimidinyl, 4-piperidyl), which is optionally
substituted by 1 to 5 substituents selected from (i) halogen, (ii)
C.sub.1-4 alkyl, (iii) C.sub.1-4 alkyl-carbonyl, (iv) optionally
halogenated C.sub.1-4 alkoxy-carbonyl, (v) C.sub.3-8
cycloalkyl-carbonyl, and (vi) a carbamoyl group optionally
substituted by substituent(s) selected from (a) optionally
halogenated C.sub.1-8 alkyl, (b) C.sub.3-8 cycloalkyl, and (c)
C.sub.6-18 aryl optionally substituted by substituent(s) selected
from halogen, C.sub.1-4 alkyl and C.sub.1-4 alkyloxy; R.sup.1c is
(i) a hydrogen atom, (ii) a C.sub.2-4 alkenyl group optionally
substituted by hydroxy, or (iii) a 5- to 8-membered heterocyclic
group having 1 to 3 hetero atoms selected from a nitrogen atom, an
oxygen atom and a sulfur atom;
R.sup.2c is
[0032] (i) a C.sub.1-4 alkyl group optionally substituted by
substituent(s) selected from (a) halogen, (b) hydroxy, (c)
C.sub.1-4 alkyloxy, (d) carboxy, (e) C.sub.1-4 alkoxy-carbonyl, (f)
--O--(CH.sub.2).sub.n--OH, (g) --O--(CH.sub.2).sub.n--O--C.sub.1-4
alkyl, (h) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, and (i)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-14 alkyl
wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom
or a C.sub.1-4 alkyl group, or (ii) a C.sub.6-18 aryl-C.sub.1-4
alkyl group optionally substituted by C.sub.1-4 alkyl optionally
having hydroxy; R.sup.3c is a hydrogen atom or a C.sub.1-6 alkyl
group; or R.sup.2c and R.sup.3c are optionally bonded to form
C.sub.2-4 alkylene, [40] the compound of the above-mentioned [17],
wherein B.sup.c is a benzene ring optionally substituted by 1 to 4
substituents selected from halogen and C.sub.1-4 alkyl; C.sup.c is
a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom,
which is optionally substituted by 1 to 5 substituents selected
from (i) C.sub.1-4 alkyl, (ii) C.sub.1-4 alkyl-carbonyl, (iii)
optionally halogenated C.sub.1-4 alkoxy-carbonyl, (iv) C.sub.3-8
cycloalkyl-carbonyl, and (v) a carbamoyl group optionally
substituted by substituent(s) selected from (a) optionally
halogenated C.sub.1-8 alkyl, (b) C.sub.3-8 cycloalkyl, and (c)
C.sub.6-18 aryl optionally substituted by halogen; R.sup.1c is a
hydrogen atom; R.sup.2c is a C.sub.1-4 alkyl group optionally
substituted by substituent(s) selected from (a) hydroxy, (b)
C.sub.1-4 alkyloxy, (c) --O--(CH.sub.2).sub.n--OH, (d)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, and (e)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl wherein
n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group; R.sup.3c is a hydrogen atom or a C.sub.1-6
alkyl group, [41] the compound of the above-mentioned [40], wherein
R.sup.2c is a C.sub.1-4 alkyl group optionally substituted by
substituent(s) selected from (a) --O--(CH.sub.2).sub.n--OH, and (b)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is an integer
of 1 to 4, [42] the compound of the above-mentioned [18], wherein
B.sup.d is a benzene ring optionally substituted by halogen;
C.sup.d is a 5- to 8-membered heterocyclic group having 1 to 3
hetero atoms selected from a nitrogen atom, an oxygen atom and a
sulfur atom; R.sup.1d is a hydrogen atom;
R.sup.2d is
[0033] (i) C.sub.1-4 alkyl optionally substituted by substituent(s)
selected from (a) C.sub.1-4 alkyloxy, (b)
--O--(CH.sub.2).sub.n--OH, and (c)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl wherein
n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, or (ii) a 5- to 8-membered
heterocycle-C.sub.1-4 alkyl group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom,
which is optionally substituted by substituent(s) selected from (a)
carboxy, and (b) C.sub.1-4 alkoxy-carbonyl; R.sup.3d is a hydrogen
atom or a C.sub.1-6 alkyl group; and Z.sup.d is a C.sub.1-3
alkylene group, [43] the compound of the above-mentioned [18],
wherein B.sup.d is a benzene ring optionally substituted by
halogen; C.sup.d is a 5- to 8-membered heterocyclic group having 1
to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and
a sulfur atom; R.sup.1d is a hydrogen atom; R.sup.2d is a C.sub.1-4
alkyl group optionally substituted by C.sub.1-4 alkyloxy; R.sup.3d
is a hydrogen atom or a C.sub.1-6 alkyl group; and Z.sup.d is a
methylene group, [44] the compound of the above-mentioned [19],
wherein R.sup.2e is (i) a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.2-8 alkynyl group, a C.sub.1-8
alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from the
group (substituent group T) consisting of (a) halogen, (b) oxo, (c)
optionally halogenated C.sub.1-4 alkyl, (d) --(CH.sub.2).sub.m-Q,
(e) --(CH.sub.2).sub.m-Z.sup.1- (optionally halogenated C.sub.1-4
alkyl), (f) --(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2- (CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i) --(CH.sub.2).sub.m-Z.sup.2-
(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8 cycloalkyl, (j)
--(CH.sub.2).sub.m-Z.sup.1- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and (l)
--(CH.sub.2).sub.m-Z.sup.2- (CH.sub.2).sub.n-Z.sup.1-
(CH.sub.2).sub.m-Z.sup.1-C.sub.1-4 alkyl wherein m is an integer of
0 to 4, n is an integer of 1 to 4, Q is hydroxy, carboxy, cyano,
nitro, --NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.8)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH--, R.sup.6 and R.sup.7 are the same or different and
each is a hydrogen atom or a C.sub.1-4 alkyl group, or R.sup.6 and
R.sup.7 are bonded to form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group,
R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.9
is a C.sub.1-4 alkyl group, or (ii) a carbamoyl group optionally
having 1 or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or unsaturated aliphatic heterocyclic group optionally
substituted by substituent(s) selected from substituent group T,
[45] the compound of the above-mentioned [19], wherein B.sup.e is a
benzene ring optionally substituted by halogen; C.sup.e is a phenyl
group optionally substituted by optionally halogenated C.sub.1-4
alkyl; R.sup.2e is a C.sub.1-4 alkyl group optionally substituted
by --O--(CH.sub.2).sub.n--OH wherein n is an integer of 1 to 4,
[46] the compound of the above-mentioned [19], wherein B.sup.e is a
benzene ring optionally substituted by halogen; C.sup.e is a phenyl
group optionally substituted by optionally halogenated C.sub.1-4
alkyl; R.sup.2e is a C.sub.1-4 alkyl group substituted by
--O--(CH.sub.2).sub.n--OH wherein n is an integer of 1 to 4, [47]
the compound of the above-mentioned [20], wherein R.sup.2f is (i) a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8
alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18
aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18
aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, a C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from the
group (substituent group T) consisting of (a) halogen, (b) oxo, (c)
optionally halogenated C.sub.1-4 alkyl, (d) --(CH.sub.2).sub.m-Q,
(e) --(CH.sub.2).sub.m-Z.sup.1- (optionally halogenated C.sub.1-4
alkyl), (f) --(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i) --(CH.sub.2).sub.m-Z.sup.2
(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8 cycloalkyl, (j)
--(CH.sub.2).sub.m-Z.sup.1- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and (l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--C(.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH--, R.sup.6 and R.sup.7 are the same or different and
each is a hydrogen atom or a C.sub.1-4 alkyl group, or R.sup.6 and
R.sup.7 are bonded to form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group,
R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.9
is a C.sub.1-4 alkyl group, or (ii) a carbamoyl group optionally
having 1 or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or unsaturated aliphatic heterocyclic group optionally
substituted by substituent(s) selected from substituent group T,
[48] the compound of the above-mentioned [20], wherein B.sup.f is a
benzene ring optionally substituted by halogen; C.sup.f is a phenyl
group optionally substituted by halogen;
R.sup.2f is
[0034] (i) a C.sub.1-4 alkyl group optionally substituted by 1 to 5
substituents selected from the group consisting of (a) hydroxy, (b)
--O--(CH.sub.2).sub.n--OH, (c)
--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--(CH.sub.2).sub.n-heterocyclic group (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom), and (e)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, wherein n
is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, (ii) a C.sub.6-18 aryl group optionally
substituted by 1 to 5 substituents selected from the group
consisting of (a) C.sub.1-4 alkyl optionally substituted by
substituent(s) selected from hydroxy, --NR.sup.8--(CH.sub.2)--OH,
--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl,
--NR.sup.8--(CH.sub.2).sub.n-heterocyclic group (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom) and --NR.sup.8--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, and (b) --CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4
alkyl, wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen
atom or a C.sub.1-4 alkyl group, or (iii) a C.sub.6-18
aryl-C.sub.1-4 alkyl group optionally substituted by 1 to 5
substituents selected from the group consisting of (a) carboxy, (b)
C.sub.1-4 alkoxy-carbonyl, and (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group; R.sup.3f is a hydrogen atom or a C.sub.1-6 alkyl
group; or R.sup.2f and R.sup.3f are optionally bonded to form
C.sub.2-4 alkylene; and Z.sup.f is a C.sub.1-3 alkylene group, [49]
the compound of the above-mentioned [20], wherein B.sup.f is a
benzene ring optionally substituted by halogen; C.sup.f is a phenyl
group optionally substituted by halogen; R.sup.2f is a C.sub.1-4
alkyl group optionally substituted by 1 to 5 substituents selected
from the group consisting of (a) hydroxy, and (b)
--O--(CH.sub.2).sub.n--OH wherein n is an integer of 1 to 4;
R.sup.3f is a hydrogen atom or a C.sub.1-6 alkyl group; and Z.sup.f
is methylene, [50] the compound of the above-mentioned [49],
wherein R.sup.2f is a C.sub.1-4 alkyl group substituted by
--O--(CH.sub.2).sub.n--OH wherein n is an integer of 1 to 4, [51]
the compound of the above-mentioned [21], wherein R.sup.2g is (i) a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8
alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18
aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18
aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, a C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from the
group (substituent group T) consisting of (a) halogen, (b) oxo, (c)
optionally halogenated C.sub.1-4 alkyl, (d) --(CH.sub.2).sub.m-Q,
(e) --(CH.sub.2).sub.m-Z.sup.1- (optionally halogenated C.sub.1-4
alkyl), (f) --(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2)-Z.sup.1-C.sub.3-8 cycloalkyl,
(j) --(CH.sub.2).sub.n-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.8)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--, --C((.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.8)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2), and (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH--, R.sup.6 and R.sup.7 are the same or different and
each is a hydrogen atom or a C.sub.1-4 alkyl group, or R.sup.6 and
R.sup.7 are bonded to form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group,
R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.9
is a C.sub.1-4 alkyl group, or (ii) a carbamoyl group optionally
having 1 or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or unsaturated aliphatic heterocyclic group optionally
substituted by substituent(s) selected from substituent group T,
[52] the compound of the above-mentioned [21], wherein B.sup.g is a
benzene ring optionally substituted by C.sub.1-4 alkyl; C.sup.g is
a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom,
which is optionally substituted by C.sub.1-4 alkyl
R.sup.2g is
[0035] (i) a C.sub.1-4 alkyl group optionally substituted by
hydroxy, (ii) a C.sub.6-18 aryl group optionally substituted by
substituent(s) selected from (a) nitro, (b) amino, (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl,
(e) --NR.sup.8--CO--(CH.sub.2)--NR.sup.6R.sup.7,
[0036] (f) --NR.sup.8--CO--(CH.sub.2).sub.n--COOH (g)
--NR.sup.8--CO--(CH.sub.2)--CO.sub.2--C.sub.1-4 alkyl, and (h)
--NR.sup.8--CO--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--O--C.sub.1-4
alkyl, wherein m is an integer of 0 to 4, n is an integer of 1 to
4, R.sup.6 and R.sup.7 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.8 is a hydrogen
atom or a C.sub.1-4 alkyl group, or (iii) a C.sub.6-18
aryl-C.sub.1-4 alkyl group optionally substituted by substituent(s)
selected from (a) carboxy, (b) C.sub.1-4 alkoxy-carbonyl, and (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group; R.sup.3g is a hydrogen atom or a C.sub.1-6 alkyl
group; or R.sup.2g and R.sup.3g are optionally bonded to form
C.sub.2-4 alkylene, [53] the compound of the above-mentioned [21],
wherein R.sup.2g is (i) a C.sub.6-18 aryl group optionally
substituted by substituent(s) selected from (a) nitro, (b) amino,
(c) --CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (e)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, (f)
--NR.sup.8--CO--(CH.sub.2).sub.n--COOH (g)
--NR.sup.8--CO--(CH.sub.2)--CO.sub.2--C.sub.1-4 alkyl, and (h)
--NR.sup.8--CO--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--O--C.sub.1-4
alkyl, wherein m is an integer of 0 to 4, n is an integer of 1 to
4, R.sup.6 and R.sup.7 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.8 is a hydrogen
atom or a C.sub.1-4 alkyl group, or (ii) a C.sub.6-18
aryl-C.sub.1-4 alkyl group substituted by substituent(s) selected
from (a) carboxy, (b) C.sub.1-4 alkoxy-carbonyl, and (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group, [54] the compound of the above-mentioned [1], wherein
A is a C.sub.6-18 aryl group substituted by substituent(s) selected
from (i) a phenyloxy group optionally substituted by 1 to 5
substituents selected from (a) halogen, (b) optionally halogenated
C.sub.1-4 alkyl, (c) hydroxy-C.sub.1-4 alkyl, (d)
heterocycle-C.sub.1-4 alkyl (preferably, 5- to 8-membered
heterocycle-C.sub.1-4 alkyl, said 5- to 8-membered heterocycle has
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, such as imidazolyl,
triazolyl and the like), (e) optionally halogenated C.sub.1-4
alkyloxy, (f) C.sub.1-4 alkyl-carbonyl, (g) cyano, (h) carbamoyl
optionally substituted by C.sub.1-8 alkyl, and (i) C.sub.1-4
alkoxy-carbonyl, (ii) a phenyl-C.sub.1-3 alkyloxy group optionally
substituted by 1 to 5 substituents selected from (a) halogen, (b)
optionally halogenated C.sub.1-4 alkyl, (c) hydroxy-C.sub.1-4
alkyl, (d) heterocycle-C.sub.1-4 alkyl (preferably, 5- to
8-membered heterocycle-C.sub.1-4 alkyl, said 5- to 8-membered
heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom,
an oxygen atom and an optionally oxidized sulfur atom, such as
imidazolyl, triazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) C.sub.1-4 alkyl-carbonyl, (g) cyano, (h)
carbamoyl optionally substituted by C.sub.1-8 alkyl, and (i)
C.sub.1-4 alkoxy-carbonyl, (iii) a 5- to 8-membered heterocycleoxy
group containing 1 to 3 hetero atoms selected from a nitrogen atom,
an oxygen atom and a sulfur atom, which is optionally substituted
by 1 to 5 substituents selected from (a) halogen, (b) optionally
halogenated C.sub.1-4 alkyl, (c) hydroxy-C.sub.1-4 alkyl, (d)
heterocycle-C.sub.1-4 alkyl (preferably, 5- to 8-membered
heterocycle-C.sub.1-4 alkyl, said 5- to 8-membered heterocycle has
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, such as imidazolyl,
triazolyl and the like), (e) optionally halogenated C.sub.1-4
alkyloxy, (f) C.sub.1-4 alkyl-carbonyl, (g) cyano, (h) carbamoyl
optionally substituted by C.sub.1-8 alkyl, and (i) C.sub.1-4
alkoxy-carbonyl, and (iv) 5- to 8-membered heterocycle-C.sub.1-3
alkyloxy containing 1 to 3 hetero atoms selected from a nitrogen
atom, an oxygen atom and a sulfur atom, which is optionally
substituted by 1 to 5 substituents selected from (a) halogen, (b)
optionally halogenated C.sub.1-4 alkyl, (c) hydroxy-C.sub.1-4
alkyl, (d) heterocycle-C.sub.1-4 alkyl (preferably, 5- to
8-membered heterocycle-C.sub.1-4 alkyl, said 5- to 8-membered
heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom,
an oxygen atom and an optionally oxidized sulfur atom, such as
imidazolyl, triazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) C.sub.1-4 alkyl-carbonyl, (g) cyano, (h)
carbamoyl optionally substituted by C.sub.1-8 alkyl, and (i)
C.sub.1-4 alkoxy-carbonyl; wherein the C.sub.6-18 aryl group is
optionally further substituted by 1 to 4 substituents selected from
halogen, C.sub.1-4 alkyl, hydroxy-C.sub.1-4 alkyl and C.sub.1-4
alkyloxy;
R.sup.1 is
[0037] (i) a hydrogen atom, (ii) a cyano group, or (iii) a
C.sub.1-4 alkyl group or a C.sub.2-4 alkenyl group, each of which
is optionally substituted by
--NR.sup.8--CO--(CH.sub.2)--NR.sup.6R.sup.7 wherein n is an integer
of 1 to 4, R.sup.6 and R.sup.7 are the same or different and each
is a hydrogen atom or a C.sub.1-4 alkyl group, R.sup.8 is a
hydrogen atom or a C.sub.1-4 alkyl group, and when n is not less
than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--;
R.sup.2 is
[0038] a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group or a
C.sub.2-8 alkynyl group, each of which is optionally substituted by
substituent(s) selected from (a) hydroxy, (b) carboxy, (c) cyano,
(d) optionally halogenated C.sub.1-4 alkyloxy, (e)
--O--(CH.sub.2).sub.n--OH, (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (h) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (i)
--O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (j)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1--
4 alkyl, (m) --O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (n)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4
alkyl,
(q) --NR.sup.6R.sup.7,
[0039] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (v)
--NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, (x)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (z) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc)
--NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(dd) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C((.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl,
(ii) --S-- (CH.sub.2)--OH,
[0040] (jj) --SO--(CH.sub.2).sub.n--OH, (kk)
--SO.sub.2--(CH.sub.2).sub.n--OH, and (ll) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--O--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like)
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
(CH.sub.2).sub.n is optionally substituted by halogenated C.sub.1-4
alkyl or hydroxy, and when n is not less than 2, a subset
--CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH--; R.sup.3 is a hydrogen atom or a C.sub.1-6 alkyl
group; or, R.sup.1 and R.sup.2 are optionally bonded to form
##STR00023##
R.sup.2 and R.sup.3 are optionally bonded to form C.sub.2-4
alkylene optionally substituted by an imino group. Particularly
preferably, R.sup.2 is a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group or a C.sub.2-8 alkynyl group (particularly C.sub.1-8 alkyl
group), each of which is optionally substituted by substituent(s)
selected from (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally
halogenated C.sub.1-4 alkyloxy, (e) --O--(CH.sub.2).sub.n--OH
(wherein (CH.sub.2).sub.n is optionally substituted by hydroxy),
(f) --O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (h) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (i)
--O--(CH.sub.2)--SO.sub.2--C.sub.6-18 aryl,
(j) --O--(CH.sub.2)--SO.sub.2--(CH.sub.2)--OH,
[0041] (k) --O--(CH.sub.2).sub.n--NR.sup.8--CO--C.sub.1-4 alkyl,
(l)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1--
4 alkyl, (m) --O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (n) --CO--NR.sup.8--
(CH.sub.2).sub.n--OH, (o) --CO--NR.sup.8--
(CH.sub.2).sub.n--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4 alkyl,
(q) --NR.sup.6R.sup.7,
[0042] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2)--OH (wherein (CH.sub.2).sub.n is
optionally substituted by optionally halogenated C.sub.1-4 alkyl or
hydroxy), (v) --NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7 (when n is not
less than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2), is
optionally replaced by --CH.dbd.CH--), (x)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (z) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (wherein (CH.sub.2).sub.n
is optionally substituted by C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc)
--NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(dd) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl, (ii)
--S--(CH.sub.2).sub.n--OH, (jj) --SO--(CH.sub.2).sub.n--OH, (kk)
--SO.sub.2--(CH.sub.2).sub.n--OH, and (ll) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--O--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
[55] the compound of the above-mentioned [1], wherein A is a
C.sub.6-18 aryl group substituted by substituent(s) selected from
(i) a phenyloxy group substituted by 1 to 5 substituents selected
from (a) halogen, (b) optionally halogenated C.sub.1-4 alkyl, (c)
hydroxy-C.sub.1-4 alkyl, (d) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted
by C.sub.1-18 alkyl, and (h) C.sub.1-4 alkoxy-carbonyl, (ii) a
phenyl-C.sub.1-3 alkyloxy group substituted by 1 to 5 substituents
selected from (a) halogen, (b) optionally halogenated C.sub.1-4
alkyl, (c) hydroxy-C.sub.1-4 alkyl, (d) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted
by C.sub.1-8 alkyl, and (h) C.sub.1-4 alkoxy-carbonyl, (iii) a 5-
to 8-membered heterocycleoxy group containing 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom,
which is substituted by 1 to 5 substituents selected from (a)
halogen, (b) optionally halogenated C.sub.1-4 alkyl, (c)
hydroxy-C.sub.1-4 alkyl, (d) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted
by C.sub.1-8 alkyl, and (h) C.sub.1-4 alkoxy-carbonyl, and (iv) 5-
to 8-membered heterocycle-C.sub.1-3 alkyloxy containing 1 to 3
hetero atoms selected from a nitrogen atom, an oxygen atom and a
sulfur atom, which is substituted by 1 to 5 substituents selected
from (a) halogen, (b) optionally halogenated C.sub.1-4 alkyl, (c)
hydroxy-C.sub.1-4 alkyl, (d) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted
by C.sub.1-8 alkyl, and (h) C.sub.1-4 alkoxy-carbonyl; wherein the
C.sub.6-18 aryl group is optionally further substituted by 1 to 4
substituents selected from halogen and optionally halogenated
C.sub.1-4 alkyl; R.sup.1 is a hydrogen atom; R.sup.2 is a C.sub.1-8
alkyl group, a C.sub.2-8 alkenyl group or a C.sub.2-8 alkynyl
group, each of which is substituted by substituent(s) selected from
(a) hydroxy, (b) optionally halogenated C.sub.1-4 alkyloxy, (c)
--O--(CH.sub.2).sub.n--OH, (d)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (e)
--O--(CH.sub.2)--O--C.sub.1-4 alkyl, (f)
--O--(CH.sub.2)--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (g) --O--(CH.sub.2)--SO.sub.2--C.sub.6-18 aryl, (h)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (i)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (j) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (k)
--CO--NR.sup.8--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl),
(l) --NR.sup.6R.sup.7,
[0043] (m) --NR.sup.8--(CH.sub.2).sub.n--OH, (n)
--NR.sup.8--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl,
(o)--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (p)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (q)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (r) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (s)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(t) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (u)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(v) --NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (w) --S--(CH.sub.2).sub.n--OH, (x)
--SO--(CH.sub.2).sub.n--OH, (y) --SO.sub.2--(CH.sub.2).sub.n--OH,
and (z) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2--SO.sub.2--C.sub.1-4 alkyl, --SO.sub.2--NH--C.sub.1-4
alkyl, --SO.sub.2NH.sub.2 and the like), wherein n is an integer of
1 to 4, R.sup.6 and R.sup.7 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, R.sup.8 is a hydrogen
atom or a C.sub.1-4 alkyl group, and (CH.sub.2).sub.n is optionally
substituted by C.sub.1-4 alkyl or hydroxy); R.sup.3 is a hydrogen
atom or a C.sub.1-6 alkyl group; or, R.sup.1 and R.sup.2 are
optionally bonded to form
##STR00024##
R.sup.2 and R.sup.3 are optionally bonded to form C.sub.2-4
alkylene, particularly preferably, R.sup.2 is a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group or a C.sub.2-8 alkynyl group
(particularly, a C.sub.1-8 alkyl group), each of which is
substituted by substituent(s) selected from (a) hydroxy, (b)
optionally halogenated C.sub.1-4 alkyloxy, (c)
--O--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is optionally
substituted by hydroxy), (d)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (e)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (f)
--O--(CH.sub.2).sub.n--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (g) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (h)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (i)
--O--(CH.sub.2)--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (j) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (k)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl),
(l) --NR.sup.6R.sup.7,
[0044] (m) --NR.sup.8--(CH.sub.2).sub.n--OH, (n)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by C.sub.1-4 alkyl), (p)
--NR.sup.8--CO--(CH.sub.2)--O--C.sub.1-4 alkyl, (q)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (r) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (wherein (CH.sub.2).sub.n
is optionally substituted by C.sub.1-4 alkyl), (s)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(t) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (u) --NR.sup.8--CO--NH--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (v) --NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (w) --S-- (CH.sub.2).sub.n--OH, (x)
--SO--(CH.sub.2).sub.n--OH,
(y) --SO.sub.2--(CH.sub.2)--OH, and
[0045] (z) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
[56] the compound of the above-mentioned [55], wherein R.sup.2 is
(i) a C.sub.5-8 alkyl group substituted by hydroxy, (ii) a
C.sub.1-8 alkyl group substituted by substituent(s) selected from
(a) halogenated C.sub.1-4 alkyloxy,
(b) --O--(CH.sub.2)--OH,
[0046] (c) --O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (d)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (e) --O--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (f) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18
aryl, (g) --O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (h)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (i)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (j)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (k)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (l)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (m)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (n) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(p) --NR.sup.8--CO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl,
(q) --NR.sup.8--CO--NH--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl, (r)
--NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl,
(s) --S--(CH.sub.2)--OH,
(t) --SO--(CH.sub.2)--OH,
[0047] (u) --SO.sub.2--(CH.sub.2).sub.n--OH, and (v) --NR.sup.8CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--NH--C.sub.1-4 alkyl, --CONH.sub.2,
--SO.sub.2--C.sub.1-4 alkyl, --SO.sub.2--NH--C.sub.1-4 alkyl,
--SO.sub.2NH.sub.2 and the like), wherein n is an integer of 1 to
4, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, and
(CH.sub.2).sub.n is optionally substituted by C.sub.1-4 alkyl,
(iii) a C.sub.2-8 alkenyl group optionally substituted by hydroxy,
or (iv) a C.sub.2-8 alkynyl group optionally substituted by
hydroxy, particularly preferably, R.sup.2 is (i) a C.sub.5-8 alkyl
group substituted by hydroxy, (ii) a C.sub.1-8 alkyl group
substituted by substituent(s) selected from (a) halogenated
C.sub.1-4 alkyloxy, (b) --O--(CH.sub.2).sub.n--OH (wherein
(CH.sub.2).sub.n is optionally substituted by hydroxy), (c)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (d) --O--(CH.sub.2)--O--
(optionally halogenated C.sub.1-4 alkyl), (e)
--O--(CH.sub.2).sub.n--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (f) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.618 aryl, (g)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (h) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (i)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (j)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (k)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by C.sub.1-4 alkyl), (l)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (m)
--NR.sup.8CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (n) --NR.sup.8--CO(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (wherein (CH.sub.2), is
optionally substituted by C.sub.1-4 alkyl), (o)
--NR.sup.8--CO(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl, (p)
--NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(q) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (r) --NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (s) --S--(CH.sub.2).sub.n--OH, (t)
--SO--(CH.sub.2).sub.n--OH, (u) --SO.sub.2--(CH.sub.2).sub.n--OH,
and (v) --NR.sup.8CO-- (optionally substituted heterocyclic group)
(preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom
or a C.sub.1-4 alkyl group, (iii) a C.sub.2-8 alkenyl group
optionally substituted by hydroxy, or (iv) a C.sub.2-8 alkynyl
group optionally substituted by hydroxy, [57] the compound of the
above-mentioned [1], which is selected from the following (A) to
(H): (A) a compound (I) wherein
W is CR.sup.1;
[0048] A is a phenyloxy-C.sub.6-18 aryl group wherein the phenyloxy
moiety is optionally substituted by 1 to 5 substituents selected
from (i) halogen, (ii) optionally halogenated C.sub.1-4 alkyl,
(iii) hydroxy-C.sub.1-4 alkyl, (iv) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl, triazolyl and the like), (v) optionally
halogenated C.sub.1-4 alkyloxy, (vi) C.sub.1-4 alkyl-carbonyl,
(vii) cyano, (viii) carbamoyl optionally substituted by C.sub.1-8
alkyl, and (ix) C.sub.1-4 alkoxy-carbonyl, and the C.sub.6-18 aryl
moiety is optionally further substituted by 1 to 4 substituents
selected from halogen, C.sub.1-4 alkyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyloxy, carboxy and C.sub.1-4 alkoxy-carbonyl; X.sup.1
is --NR.sup.3'-- wherein R.sup.3' is a hydrogen atom or a C.sub.1-6
alkyl group;
R.sup.1 is
[0049] (i) a hydrogen atom, (ii) a cyano group, or (iii) a
C.sub.1-4 alkyl group or a C.sub.2-4 alkenyl group, each of which
is optionally substituted by
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7 wherein n is an
integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, R.sup.8 is
a hydrogen atom or a C.sub.1-4 alkyl group, and when n is not less
than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--; and R.sup.2 is (i) a hydrogen
atom or (ii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group or
a C.sub.2-8 alkynyl group, each of which is optionally substituted
by substituent(s) selected from (a) hydroxy, (b) carboxy, (c)
cyano, (d) optionally halogenated C.sub.1-4 alkyloxy, (e)
--O--(CH.sub.2).sub.n--OH, (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (h) --O--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (i) --O--(CH.sub.2)--SO.sub.2--C.sub.6-18 aryl,
(j) --O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2)--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (m) --O--(CH.sub.2)--NR.sup.8--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (n) --CO--NR.sup.8
(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4
alkyl,
(q) --NR.sup.6R.sup.7,
[0050] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (v)
--NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, (x)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl) (z) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc)
--NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(dd) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(ii) --S-- (CH.sub.2).sub.n--OH, (jj) --SO--(CH.sub.2).sub.n--OH,
(kk) --SO.sub.2--(CH.sub.2).sub.n--OH, and (ll) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--O--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
(CH.sub.2).sub.n is optionally substituted by optionally
halogenated C.sub.1-4 alkyl or hydroxy, and when n is not less than
2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2), is optionally
replaced by --CH.dbd.CH--; or R.sup.1 and R.sup.2 are optionally
bonded to form
##STR00025##
R.sup.2 and R.sup.3' are optionally bonded to form C.sub.2-4
alkylene optionally substituted by an imino group, particularly
preferably, R.sup.2a is a C.sub.1-- alkyl group, a C.sub.2-8
alkenyl group or a C.sub.2-8 alkynyl group (particularly, C.sub.1-8
alkyl group), each of which is optionally substituted by
substituent(s) selected from (a) hydroxy, (b) carboxy, (c) cyano,
(d) optionally halogenated C.sub.1-4 alkyloxy, (e)
--O--(CH.sub.2).sub.n--OH (wherein (CH.sub.2), is optionally
substituted by hydroxy), (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (h) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (i)
--O--(CH.sub.2)--SO.sub.2--C.sub.6-18 aryl, (j)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2)--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1--
4 alkyl, (m) --O--(CH.sub.2)--NR.sup.8--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (n)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4
alkyl,
(q) --NR.sup.6R.sup.7,
(r) --NR.sup.8--(CH.sub.2)--OH,
[0051] (s) --NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(t) --NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by optionally halogenated C.sub.1-4 alkyl or
hydroxy), (v) --NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2)--NR.sup.6R.sup.7 (when n is not less
than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--), (x)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2)--SO-- (optionally halogenated C.sub.1-4
alkyl), (z) --NR.sup.8--CO--(CH.sub.2)--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl) (wherein (CH.sub.2).sub.n is
optionally substituted by C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc) --NR.sup.8--CO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (dd) --NR.sup.8--CO--NH--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2)--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl,
(ii) --S--(CH.sub.2)--OH,
[0052] (jj) --SO--(CH.sub.2).sub.n--OH, (kk)
--SO.sub.2--(CH.sub.2).sub.n--OH, and (ll) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--O--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
(B) a compound (I) wherein
W is CR.sup.1;
[0053] A is phenyl-C.sub.1-3 alkyloxy-C.sub.6-18 aryl group wherein
the phenyl moiety is optionally substituted by 1 to 5 substituents
selected from halogen, optionally halogenated C.sub.1-4 alkyl and
cyano, and the C.sub.6-18 aryl moiety is optionally further
substituted by 1 to 4 substituents selected from halogen, C.sub.1-4
alkyl optionally having hydroxy and C.sub.1-4 alkyloxy; X.sup.1 is
--NR.sup.3'-- wherein R.sup.3' is a hydrogen atom or a C.sub.1-6
alkyl group; R.sup.1 is (i) a hydrogen atom, (ii) a C.sub.1-4 alkyl
group or a C.sub.2-4 alkenyl group, each of which is optionally
substituted by substituent(s) selected from (a) hydroxy, (b) amino,
(c) --NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, and (d)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl wherein n is
an integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, R.sup.8 is
a hydrogen atom or a C.sub.1-4 alkyl group, and when n is not less
than 2, a subset --CH.sub.2--CH.sub.2 of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--, or (iii) a C.sub.6-18 aryl
group optionally substituted by substituent(s) selected from (a)
amino, (b) carboxy, and (c)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group, or (iv) a 5- to 8-membered heterocyclic group having 1
to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and
a sulfur atom; and R.sup.2 is (i) a hydrogen atom, (ii) a C.sub.1-8
alkyl group optionally substituted by substituent(s) selected from
(a) halogen, (b) hydroxy, (c) C.sub.1-4 alkyloxy,
(d) --O--(CH.sub.2)--OH,
[0054] (e) --O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (f)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH,
(g) --NR.sup.6R.sup.7, and
[0055] (h) --NR.sup.8--(CH.sub.2).sub.n--OH wherein n is an integer
of 1 to 4, R.sup.6 and R.sup.7 are the same or different and each
is a hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.8 is a
hydrogen atom or a C.sub.1-4 alkyl group, (iii) a C.sub.6-18
aryl-C.sub.1-4 alkyl group optionally substituted by substituent(s)
selected from (a) C.sub.1-4 alkyl optionally having hydroxy, (b)
carboxy, (c) C.sub.1-4 alkoxy-carbonyl, (d) 5- to 8-membered
heterocycle-carbonyl having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and a sulfur atom, which optionally
has substituent(s) selected from hydroxy and C.sub.1-4 alkyl, and
(e) C.sub.1-4 alkyl-carbamoyl optionally having substituent(s)
selected from hydroxy and carbamoyl, (iv) a C.sub.6-18
aryl-carbonyl group optionally substituted by C.sub.14 alkoxy, (v)
a C.sub.6-18 aryl-sulfonyl group optionally substituted by
C.sub.1-4 alkoxy, or (vi) a 5- to 8-membered heterocycle-C.sub.1-4
alkyl group having 1 to 3 hetero atoms selected from a nitrogen
atom, an oxygen atom and a sulfur atom, which is optionally
substituted by substituent(s) selected from (a) carboxy, and (b)
C.sub.1-4 alkoxy-carbonyl; or R.sup.2 and R.sup.3' are optionally
bonded to form C.sub.2-4 alkylene, (C) a compound (I) wherein W is
CR.sup.1; A is a 5- to 8-membered heterocycleoxy-C.sub.6-18 aryl
group containing 1 to 3 hetero atoms selected from a nitrogen atom,
an oxygen atom and a sulfur atom, wherein the heterocycleoxy moiety
is optionally substituted by 1 to 5 substituents selected from (i)
halogen, (ii) C.sub.1-4 alkyl, (iii) C.sub.1-4 alkyl-carbonyl, (iv)
optionally halogenated C.sub.1-4 alkoxy-carbonyl, (v) C.sub.3-8
cycloalkyl-carbonyl, and (vi) a carbamoyl group optionally
substituted by substituent(s) selected from (a) optionally
halogenated C.sub.1-18 alkyl, (b) C.sub.3-8 cycloalkyl, and (c)
C.sub.6-18 aryl optionally substituted by substituent(s) selected
from halogen, C.sub.1-4 alkyl and C.sub.1-4 alkyloxy, and the
C.sub.6-18 aryl moiety is optionally further substituted by 1 to 4
substituents selected from halogen and optionally halogenated
C.sub.1-4 alkyl; X.sup.1 is --NR.sup.3'-- wherein R.sup.3' is a
hydrogen atom or a C.sub.1-6 alkyl group; R.sup.1 is (i) a hydrogen
atom, (ii) a C.sub.1-4 alkyl group or a C.sub.2-4 alkenyl group,
each of which is optionally substituted by substituent(s) selected
from (a) hydroxy, (b) amino, (c)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, and (d)
--NR--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is an
integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, R.sup.8 is
a hydrogen atom or a C.sub.1-4 alkyl group, and when n is not less
than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2), is optionally
replaced by --CH.dbd.CH--, (iii) a C.sub.6-18 aryl group optionally
substituted by substituent(s) selected from (a) C.sub.1-4 alkyl
optionally substituted by substituent(s) selected from hydroxy,
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl and
--NR.sup.8--CO--(CH.sub.2)--O--C.sub.1-4 alkyl, (b) amino, (c)
C.sub.1-4 alkyloxy, (d) carboxy, and (e)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group, or (iv) a 5- to 8-membered heterocyclic group having 1
to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and
a sulfur atom; and R.sup.2 is (i) a hydrogen atom, (ii) a C.sub.1-4
alkyl group optionally substituted by substituent(s) selected from
(a) halogen, (b) hydroxy, (c) C.sub.1-4 alkyloxy, (d) carboxy, (e)
C.sub.1-4 alkoxy-carbonyl, (f) --O--(CH.sub.2).sub.n--OH, (g)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl,
(h) --CO--NR.sup.8--(CH.sub.2)--OH, and
[0056] (i) --NR.sup.8--CO--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl
wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom
or a C.sub.1-4 alkyl group, or (iii) a C.sub.6-18 aryl-C.sub.1-4
alkyl group optionally substituted by C.sub.1-4 alkyl optionally
having hydroxy; or R.sup.2 and R.sup.3' are optionally bonded to
form C.sub.2-4 alkylene, (D) a compound (I) wherein
W is CR.sup.1;
[0057] A is 5- to 8-membered heterocycle-C.sub.1-3
alkyloxy-C.sub.6-18 aryl group containing 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom
wherein the C.sub.6-18 aryl moiety is optionally further
substituted by halogen; X.sup.1 is --NR.sup.3' wherein R.sup.3' is
a hydrogen atom or a C.sub.1-6 alkyl group; R.sup.1 is (i) a
hydrogen atom or (ii) a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom; and R.sup.2 is (i) a hydrogen atom, (ii)
C.sub.1-4 alkyl optionally substituted by substituent(s) selected
from (a) C.sub.1-4 alkyloxy, (b) --O--(CH.sub.2).sub.n--OH, and (c)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl wherein
n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, or (iii) a 5- to 8-membered
heterocycle-C.sub.1-4 alkyl group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom,
which is optionally substituted by substituent(s) selected from (a)
carboxy, and (b) C.sub.1-4 alkoxy-carbonyl, (E) a compound (I)
wherein
W is N;
[0058] A is a phenyloxy-C.sub.6-18 aryl group wherein the phenyloxy
moiety is optionally substituted by 1 to 5 substituents selected
from optionally halogenated C.sub.1-4 alkyl and cyano, and the
C.sub.6-18 aryl moiety is optionally further substituted by 1 to 4
substituents selected from halogen and C.sub.1-4 alkyl; X.sup.1 is
--NR.sup.3'-- wherein R.sup.3 is a hydrogen atom or a C.sub.1-6
alkyl group; and R.sup.2 is (i) a hydrogen atom or (ii) a C.sub.1-4
alkyl group optionally substituted by --O--(CH.sub.2).sub.n--OH
wherein n is an integer of 1 to 4, (F) a compound (I) wherein
W is N;
[0059] A is a phenyl-C.sub.1-3 alkyloxy-C.sub.6-18 aryl group
wherein the phenyl moiety is optionally substituted by 1 to 5
substituents selected from halogen and cyano, and the C.sub.6-18
aryl moiety is optionally further substituted by 1 to 4
substituents selected from halogen and C.sub.1-4 alkyl; X.sup.1 is
--NR.sup.3-- wherein R.sup.3 is a hydrogen atom or a C.sub.1-6
alkyl group; and R.sup.2 is (i) a hydrogen atom, (ii) a C.sub.1-4
alkyl group optionally substituted by 1 to 5 substituents selected
from the group consisting of (a) hydroxy, (b)
--O--(CH.sub.2).sub.n--OH, (c)
--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--(CH.sub.2).sub.n-heterocyclic group (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom), and (e)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl wherein n
is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, (iii) a C.sub.6-18 aryl group optionally
substituted by C.sub.1-4 alkyl optionally substituted by
substituent(s) selected from hydroxy, --NR.sup.8--(CH.sub.2)--OH,
--NR.sup.8--(CH.sub.2).sub.n-heterocyclic group (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom) and
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, or (iv) a
C.sub.6-18 aryl-C.sub.1-14 alkyl group optionally substituted by 1
to 5 substituents selected from the group consisting of (a)
carboxy, (b) C.sub.1-4 alkoxy-carbonyl, and (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-14 alkyl wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group; or R.sup.2 and R.sup.3' are optionally bonded to form
C.sub.2-4 alkylene, (G) a compound (I) wherein
W is N;
[0060] A is a 5- to 8-membered heterocycleoxy-C.sub.6-18 aryl group
containing 1 to 3 hetero atoms selected from a nitrogen atom, an
oxygen atom and a sulfur atom wherein the heterocycleoxy moiety is
optionally substituted by C.sub.1-4 alkyl, and the C.sub.6-18 aryl
moiety is optionally further substituted by C.sub.1-4 alkyl;
X.sup.1 is --NR.sup.3'-- wherein R.sup.3' is a hydrogen atom or a
C.sub.1-6 alkyl group; and R.sup.2 is (i) a hydrogen atom, (ii) a
C.sub.1-4 alkyl group optionally substituted by hydroxy, (iii) a
C.sub.6-18 aryl group optionally substituted by substituent(s)
selected from (a) nitro, (b) amino, (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (e)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, (f)
--NR.sup.8--CO--(CH.sub.2).sub.n--COOH (g)
--NR.sup.8--CO--(CH.sub.2).sub.n--CO.sub.2--C.sub.1-4 alkyl, and
(h) --NR.sup.8--CO--(CH.sub.2)-mO (CH.sub.2).sub.n--O--C.sub.1-4
alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4,
R.sup.6 and R.sup.7 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.8 is a hydrogen
atom or a C.sub.1-4 alkyl group, or (iv) a C.sub.6-18
aryl-C.sub.1-4 alkyl group optionally substituted by substituent(s)
selected from (a) carboxy, (b) C.sub.1-4 alkoxy-carbonyl, (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group); or R.sup.2 and R.sup.3' are optionally bonded to form
C.sub.2-4 alkylene, (H) a compound (I) wherein
W is CH;
[0061] A is a C.sub.6-18 aryl group optionally substituted by
substituent(s) selected from (a) carboxy, (b) C.sub.1-4
alkoxy-carbonyl, (c) a 5- to 8-membered heterocycle-carbonyl group
containing 1 to 3 hetero atoms selected from a nitrogen atom, an
oxygen atom and a sulfur atom (preferably, a 5- to 8-membered
cyclic amino-carbonyl group optionally having 1 or 2 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom),
which is optionally substituted by C.sub.6-18 aryl-C.sub.1-4 alkyl;
(d) a carbamoyl group optionally substituted by C.sub.6-18
aryl-C.sub.1-4 alkyl, and (e) a ureido group optionally substituted
by C.sub.6-18 aryl-C.sub.1-4 alkyl; X.sup.1 is --NR.sup.3'--
wherein R.sup.3' is a hydrogen atom or a C.sub.1-6 alkyl group; and
R.sup.2 is a hydrogen atom, [58] the compound of the
above-mentioned [1], wherein A is (i) a C.sub.6-18 aryl group or
(ii) a 5- to 8-membered heteroaryl group containing, as an atom
(ring atom) constituting a ring system, 1 to 4 hetero atoms
selected from an oxygen atom, an optionally oxidized sulfur atom
and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and
a nitrogen atom), each of which is optionally substituted by 1 to 5
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl, hydroxy, optionally halogenated C.sub.1-4
alkyloxy, C.sub.1-4 alkyloxymethyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino, C.sub.1-4
alkylsulfonylamino and a group of the formula --Y.sup.2--B, wherein
Y.sup.2 is a single bond, --O--, --O--(C.sub.1-3 alkylene)-, --NH--
or --S--,
B is
[0062] (A) (i) a C.sub.6-18 aryl group, (ii) a 5- to 8-membered
heteroaryl group containing, as an atom (ring atom) constituting a
ring system, 1 to 4 hetero atoms selected from an oxygen atom, an
optionally oxidized sulfur atom and a nitrogen atom (preferably, an
oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or
unsaturated aliphatic heterocyclic group, (iii) a C.sub.3-8
cycloalkyl group, (iv) a carbamoyl group, (v) a C.sub.6-18
aryl-carbonyl group or (vi) a C.sub.6-18 aryl-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted by 1
to 5 substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl, hydroxy, optionally halogenated C.sub.1-4
alkyloxy, C.sub.1-4 alkyloxymethyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino or (B) a ureido group optionally having 1 or 2
C.sub.1-8 alkyl group(s) optionally substituted by substituent(s)
selected from substituent group T, wherein the ureido group has two
substituents, and they optionally form, together with the adjacent
nitrogen atom, a 3- to 8-membered saturated or unsaturated
aliphatic heterocyclic group optionally substituted by
substituent(s) selected from substituent group T, wherein the
substituent group T is a group consisting of (a) halogen, (b) oxo,
(c) optionally halogenated C.sub.1-4 alkyl, (d)
--(CH.sub.2).sub.m-Q, (e) --(CH.sub.2).sub.m-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (f)
--(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2 (CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7, --OCONH.sub.2 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH-- or --C.ident.C--, R.sup.6 and R.sup.7 are the same or
different and each is a hydrogen atom or a C.sub.1-4 alkyl group,
or R.sup.6 and R.sup.7 form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl, hydroxy,
optionally halogenated C.sub.1-4 alkyloxy, C.sub.1-4
alkyloxymethyl, hydroxy C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, R.sup.8 is a
hydrogen atom or C.sub.1-4 alkyl, and R.sup.9 is C.sub.1-4 alkyl,
R.sup.3 is (i) a hydrogen atom, or (ii) a C.sub.1-8 alkyl group, a
C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group or a C.sub.3-8
cycloalkyl group, each of which is optionally substituted by 1 to 3
substituents selected from halogen, hydroxy, C.sub.1-4 alkyloxy,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino, or R.sup.3 is optionally bonded to a carbon
atom or a hetero atom on the aryl group or the heteroaryl group
represented by A to form a saturated or unsaturated 4- to
8-membered nitrogen-containing heterocycle, which is optionally
substituted by 1 to 3 substituents selected from halogen, hydroxy,
C.sub.1-4 alkyloxy, C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4
alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino,
C.sub.1-4 alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and
C.sub.1-4 alkylsulfonylamino, Y.sup.1 is (i) a single bond or (ii)
C.sub.1-4 alkylene or --O--(C.sub.1-4 alkylene)-, each of which is
optionally substituted by 1 to 3 substituents selected from
halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, R.sup.1 is
(i) a hydrogen atom or (ii) a group represented by the formula
--X.sup.2--R.sup.4, wherein X.sup.2 is a single bond, --NH-- or
--O--, and R.sup.4 is (i) a hydrogen atom, (ii) a cyano group,
(iii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a
C.sub.2-8 alkynyl group, a C.sub.1-8 alkyl-carbonyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a heterocyclic
group (e.g., a 5- to 8-membered heteroaryl group containing, as an
atom (ring atom) constituting a ring system, 1 to 4 hetero atoms
selected from an oxygen atom, an optionally oxidized sulfur atom
and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and
a nitrogen atom) or a saturated or unsaturated aliphatic
heterocyclic group), a heterocycle-C.sub.1-4 alkyl group, a
heterocycle-carbonyl group or a heterocycle-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted by 1
to 5 substituents selected from substituent group T, or (iv) a
carbamoyl group optionally having 1 or 2 C.sub.1-8 alkyl group(s)
optionally substituted by substituent(s) selected from substituent
group T, wherein the carbamoyl group has two substituents, and they
optionally form, together with the adjacent nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group
optionally substituted by substituent(s) selected from substituent
group T, R.sup.2 is (i) a hydrogen atom, (ii) a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a
C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
substituent group T, or (iii) a carbamoyl group optionally having 1
or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or an unsaturated aliphatic heterocyclic group, which is
optionally substituted by substituent(s) selected from substituent
group T, or R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3 are
optionally bonded to form a saturated or unsaturated 4- to
8-membered heterocycle optionally substituted by 1 to 5
substituents selected from substituent group T, [59] the compound
of the above-mentioned [15], wherein R.sup.1a is (i) a hydrogen
atom or (ii) a group represented by the formula --X.sup.2--R.sup.4,
wherein X.sup.2 is a single bond, --NH-- or --O--, and R.sup.4 is
(i) a hydrogen atom, (ii) a cyano group, (iii) a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a
C.sub.1-8 alkyl-carbonyl group, a C.sub.3-8 cycloalkyl group, a
C.sub.6-18 aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a
C.sub.6-18 aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4
alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to
8-membered heteroaryl group containing, as an atom (ring atom)
constituting a ring system, 1 to 4 hetero atoms selected from an
oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom
(preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or
a saturated or unsaturated aliphatic heterocyclic group), a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
substituent group T, or (iv) a carbamoyl group optionally having 1
or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or an unsaturated aliphatic heterocyclic group, which is
optionally substituted by substituent(s) selected from substituent
group T, R.sup.2a is (i) a hydrogen atom, (ii) a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a
C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
substituent group T, or (iii) a carbamoyl group optionally having 1
or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or an unsaturated aliphatic heterocyclic group, which is
optionally substituted by substituent(s) selected from substituent
group T, or R.sup.1a and R.sup.2a, or R.sup.2a and R.sup.3a are
optionally bonded to form a saturated or unsaturated 4- to
8-membered heterocycle optionally substituted by 1 to 5
substituents selected from substituent group T, R.sup.3a is (i) a
hydrogen atom, or (ii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group or a C.sub.3-8 cycloalkyl group,
each of which is optionally substituted by 1 to 3 substituents
selected from halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4
alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl, cyano,
carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4 alkyl-carbonylamino,
C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, or
R.sup.3a is optionally bonded to a carbon atom of the adjacent
phenyl group to form a saturated or unsaturated 4- to 8-membered
nitrogen-containing heterocycle, which is optionally substituted by
1 to 3 substituents selected from halogen, hydroxy, C.sub.1-4
alkyloxy, C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4
alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino,
C.sub.1-4 alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and
C.sub.1-4 alkylsulfonylamino, B.sup.a is a benzene ring optionally
substituted by 1 to 5 substituents selected from halogen,
optionally halogenated C.sub.1-4 alkyl, hydroxy, optionally
halogenated C.sub.1-4 alkyloxy, C.sub.1-4 alkyloxymethyl,
hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, carboxy,
C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro,
amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, and C.sup.a
is a C.sub.6-18 aryl group optionally substituted by 1 to 5
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl, hydroxy, optionally halogenated C.sub.1-4
alkyloxy, C.sub.1-4 alkyloxymethyl, hydroxy-C.sub.2-4 alkyl,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino, [60] the compound of the above-mentioned [16],
wherein R.sup.1b is (i) a hydrogen atom or (ii) a group represented
by the formula --X.sup.2--R.sup.4, wherein X.sup.2 is a single
bond, --NH-- or --O--, and R.sup.4 is (i) a hydrogen atom, (ii) a
cyano group, (iii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a C.sub.1-8 alkyl-carbonyl group,
a C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a heterocyclic
group (e.g., a 5- to 8-membered heteroaryl group containing, as an
atom (ring atom) constituting a ring system, 1-4 hetero atoms
selected from an oxygen atom, an optionally oxidized sulfur atom
and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and
a nitrogen atom) or a saturated or unsaturated aliphatic
heterocyclic group), a heterocycle-C.sub.1-4 alkyl group, a
heterocycle-carbonyl group or a heterocycle-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted by 1
to 5 substituents selected from substituent group T, or (iv) a
carbamoyl group optionally having 1 or 2 C.sub.1-8 alkyl group(s)
optionally substituted by substituent(s) selected from substituent
group T, wherein the carbamoyl group has two substituents, and they
optionally form, together with the adjacent nitrogen atom, a 3- to
8-membered saturated or an unsaturated aliphatic heterocyclic
group, which is optionally substituted by substituent(s) selected
from substituent group T, R.sup.2b is (i) a hydrogen atom, (ii) a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8
alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18
aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18
aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, a C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C
.sub.1-4 alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
substituent group T, or (iii) a carbamoyl group optionally having 1
or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or an unsaturated aliphatic heterocyclic group, which is
optionally substituted by substituent(s) selected from substituent
group T, or R.sup.1b and R.sup.2b, or R.sup.2b and R.sup.3b are
optionally bonded to form a saturated or unsaturated 4- to
8-membered heterocycle optionally substituted by 1 to 5
substituents selected from substituent group T, R.sup.3b is (i) a
hydrogen atom, or (ii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group or a C.sub.3-8 cycloalkyl group,
each of which is optionally substituted by 1 to 3 substituents
selected from halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4
alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl, cyano,
carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4 alkyl-carbonylamino,
C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, or
R.sup.3b is optionally bonded to a carbon atom of the adjacent
phenyl group to form a saturated or unsaturated 4- to 8-membered
nitrogen-containing heterocycle, which is optionally substituted by
1 to 3 substituents selected from halogen, hydroxy, C.sub.1-4
alkyloxy, C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4
alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino,
C.sub.1-4 alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and
C.sub.1-4 alkylsulfonylamino, B.sup.b is a benzene ring optionally
substituted by 1 to 5 substituents selected from halogen,
optionally halogenated C.sub.1-4 alkyl, hydroxy, optionally
halogenated C.sub.1-4 alkyloxy, C.sub.1-4 alkyloxymethyl,
hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, carboxy,
C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro,
amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, C.sup.b is a
C.sub.6-18 aryl group optionally substituted by 1 to 5 substituents
selected from halogen, optionally halogenated C.sub.1-4 alkyl,
hydroxy, optionally halogenated C.sub.1-4 alkyloxy, C.sub.1-4
alkyloxymethyl, hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, and Z.sup.b
is a C.sub.1-3 alkylene group optionally substituted by 1 to 3
substituents selected from halogen, hydroxy, C.sub.1-4 alkyloxy,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino, [61] the compound of the above-mentioned [17],
wherein R.sup.1c is (i) a hydrogen atom or (ii) a group represented
by the formula --X.sup.2--R.sup.4, wherein X.sup.2 is a single
bond, --NH-- or --O--, and R.sup.4 is (i) a hydrogen atom, (ii) a
cyano group, (iii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a C.sub.1-8 alkyl-carbonyl group,
a C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a heterocyclic
group (e.g., a 5- to 8-membered heteroaryl group containing, as an
atom (ring atom) constituting a ring system, 1 to 4 hetero atoms
selected from an oxygen atom, an optionally oxidized sulfur atom
and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and
a nitrogen atom) or a saturated or unsaturated aliphatic
heterocyclic group), a heterocycle-C.sub.1-4 alkyl group, a
heterocycle-carbonyl group or a heterocycle-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted by 1
to 5 substituents selected from substituent group T, or (iv) a
carbamoyl group optionally having 1 or 2 C.sub.1-8 alkyl group(s)
optionally substituted by substituent(s) selected from substituent
group T, wherein the carbamoyl group has two substituents, and they
optionally form, together with the adjacent nitrogen atom, a 3- to
8-membered saturated or an unsaturated aliphatic heterocyclic
group, which is optionally substituted by substituent(s) selected
from substituent group T, R.sup.2c is (i) a hydrogen atom, (ii) a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8
alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18
aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18
aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, a C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
substituent group T, or (iii) a carbamoyl group optionally having 1
or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or an unsaturated aliphatic heterocyclic group, which is
optionally substituted by substituent(s) selected from substituent
group T, or R.sup.1c and R.sup.2c, or R.sup.2c and R.sup.3c are
optionally bonded to form a saturated or unsaturated 4- to
8-membered heterocycle optionally substituted by 1 to 5
substituents selected from substituent group T, R.sup.3c is (i) a
hydrogen atom, or (ii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group or a C.sub.3-8 cycloalkyl group,
each of which is optionally substituted by 1 to 3 substituents
selected from halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4
alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl, cyano,
carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4 alkyl-carbonylamino,
C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, or
R.sup.3c is optionally bonded to a carbon atom of the adjacent
phenyl group to form a saturated or unsaturated 4- to 8-membered
nitrogen-containing heterocycle, which is optionally substituted by
1 to 3 substituents selected from halogen, hydroxy, C.sub.1-4
alkyloxy, C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4
alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino,
C.sub.1-4 alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and
C.sub.1-4 alkylsulfonylamino, B.sup.c is a benzene ring optionally
substituted by 1 to 5 substituents selected from halogen,
optionally halogenated C.sub.1-4 alkyl, hydroxy, optionally
halogenated-C.sub.1-4 alkyloxy, C.sub.1-4 alkyloxymethyl,
hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, carboxy,
C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro,
amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, and C.sup.c
is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and an optionally
oxidized sulfur atom, which is optionally substituted by 1 to 5
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl, hydroxy, optionally halogenated C.sub.1-4
alkyloxy, C.sub.1-4 alkyloxymethyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino, [62] the compound of the above-mentioned [18],
wherein R.sup.1d is (i) a hydrogen atom or (ii) a group represented
by the formula --X.sup.2--R.sup.4, wherein X.sup.2 is a single
bond, --NH-- or --O--, and R.sup.4 is (i) a hydrogen atom, (ii) a
cyano group, (iii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a C.sub.1-8 alkyl-carbonyl group,
a C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a heterocyclic
group (e.g., a 5- to 8-membered heteroaryl group containing, as an
atom (ring atom) constituting a ring system, 1 to 4 hetero atoms
selected from an oxygen atom, an optionally oxidized sulfur atom
and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and
a nitrogen atom) or a saturated or unsaturated aliphatic
heterocyclic group), a heterocycle-C.sub.1-4 alkyl group, a
heterocycle-carbonyl group or a heterocycle-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted by 1
to 5 substituents selected from substituent group T, or (iv) a
carbamoyl group optionally having 1 or 2 C.sub.1-8 alkyl group(s)
optionally substituted by substituent(s) selected from substituent
group T, wherein the carbamoyl group has two substituents, and they
optionally form, together with the adjacent nitrogen atom, a 3- to
8-membered saturated or an unsaturated aliphatic heterocyclic
group, which is optionally substituted by substituent(s) selected
from substituent group T, R.sup.2d is (i) a hydrogen atom, (ii) a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8
alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18
aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18
aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, a C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
substituent group T, or (iii) a carbamoyl group optionally having 1
or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or an unsaturated aliphatic heterocyclic group, which is
optionally substituted by substituent(s) selected from substituent
group T, or R.sup.1d and R.sup.2d, or R.sup.2d and R.sup.3d are
optionally bonded to form a saturated or unsaturated 4- to
8-membered heterocycle optionally substituted by 1 to 5
substituents selected from substituent group T, R.sup.3d is (i) a
hydrogen atom, or (ii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group or a C.sub.3-8 cycloalkyl group,
each of which is optionally substituted by 1 to 3 substituents
selected from halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4
alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl, cyano,
carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4 alkyl-carbonylamino,
C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, or
R.sup.3d is optionally bonded to a carbon atom of the adjacent
phenyl group to form a saturated or unsaturated 4- to 8-membered
nitrogen-containing heterocycle, which is optionally substituted by
1 to 3 substituents selected from halogen, hydroxy, C.sub.1-4
alkyloxy, C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4
alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino,
C.sub.1-4 alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and
C.sub.1-4 alkylsulfonylamino, Bd is a benzene ring optionally
substituted by 1 to 5 substituents selected from halogen,
optionally halogenated C.sub.1-4 alkyl, hydroxy, optionally
halogenated C.sub.1-4 alkyloxy, C.sub.1-4 alkyloxymethyl,
hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, carboxy,
C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro,
amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, C.sup.d is a
5- to 8-membered heterocyclic group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and an optionally
oxidized sulfur atom, which is optionally substituted by 1 to 5
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl, hydroxy, optionally halogenated C.sub.1-4
alkyloxy, C.sub.1-4 alkyloxymethyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino, and Z.sup.d is a C.sub.1-3 alkylene group
optionally substituted by 1 to 3 substituents selected from
halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, [63] the
compound of the above-mentioned [19], wherein R.sup.2e is (i) a
hydrogen atom, (ii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a C.sub.1-8 alkyl-carbonyl group,
a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a
C.sub.6-18 aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a
C.sub.6-18 aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4
alkyl-carbonyl group, a C.sub.6-18 aryl-sulfonyl group, a
heterocyclic group, a heterocycle-C.sub.1-4 alkyl group, a
heterocycle-carbonyl group or a heterocycle-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted by 1
to 5 substituents selected from substituent group T, or (iii) a
carbamoyl group optionally having 1 or 2 C.sub.1-8 alkyl group(s)
optionally substituted by substituent(s) selected from substituent
group T, wherein the carbamoyl group has two substituents, and they
optionally form, together with the adjacent nitrogen atom, a 3- to
8-membered saturated or an unsaturated aliphatic heterocyclic
group, which is optionally substituted by substituent(s) selected
from substituent group T, or R.sup.2e and R.sup.3e are optionally
bonded to form a saturated or unsaturated 4- to 8-membered
heterocycle optionally substituted by 1 to 5 substituents selected
from substituent group T, R.sup.3e is (i) a hydrogen atom, or (ii)
a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group or a C.sub.3-8 cycloalkyl group, each of which is
optionally substituted by 1 to 3 substituents selected from
halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, or R.sup.3e
is optionally bonded to a carbon atom of the adjacent phenyl group
to form a saturated or unsaturated 4- to 8-membered
nitrogen-containing heterocycle, which is optionally substituted by
1 to 3 substituents selected from halogen, hydroxy, C
.sub.1-4 alkyloxy, C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4
alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino,
C.sub.1-4 alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and
C.sub.1-4 alkylsulfonylamino, B.sup.e is a benzene ring optionally
substituted by 1 to 5 substituents selected from halogen,
optionally halogenated C.sub.1-4 alkyl, hydroxy, optionally
halogenated C.sub.1-4 alkyloxy, C.sub.1-4 alkyloxymethyl,
hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl, carboxy,
C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro,
amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, and C.sup.e
is a C.sub.6-18 aryl group optionally substituted by 1 to 5
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl, hydroxy, optionally halogenated C.sub.1-4
alkyloxy, C.sub.1-4 alkyloxymethyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino, [64] the compound of the above-mentioned [20],
wherein R.sup.f is (i) a hydrogen atom, (ii) a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a
C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
substituent group T, or (iii) a carbamoyl group optionally having 1
or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or an unsaturated aliphatic heterocyclic group, which is
optionally substituted by substituent(s) selected from substituent
group T, or R.sup.2f and R.sup.3f are optionally bonded to form a
saturated or unsaturated 4- to 8-membered heterocycle optionally
substituted by 1 to 5 substituents selected from substituent group
T, R.sup.3f is (i) a hydrogen atom, or (ii) a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group or a
C.sub.3-8 cycloalkyl group, each of which is optionally substituted
by 1 to 3 substituents selected from halogen, hydroxy, C.sub.1-4
alkyloxy, C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4
alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino,
C.sub.1-4 alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and
C.sub.1-4 alkylsulfonylamino, or R.sup.3f is optionally bonded to a
carbon atom of the adjacent phenyl group to form a saturated or
unsaturated 4- to 8-membered nitrogen-containing heterocycle, which
is optionally substituted by 1 to 3 substituents selected from
halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, B.sup.f is a
benzene ring optionally substituted by 1 to 5 substituents selected
from halogen, optionally halogenated C.sub.1-4 alkyl, hydroxy,
optionally halogenated C.sub.1-4 alkyloxy, C.sub.1-4
alkyloxymethyl, hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, C.sup.f is a
C.sub.6-18 aryl group optionally substituted by 1 to 5 substituents
selected from halogen, optionally halogenated C.sub.1-4 alkyl,
hydroxy, optionally halogenated C.sub.1-4 alkyloxy, C.sub.1-4
alkyloxymethyl, hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, and Z.sup.f
is a C.sub.1-3 alkylene group optionally substituted by 1 to 3
substituents selected from halogen, hydroxy, C.sub.1-4 alkyloxy,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino, [65] the compound of the above-mentioned [21],
wherein R.sup.2g is (i) a hydrogen atom, (ii) a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a
C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
substituent group T, or (iii) a carbamoyl group optionally having 1
or 2 C.sub.1-8 alkyl group(s) optionally substituted by
substituent(s) selected from substituent group T, wherein the
carbamoyl group has two substituents, and they optionally form,
together with the adjacent nitrogen atom, a 3- to 8-membered
saturated or an unsaturated aliphatic heterocyclic group, which is
optionally substituted by substituent(s) selected from substituent
group T, or R.sup.2g and R.sup.3g are optionally bonded to form a
saturated or unsaturated 4- to 8-membered heterocycle optionally
substituted by 1 to 5 substituents selected from substituent group
T, R.sup.3g is (i) a hydrogen atom, or (ii) a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group or a
C.sub.3-8 cycloalkyl group, each of which is optionally substituted
by 1 to 3 substituents selected from halogen, hydroxy, C.sub.1-4
alkyloxy, C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4
alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino,
C.sub.1-4 alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and
C.sub.1-4 alkylsulfonylamino, or R.sup.3g is optionally bonded to a
carbon atom of the adjacent phenyl group to form a saturated or
unsaturated 4- to 8-membered nitrogen-containing heterocycle
optionally substituted by 1 to 3 substituents selected from
halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, B.sup.g is a
benzene ring optionally substituted by 1 to 5 substituents selected
from halogen, optionally halogenated C.sub.1-4 alkyl, hydroxy,
optionally halogenated C.sub.1-4 alkyloxy, C.sub.1-4
alkyloxymethyl, hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl-carbonyl,
carboxy, C.sub.1-4 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl,
nitro, amino, C.sub.1-4 alkyl-carbonylamino, C.sub.1-4
alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino, C.sup.g is a
5- to 8-membered heterocyclic group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and an optionally
oxidized sulfur atom, which is optionally substituted by 1 to 5
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl, hydroxy, optionally halogenated C.sub.1-4
alkyloxy, C.sub.1-4 alkyloxymethyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino, and the like.
[0063] According to the present invention, a fused pyrimidine
compound having a superior tyrosine kinase inhibitory action, which
is low toxic and highly satisfactory as a pharmaceutical product, a
production method thereof and use thereof can be provided.
[0064] In the present specification, unless otherwise specified,
the "aryl" in the "aryl group" and the substituents includes a
monocyclic aryl group and a fused polycyclic aryl group. As the
"aryl group", for example, a C.sub.6-18 aryl group can be
mentioned. As the "C.sub.6-18 aryl group", for example, phenyl,
biphenylyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl can
be mentioned.
[0065] In the present specification, as the "heterocyclic group"
(and "heterocycle-" in the substituents), for example, a 5- to
8-membered heteroaryl group or a saturated or unsaturated aliphatic
heterocyclic group containing, as an atom (ring atom) constituting
a ring system, one or more (preferably 1 to 4, more preferably 1 or
2) hetero atoms selected from an oxygen atom, an optionally
oxidized sulfur atom and a nitrogen atom and the like (preferably,
an oxygen atom, a sulfur atom and a nitrogen atom etc.) can be
mentioned.
[0066] In the present specification, unless otherwise specified, as
the "aliphatic hydrocarbon group", a linear or branched aliphatic
hydrocarbon group having 1 to 15 carbon atom (preferably, 1 to 8
carbon atom) can be mentioned. As such "aliphatic hydrocarbon
group", for example, a ClB alkyl group, a C.sub.2-8 alkenyl group,
a C.sub.2-8 alkynyl group, a C.sub.3-8 cycloalkyl group and the
like can be mentioned.
[0067] In the present specification, unless otherwise specified, as
the "heteroaryl group", an aromatic monocyclic heterocyclic group
(e.g., 5- or 6-membered aromatic monocyclic heterocyclic group such
as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl and the like) and an aromatic
fused heterocyclic group (e.g., 8 to 12-membered aromatic fused
heterocyclic group such as benzofuranyl, isobenzofuranyl,
benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl,
benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl,
1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,
cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
naphthyridinyl, purinyl, pteridinyl, carbazolyl,
.alpha.-carbolinyl, .beta.-carbolinyl, .gamma.-carbolinyl,
acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,
phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl,
indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,
imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,
imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,
1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl and
the like) and the like can be mentioned. As the aromatic fused
heterocyclic group, a heterocycle wherein the aforementioned 5- or
6-membered aromatic monocyclic heterocyclic group is fused with a
benzene ring and a heterocycle wherein the same or different two
heterocycles of the aforementioned 5- or 6-membered aromatic
monocyclic heterocyclic group are fused are preferable.
[0068] In the present specification, unless otherwise specified, as
the "aliphatic heterocyclic group", for example, a 3- to 8-membered
(preferably 5- or 6-membered) saturated or unsaturated (preferably
saturated) aliphatic heterocyclic group such as oxiranyl,
azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,
thiomorpholinyl, piperazinyl, dihydro-1,2,4-oxadiazolyl and the
like, and the like can be mentioned.
[0069] In the present specification, unless otherwise specified, as
the "C.sub.1-8 alkyl group", for example, methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl,
t-pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-octyl and the
like can be mentioned, with preference given to a C.sub.1-6 alkyl
group. In the present specification, moreover, unless otherwise
specified, as the "C.sub.1-4 alkyl group", for example, methyl,
ethyl, n-propyl, i-propyl, n-butyl and i-butyl can be
mentioned.
[0070] In the present specification, unless otherwise specified, as
the "C.sub.2-8 alkenyl group", for example, vinyl, (1- or
2-)propenyl, (1-, 2- or 3-)butenyl, pentenyl, octenyl and
(1,3-)butadienyl can be mentioned, with preference given to a
C.sub.2-4 alkenyl group.
[0071] In the present specification, unless otherwise specified, as
the "C.sub.2-8 alkynyl group", for example, ethynyl, (1- or
2-)propynyl, (1-, 2- or 3-)butynyl, pentynyl and octynyl can be
mentioned, with preference given to a C.sub.2-4 alkynyl group.
[0072] In the present specification, unless otherwise specified, as
the "C.sub.3-8 cycloalkyl group", for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl can
be mentioned, with preference given to a C.sub.3-6 cycloalkyl
group.
[0073] In the present specification, unless otherwise specified, as
the "C.sub.1-4 alkylene", for example, methylene, ethylene,
trimethylene, tetramethylene and propylene and the like can be
mentioned.
[0074] In the present specification, unless otherwise specified, as
the "--O--(C.sub.1-4 alkylene)--", for example, --OCH.sub.2--,
--OCH.sub.2CH.sub.2--, --OCH.sub.2).sub.3--, --O(CH.sub.2).sub.4--,
--OCH(CH.sub.3)--, --OC(CH.sub.3).sub.2--, --OCH(CH.sub.3)
CH.sub.2--, --OCH.sub.2CH(CH.sub.3)--,
--OC(CH.sub.3).sub.2CH.sub.2-- and --OCH.sub.2C(CH.sub.3).sub.2--
and the like can be mentioned.
[0075] In the present specification, unless otherwise specified, as
the "C.sub.6-18 aryl-carbonyl group", for example, benzoyl,
naphthoyl, anthrylcarbonyl, phenanthrylcarbonyl and
acenaphthylenylcarbonyl and the like can be mentioned.
[0076] In the present specification, unless otherwise specified, as
the "C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group", for example,
benzylcarbonyl, 3-phenylpropionyl, 2-phenylpropionyl,
4-phenylbutyryl and 5-phenylpentanoyl and the like can be
mentioned.
[0077] In the present specification, unless otherwise specified, as
the "halogen", fluorine, chlorine, bromine and iodine can be
mentioned.
[0078] As the "5- to 8-membered heterocycle-carbonyl group
containing 1 to 3 hetero atoms selected from a nitrogen atom, an
oxygen atom and a sulfur atom", "a 5- to 8-membered cyclic
amino-carbonyl group optionally having 1 or 2 hetero atoms selected
from a nitrogen atom, an oxygen atom and a sulfur atom" is
preferable, for example, pyrrolidin-1-ylcarbonyl,
piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
morpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl and the like can
be mentioned.
[0079] In the above-mentioned formula, as the "aryl group" for A, a
C.sub.6-18 aryl group is preferable, and phenyl is more
preferable.
[0080] The "aryl group" is optionally substituted by a group of the
formula --Y.sup.2--B, wherein Y.sup.2 is a single bond, --O--,
--O--(C.sub.1-3 alkylene)-(preferably --OCH.sub.2--), --NH-- or
--S--, and B is an aryl group, a heterocyclic group, a C.sub.3-8
cycloalkyl group, a carbamoyl group, a ureido group, a C.sub.6-18
aryl-carbonyl group or a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, each of which is optionally substituted.
[0081] As Y.sup.2, a single bond, --O-- or --OCH.sub.2-- is
preferable, and --O-- or --OCH.sub.2-- is more preferable.
[0082] As the "aryl group" for B, a C.sub.6-18 aryl group is
preferable, and phenyl is more preferable.
[0083] As the "heterocyclic group" for B, the aforementioned "5 or
6-membered aromatic monocyclic heterocyclic group" is preferable,
and pyridyl is more preferable.
[0084] The "aryl group", "heterocyclic group", "C.sub.6-18
aryl-carbonyl group" or "C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group" for B may have, for example, 1 to 5, the same or different
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl, hydroxy, optionally halogenated C.sub.1-4
alkyloxy, C.sub.1-4 alkyloxymethyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino, at any substitutable position(s).
[0085] The "aryl group" for A may have, besides a group of the
above-mentioned formula --Y.sup.2--B, 1 to 5, the same or different
substituents at any substitutable position(s). As such substituent,
substituents similar to those exemplified for "aryl group" or
"heterocyclic group" for B can be mentioned.
[0086] As the "aliphatic hydrocarbon group" for R.sup.3, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group and a C.sub.3-8 cycloalkyl group are preferable.
[0087] The "aliphatic hydrocarbon group" for R.sup.3 is optionally
substituted by 1 to 3 substituents selected from halogen, hydroxy,
C.sub.1-4 alkyloxy, C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4
alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino,
C.sub.1-4 alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and
C.sub.1-4 alkylsulfonylamino.
[0088] The "C.sub.1-4 alkylene" and "--O--(C.sub.1-4 alkylene)-"
for Y.sup.1 are optionally substituted by 1 to 3 substituents
selected from halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4
alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl, cyano,
carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4 alkyl-carbonylamino,
C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino.
[0089] As X.sup.1, --NR.sup.3-- wherein R.sup.3 is as defined above
is preferable.
[0090] As the "optionally substituted group bonded via a carbon
atom, a nitrogen atom or an oxygen atom" for R.sup.1, a group of
the formula --X.sup.2--R.sup.4 can be mentioned, wherein X.sup.2 is
a single bond, --NH-- or --O--, and R.sup.4 is a hydrogen atom, a
cyano group, or a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group,
a C.sub.2-8 alkynyl group, a carbamoyl group, a C.sub.1-8
alkyl-carbonyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18
aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18
aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, a heterocyclic group, a heterocycle-C.sub.1-4 alkyl group, a
heterocycle-carbonyl group or a heterocycle-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted.
[0091] The "C.sub.1-8 alkyl group", "C.sub.2-8 alkenyl group",
"C.sub.2-8 alkynyl group", "C.sub.1-8 alkyl-carbonyl group",
"C.sub.3-8 cycloalkyl group", "C.sub.6-18 aryl group", "C.sub.6-18
aryl-C.sub.1-4 alkyl group", "C.sub.6-18 aryl-carbonyl group",
"C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group", "heterocyclic
group", "heterocycle-C.sub.1-4 alkyl group", "heterocycle-carbonyl
group" and "heterocycle-C.sub.1-4 alkyl-carbonyl group" are, for
example, optionally substituted by one or more (preferably 1 to 5,
more preferably 1 to 3) substituent(s) selected from
(a) halogen, (b) oxo, (c) optionally halogenated C.sub.1-4 alkyl,
(d) --(CH.sub.2).sub.m-Q, (e) --(CH.sub.2).sub.m-Z.sup.1-
(optionally halogenated C.sub.1-4 alkyl), (f)
--(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2)-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom) (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl (hereinafter to be sometimes to be referred to
as substituent group T).
[0092] In these formulas, m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, and
Z.sup.2 is --O--, --CO--, --C(OH)R.sup.8--,
--C(.dbd.N--OR.sup.8)--, --S--, --SO--, --SO.sub.2--, --NR.sup.8--,
--N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--,
--CO--O--, --O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--. In these formulas, (CH.sub.2).sub.m and
(CH.sub.2).sub.n are optionally substituted by one or more
(preferably 1 to 5, more preferably 1 to 3) substituents selected
from, for example, halogen, optionally halogenated C.sub.1-4 alkyl
and hydroxy, and when m or n is not less than 2, a subset
--CH.sub.2CH.sub.2-- of (CH.sub.2).sub.m and (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH-- or --C.ident.C--.
[0093] In these formulas, R.sup.6 and R.sup.7 are the same or
different and each is a hydrogen atom or C.sub.1-4 alkyl, or
R.sup.6 and R.sup.7 form a ring together with a nitrogen atom. In
these formulas, moreover, R.sup.8 is a hydrogen atom or C.sub.1-4
alkyl and R.sup.9 is C.sub.1-4 alkyl. When R.sup.6 and R.sup.7 form
a ring together with a nitrogen atom, as the nitrogen-containing
heterocyclic group, for example, a 3 to 8-membered (preferably 5 or
6-membered) saturated or unsaturated (preferably saturated)
aliphatic heterocyclic group such as azetidinyl, pyrrolidinyl,
piperidinyl, homopiperidinyl, heptamethyleneimino, morpholinyl,
thiomorpholinyl, piperazinyl, homopiperazinyl and the like, and the
like can be mentioned.
[0094] As X.sup.2, a single bond is preferable.
[0095] As R.sup.4, a hydrogen atom or a C.sub.1-8 alkyl group, a
C.sub.2-8 alkenyl group, a C.sub.6-18 aryl group or heterocyclic
group, each of which is optionally substituted is preferable. As
the "C.sub.6-18 aryl group" for R.sup.4, phenyl is preferable. As
the "heterocyclic group" for R.sup.4, the aforementioned "5 or
6-membered aromatic monocyclic heterocyclic group" is preferable,
and furyl is preferable.
[0096] As the "optionally substituted group bonded via a carbon
atom or a sulfur atom" for R.sup.2, a C.sub.1-8 alkyl group, a
C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a carbamoyl
group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl
group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18 aryl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl
group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a
C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted, can be mentioned.
[0097] The "C.sub.1-8 alkyl group", "C.sub.2-8 alkenyl group",
"C.sub.2-8 alkynyl group", "C.sub.1-8 alkyl-carbonyl group",
"C.sub.1-8 alkylsulfonyl group", "C.sub.3-8 cycloalkyl group",
"C.sub.6-18 aryl group", "C.sub.6-18 aryl-C.sub.1-4 alkyl group",
"C.sub.6-18 aryl-carbonyl group", "C.sub.6-18 aryl-C.sub.1-4
alkyl-carbonyl group", "C.sub.6-18 aryl-sulfonyl group",
"heterocyclic group", "heterocycle-C.sub.1-4 alkyl group",
"heterocycle-carbonyl group" and "heterocycle-C.sub.1-4
alkyl-carbonyl group" are optionally substituted by, for example,
one or more (preferably 1 to 5, more preferably 1 to 3)
substituents selected from the above-mentioned substituent group
T.
[0098] As R.sup.2, a hydrogen atom or a C.sub.1-8 alkyl group, a
C.sub.6-18 aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a
C.sub.6-18 aryl-carbonyl group, a C.sub.6-18 aryl-sulfonyl group or
heterocycle-C.sub.1-4 alkyl group, each of which is optionally
substituted, is preferable.
[0099] As the "C.sub.6-18 aryl group" for R.sup.2, phenyl is
preferable. As the "C.sub.6-18 aryl-C.sub.1-4 alkyl group" for
R.sup.2, benzyl is preferable. As the "C.sub.6-18 aryl-carbonyl
group" for R.sup.2, benzoyl is preferable. As the "C.sub.6-18
aryl-sulfonyl group" for R.sup.2, phenylsulfonyl is preferable. As
the "heterocyclic group" or "heterocycle-" of
"heterocycle-C.sub.1-4 alkyl group", "heterocycle-carbonyl group"
and "heterocycle-C.sub.1-4 alkyl-carbonyl group" for R.sup.2, the
aforementioned "5 or 6-membered aromatic monocyclic heterocyclic
group" or the aforementioned "aliphatic heterocyclic group" is
preferable, and furyl or tetrahydrofuryl is preferable.
[0100] In the substituents that a group represented by R.sup.2 may
have, when R.sup.6 and R.sup.7 form a ring together with a nitrogen
atom, the "ring" optionally further has 1 to 5 (preferably 1 to 3)
the same or different substituents. As such substituents,
substituents similar to those exemplified for "aryl group" or
"heterocyclic group" for B can be mentioned.
[0101] The aforementioned "carbamoyl group" and "ureido group"
optionally have 1 or 2 optionally substituted C.sub.1-8 alkyl
group(s). Alternatively, the "carbamoyl group" and "ureido group"
may have two substituents and they may form an optionally
substituted ring, together with the adjacent nitrogen atom. As the
"ring" of the "optionally substituted ring", rings similar to those
formed by R.sup.6 and R.sup.7 together with a nitrogen atom as
exemplified above can be mentioned. As the "substituent" of the
"optionally substituted C.sub.1-8 alkyl group" and as the
"substituent" of the "optionally substituted ring", groups similar
to the substituents of the above-mentioned substituent group T can
be mentioned.
[0102] As the "optionally substituted carbamoyl group", carbamoyl,
C.sub.1-8 alkylcarbamoyl, di(C.sub.1-8 alkyl)carbamoyl, C.sub.6-18
aryl-C.sub.1-4 alkylcarbamoyl, azetidin-1-ylcarbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,
piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl,
thiomorpholin-4-ylcarbonyl, (C.sub.1-4
alkyl)piperidin-1-ylcarbonyl, (C.sub.6-18 aryl-C.sub.1-4
alkyl)piperidin-1-ylcarbonyl and the like can be mentioned.
[0103] As the "optionally substituted ureido group", ureido,
3-(C.sub.1-8 alkyl)ureido, 3,3-di(C.sub.1-8 alkyl)ureido,
3-(C.sub.6-18 aryl-C.sub.1-4 alkyl)ureido,
azetidine-1-ylcarbonylamino, pyrrolidin-1-ylcarbonylamino,
piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino,
morpholin-4-ylcarbonylamino, thiomorpholin-4-ylcarbonylamino,
(C.sub.1-4 alkyl)piperidin-1-ylcarbonylamino, (C.sub.6-18
aryl-C.sub.1-4 alkyl)piperidin-1-ylcarbonylamino and the like can
be mentioned.
[0104] As the "ring structure" of the optionally substituted ring
structure formed by R.sup.3 bonded to a carbon atom or a hetero
atom on the aryl group or the heteroaryl group represented by A, a
saturated or unsaturated (preferably saturated) 4- to 8-membered
(preferably 5- or 6-membered) nitrogen-containing heterocycle can
be mentioned. Specifically,
##STR00026##
The "ring structure" may have 1 to 5 (preferably 1 to 3, more
preferably 1 or 2) the same or different substituents at any
substitutable position(s). As such substituents, substituents
similar to those exemplified for "aryl group" or "heterocyclic
group" for B can be mentioned.
[0105] As the "ring structure" of the optionally substituted ring
structure formed by R.sup.1 and R.sup.2 bonded to each other, a
saturated or unsaturated (preferably saturated) 4- to 8-membered
(preferably 5- or 6-membered) heterocycle can be mentioned. When
R.sup.1 and R.sup.2 are bonded to form an optionally substituted
ring structure, for example,
##STR00027##
wherein each symbol is as defined above, and the like can be
mentioned.
[0106] As the "ring structure" of the optionally substituted ring
structure formed by R.sup.2 and R.sup.3 bonded to each other, a
saturated or unsaturated (preferably saturated) 4- to 8-membered
(preferably 5- to 7-membered) heterocycle can be mentioned. When
R.sup.2 and R.sup.3 are bonded to form an optionally substituted
ring structure, for example,
##STR00028##
wherein each symbol is as defined above, and the like can be
mentioned. The "ring structure" formed by R.sup.1 and R.sup.2, or
R.sup.2 and R.sup.3 bonded to each other may have 1 to 5
(preferably 1 to 3, more preferably 1 or 2) the same or different
substituents selected from the above-mentioned substituent group T
at any substitutable position(s).
[0107] When W is C(R.sup.1), compound (I) is represented by the
following formula (IA):
##STR00029##
wherein each symbol is as defined above.
[0108] When W is N, compound (I) is represented by the following
formula (IB) or (IC):
##STR00030##
wherein each symbol is as defined above.
[0109] Specifically, as compound (I), the following compounds
(Ia)-(Ij) and the like are preferably used.
[Compound (Ia)]
[0110] A compound represented by the formula:
##STR00031##
wherein R.sup.1a is a hydrogen atom or an optionally substituted
group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
and R.sup.2a is an optionally substituted group bonded via a carbon
atom or a sulfur atom, or R.sup.1a and R.sup.2a, or R.sup.2a and
R.sup.3a are optionally bonded to form an optionally substituted
ring structure, R.sup.3a is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3a is optionally
bonded to a carbon atom of the adjacent phenyl group to form an
optionally substituted ring structure, B.sup.a is an optionally
substituted benzene ring, and C.sup.a is an optionally substituted
C.sub.6-18 aryl group, or a salt thereof.
[0111] As the "optionally substituted group bonded via a carbon
atom, a nitrogen atom or an oxygen atom" for R.sup.1a, those
similar to the "optionally substituted group bonded via a carbon
atom, a nitrogen atom or an oxygen atom" for R.sup.1 can be
used.
[0112] As the "optionally substituted group bonded via a carbon
atom or a sulfur atom" for R.sup.2a, those similar to the
"optionally substituted group bonded via a carbon atom or a sulfur
atom" for R.sup.2 can be used.
[0113] As the "optionally substituted ring structure" formed by
R.sup.1a and R.sup.2a, or R.sup.2a and R.sup.3a bonded to each
other, those similar to the "optionally substituted ring structure"
formed by R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3 bonded to
each other can be used.
[0114] As the "optionally substituted aliphatic hydrocarbon group"
for R.sup.3a, those similar to the "optionally substituted
aliphatic hydrocarbon group" for R.sup.3 can be used.
[0115] As the "optionally substituted ring structure" for R.sup.3a,
which is formed by binding to a carbon atom of the adjacent phenyl
group, those similar to the "optionally substituted ring structure"
for R.sup.3, which is formed by binding to a carbon atom of the
adjacent phenyl group can be used.
[0116] As the substituent of the "optionally substituted benzene
ring" for B.sup.a, for example, 1 to 5, the same or different
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl, hydroxy, optionally halogenated C.sub.1-4
alkyloxy, C.sub.1-4 alkyloxymethyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl,
cyano, carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4
alkyl-carbonylamino, C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4
alkylsulfonylamino can be used.
[0117] As the "C.sub.6-18 aryl group" of the "optionally
substituted C.sub.6-18 aryl group" for C.sup.a, for example,
phenyl, biphenylyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl
and the like can be used, with preference given to a phenyl
group.
[0118] As the "substituent" of the "optionally substituted
C.sub.6-18 aryl group" for C.sup.a, those similar to the
substituents of the "optionally substituted benzene ring" for
B.sup.a can be used.
[0119] As R.sup.2a, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a carbamoyl group, a C.sub.1-8
alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
(a) halogen, (b) oxo, (c) optionally halogenated C.sub.1-4 alkyl,
(d) --(CH.sub.2).sub.m-Q, (e) --(CH.sub.2).sub.m-Z.sup.1-
(optionally halogenated C.sub.1-4 alkyl), (f)
--(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.1-(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7, --OCONH.sub.2 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, SO--,
--SO.sub.2--, --N(COR.sup.9)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--,
--CO--NR.sup.9--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--,
--NR.sup.8--CO--NH--, --NR.sup.8--SO.sub.2--, or
--NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is --O, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR)--, --S--, --SO--, --SO.sub.2--,
--NR.sup.9--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2), are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH-- or --C.ident.C--, R.sup.6 and R.sup.7 are the same or
different and each is a hydrogen atom or a C.sub.1-4 alkyl group,
or R.sup.6 and R.sup.7 are bonded to form, together with a nitrogen
atom, a 3- to 8-membered saturated or unsaturated aliphatic
heterocyclic group, R.sup.8 is a hydrogen atom or C.sub.1-4 alkyl,
and R.sup.9 is C.sub.1-4 alkyl, is preferable.
[0120] As compound (Ia), a compound wherein
B.sup.a is a benzene ring optionally substituted by 1 to 4
substituents selected from halogen, C.sub.1-4 alkyl,
hydroxy-C.sub.1-4 alkyl and C.sub.1-4 alkyloxy; C.sup.a is a phenyl
group optionally substituted by 1 to 5 substituents selected from
(i) halogen, (ii) optionally halogenated C.sub.1-4 alkyl, (iii)
hydroxy-C.sub.1-4 alkyl, (iv) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl, triazolyl and the like), (v) optionally
halogenated C.sub.1-4 alkyloxy, (vi) C.sub.1-4 alkyl-carbonyl,
(vii) cyano, (viii) carbamoyl optionally substituted by C.sub.1-8
alkyl and (ix) C.sub.1-4 alkoxy-carbonyl;
R.sup.1a is
[0121] (i) a hydrogen atom, (ii) a cyano group, or (iii) a
C.sub.1-4 alkyl group or a C.sub.2-4 alkenyl group, each of which
is optionally substituted by
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7 wherein n is an
integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, R.sup.8 is
a hydrogen atom or a C.sub.1-4 alkyl group, and when n is not less
than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--; R.sup.2a is a C.sub.1-8 alkyl
group, a C.sub.2-8 alkenyl group or a C.sub.2-8 alkynyl group, each
of which is optionally substituted by substituent(s) selected from
(a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated
C.sub.1-4 alkyloxy, (e) --O--(CH.sub.2).sub.n--OH, (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (h) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (i)
--O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (j)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2)--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2)--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (m) --O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (n)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4 alkyl,
(q) --NR.sup.6R.sup.7,
[0122] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (v)
--NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, (x)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2)--SO-- (optionally halogenated C.sub.1-4
alkyl), (z) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2)--SO.sub.2--C.sub.3-8 cycloalkyl, (bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc)
--NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(dd) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(ii) --S-- (CH.sub.2).sub.n--OH,
(jj) --SO--(CH.sub.2)--OH,
[0123] (kk) --SO.sub.2--(CH.sub.2).sub.n--OH, and (ll)
--NR.sup.8--CO-- (optionally substituted heterocyclic group)
(preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--O--C.sub.1-4 alkyl,
--CO--NH--C.sub.1-4 alkyl, --CONH.sub.2, --SO.sub.2--C.sub.1-4
alkyl, --SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the
like), wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are
the same or different and each is a hydrogen atom or a C.sub.1-4
alkyl group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
(CH.sub.2).sub.n is optionally substituted by optionally
halogenated C.sub.1-4 alkyl or hydroxy, and when n is not less than
2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is optionally
replaced by --CH.dbd.CH--; and R.sup.3a is a hydrogen atom or a
C.sub.1-6 alkyl group; or R.sup.1a and R.sup.2a are optionally
bonded to form
##STR00032##
R.sup.2a and R.sup.3a are optionally bonded to form C.sub.2-4
alkylene optionally substituted by an imino group is
preferable.
[0124] As R.sup.8, a hydrogen atom, methyl, ethyl and the like are
preferable, and a hydrogen atom is particularly preferable.
[0125] As R.sup.2, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group or a C.sub.2-8 alkynyl group, each of which is optionally
substituted by substituent(s) selected from
(a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated
C.sub.1-4 alkyloxy, (e) --O--(CH.sub.2).sub.n--OH (wherein
(CH.sub.2).sub.n is optionally substituted by hydroxy), (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g) --O--(CH.sub.2)--O--
(optionally halogenated C.sub.1-4 alkyl), (h)
--O--(CH.sub.2).sub.n--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (i) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (j)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1--
4 alkyl, (m) --O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (n)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (o)
--CO--NR--(CH.sub.2).sub.n--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4 alkyl,
(q) --NR.sup.6R.sup.7,
[0126] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by optionally halogenated C.sub.1-4 alkyl or
hydroxy), (v) --NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7 (when n is not
less than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--), (x)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (z) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (wherein (CH.sub.2).sub.n
is optionally substituted by C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc) --NR.sup.8--CO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (dd)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (ii)
--S--(CH.sub.2).sub.n--OH, (jj) --SO--(CH.sub.2).sub.n--OH, (kk)
--SO.sub.2--(CH.sub.2).sub.n--OH, and (ll) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--O--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
is preferable.
[0127] As R.sup.8, a hydrogen atom, methyl, ethyl and the like are
preferable, and a hydrogen atom is particularly preferable.
[0128] As compound (Ia), moreover, a compound wherein
B.sup.a is a benzene ring optionally substituted by 1 to 4
substituents selected from halogen and optionally halogenated
C.sub.1-4 alkyl; C.sup.a is a phenyl group substituted by 1 to 5
substituents selected from (i) halogen, (ii) optionally halogenated
C.sub.1-4 alkyl, (iii) hydroxy-C.sub.1-4 alkyl, (iv)
heterocycle-C.sub.1-4 alkyl (preferably, 5- to 8-membered
heterocycle-C.sub.1-4 alkyl, said 5- to 8-membered heterocycle has
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, such as imidazolyl and the
like), (v) optionally halogenated C.sub.1-4 alkyloxy, (vi) cyano,
and (vii) carbamoyl optionally substituted by C.sub.1-8 alkyl;
R.sup.1a is a hydrogen atom; R.sup.2a is a C.sub.1-8 alkyl group, a
C.sub.2-8 alkenyl group or a C.sub.2-8 alkynyl group, each of which
is substituted by substituent(s) selected from (a) hydroxy, (b)
optionally halogenated C.sub.1-4 alkyloxy, (c)
--O--(CH.sub.2).sub.n--OH,
(d) --O--(CH.sub.2)--O--CO--NH.sub.2,
[0129] (e) --O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (f)
--O--(CH.sub.2).sub.n--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl) (g) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (h)
--O--(CH.sub.2)--SO.sub.2--(CH.sub.2).sub.n--OH, (i)
--O--(CH.sub.2)--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl) (j) --CO--NR.sup.8--(CH.sub.2).sub.n--OH,
(k)--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl),
(l) --NR.sup.6R.sup.7,
[0130] (m) --NR.sup.8--(CH.sub.2).sub.n--OH, (n)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (p)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-14 alkyl, (q)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (r) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (s)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(t) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (u)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(v) --NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-14
alkyl, (w) --S--(CH.sub.2).sub.n--OH,
(x) --SO--(CH.sub.2)--OH,
[0131] (y) --SO.sub.2--(CH.sub.2).sub.n--OH, and (z)
--NR.sup.8--CO-- (optionally substituted heterocyclic group)
(preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, and
(CH.sub.2).sub.n is optionally substituted by C.sub.1-4 alkyl or
hydroxy; R.sup.3a is a hydrogen atom or a C.sub.1-6 alkyl group; or
R.sup.1a and R.sup.2a are optionally bonded to form
##STR00033##
R.sup.2a and R.sup.3a are optionally bonded to form C.sub.2-4
alkylene, is preferable.
[0132] Of these, as R.sup.2a, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group or a C.sub.2-8 alkynyl group (particularly, a
C.sub.1-8 alkyl group), each of which is substituted by
substituent(s) selected from (a) hydroxy,
(b) optionally halogenated C.sub.1-4 alkyloxy, (c)
--O--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is optionally
substituted by hydroxy), (d)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (e)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (f)
--O--(CH.sub.2)--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (g) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (h)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (i)
--O--(CH.sub.2).sub.n--NR.sup.8SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (j) --CO--NRB --(CH.sub.2).sub.n--OH, (k)
--CO--NR.sup.8--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl),
(l) --NR.sup.6R.sup.7,
[0133] (m) --NR.sup.8--(CH.sub.2).sub.n--OH, (n)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by C.sub.1-4 alkyl), (p)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (q)
--NR.sup.8--CO--(CH.sub.2)--SO-- (optionally halogenated C.sub.1-4
alkyl), (r) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (wherein (CH.sub.2) is
optionally substituted by C.sub.1-4 alkyl), (s)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(t) --NR.sup.8--CO.sub.2-- (CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl,
(u) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (v) --NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (w) --S-- (CH.sub.2).sub.n--OH, (x)
--SO--(CH.sub.2).sub.n--OH,
(y) --SO.sub.2--(CH.sub.2)--OH, and
[0134] (z) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, is
preferable.
[0135] As R.sup.2a, (i) a C.sub.5-8 alkyl group substituted by
hydroxy,
(ii) a C.sub.1-8 alkyl group substituted by substituent(s) selected
from (a) halogenated C.sub.1-4 alkyloxy, (b)
--O--(CH.sub.2).sub.n--OH, (c)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (d)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (e) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (f)
--O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (g)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (h) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (i)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (j)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (k)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (l)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (m)
--NR.sup.8--CO--(CH.sub.2)--SO-- (optionally halogenated C.sub.1-4
alkyl), (n) --NR.sup.8--CO--(CH.sub.2)--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(p) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (q)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(r) --NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (s) --S--(CH.sub.2).sub.n--OH,
(t) --SO--(CH.sub.2)--OH,
[0136] (u) --SO.sub.2--(CH.sub.2).sub.n--OH, and (v)
--NR.sup.8--CO-- (optionally substituted heterocyclic group)
(preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, and (CH.sub.2), is optionally substituted by
C.sub.1-4 alkyl or hydroxy, (iii) a C.sub.2-8 alkenyl group
optionally substituted by hydroxy, or (iv) a C.sub.2-8 alkynyl
group optionally substituted by hydroxy is preferable, and
particularly, as R.sup.2a, (i) a C.sub.5-8 alkyl group substituted
by hydroxy, (ii) a C.sub.1-8 alkyl group substituted by
substituent(s) selected from (a) halogenated C.sub.1-4 alkyloxy,
(b) --O--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by hydroxy), (c)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (d) --O--(CH.sub.2)--O--
(optionally halogenated C.sub.1-4 alkyl), (e)
--O--(CH.sub.2)--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (f) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (g)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl) (h) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (i)
--CO--NR.sup.8--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (j)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-14 alkyl, (k)
--NR.sup.8--CO--(CH.sub.2)--OH (wherein (CH.sub.2).sub.n is
optionally substituted by C.sub.1-4 alkyl), (l)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (m)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (n) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (wherein (CH.sub.2).sub.n
is optionally substituted by C.sub.1-4 alkyl), (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(p) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (q)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(r) --NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-14
alkyl, (s) --S-- (CH.sub.2).sub.n--OH, (t)
--SO--(CH.sub.2).sub.n--OH (u) --SO.sub.2--(CH.sub.2).sub.n--OH,
and (v) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom
or a C.sub.1-4 alkyl group, (iii) a C.sub.2-8 alkenyl group
optionally substituted by hydroxy, or (iv) a C.sub.2-8 alkynyl
group optionally substituted by hydroxy is preferable, and as
R.sup.8, a hydrogen atom, methyl, ethyl and the like are
preferable, and a hydrogen atom is particularly preferable.
[Compound (Ib)]
[0137] A compound represented by the formula:
##STR00034##
wherein R.sup.1b is a hydrogen atom or an optionally substituted
group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
R.sup.2b is an optionally substituted group bonded via a carbon
atom or a sulfur atom, or R.sup.1b and R.sup.2b, or R.sup.2b and
R.sup.3b are optionally bonded to form an optionally substituted
ring structure, R.sup.3b is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3b is optionally
bonded to a carbon atom of the adjacent phenyl group to form an
optionally substituted ring structure, B.sup.b is an optionally
substituted benzene ring, C.sup.b is an optionally substituted
C.sub.6-18 aryl group, and Z.sup.b is an optionally substituted
C.sub.1-3 alkylene group, or a salt thereof.
[0138] As the "optionally substituted group bonded via a carbon
atom, a nitrogen atom or an oxygen atom" for R.sup.1b, those
similar to the "optionally substituted group bonded via a carbon
atom, a nitrogen atom or an oxygen atom" for R.sup.1 can be
used.
[0139] As the "optionally substituted group bonded via a carbon
atom or a sulfur atom" for R.sup.2b, those similar to the
"optionally substituted group bonded via a carbon atom or a sulfur
atom" for R.sup.2 can be used.
[0140] As the "optionally substituted ring structure" formed by
R.sup.1b and R.sup.2b, or R.sup.2b and R.sup.3b bonded to each
other, those similar to the "optionally substituted ring structure"
formed by R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3 bonded to
each other can be used.
[0141] As the "optionally substituted aliphatic hydrocarbon group"
for R.sup.3b, those similar to the "optionally substituted
aliphatic hydrocarbon group" for R.sup.3 can be used.
[0142] As the "optionally substituted ring structure" formed by
R.sup.3b and a carbon atom of the adjacent phenyl group, those
similar to the "optionally substituted ring structure" formed by
R.sup.3 and a carbon atom of the adjacent phenyl group can be
used.
[0143] As the "optionally substituted benzene ring" for B.sup.b,
those similar to the "optionally substituted benzene ring" for
B.sup.a can be used.
[0144] As the "optionally substituted C.sub.6-18 aryl group" for
C.sup.b, those similar to the "optionally substituted C.sub.6-18
aryl group" for C.sup.a can be used.
[0145] As the "C.sub.1-3 alkylene group" of the "optionally
substituted C.sub.1-3 alkylene group" for Z.sup.b, methylene,
ethylene, trimethylene and propylene can be used.
[0146] As the "substituent" of the "optionally substituted
C.sub.1-3 alkylene group" for Z.sup.b, 1 to 3 substituents selected
from halogen, hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4
alkyl-carbonyl, carboxy, C.sub.1-4 alkoxy-carbonyl, cyano,
carbamoyl, sulfamoyl, nitro, amino, C.sub.1-4 alkyl-carbonylamino,
C.sub.1-4 alkoxy-carbonylamino and C.sub.1-4 alkylsulfonylamino can
be used.
[0147] As R.sup.2b, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a carbamoyl group, a C.sub.1-8
alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
(a) halogen, (b) oxo, (c) optionally halogenated C.sub.1-4 alkyl,
(d) --(CH.sub.2).sub.m-Q, (e) --(CH.sub.2).sub.m-Z.sup.1-
(optionally halogenated C.sub.1-4 alkyl), (f)
--(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl) (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7, --OCONH.sub.2 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --O--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.8)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--,
--NR.sup.8--CO--NH--, --NR.sup.8--C(.dbd.NH)--NH--,
--NR.sup.8--SO.sub.2--, or --SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m
and (CH.sub.2), are optionally substituted by 1 to 5 substituents
selected from halogen, optionally halogenated C.sub.1-4 alkyl and
hydroxy, and when m or n is not less than 2, a subset
--CH.sub.2CH.sub.2-- of (CH.sub.2).sub.m and (CH.sub.2).sub.n, is
optionally replaced by --CH.dbd.CH-- or --C.ident.C--, R.sup.6 and
R.sup.7 are the same or different and each is a hydrogen atom or a
C.sub.1-4 alkyl group, or R.sup.6 and R.sup.7 are bonded to form,
together with a nitrogen atom, a 3- to 8-membered saturated or
unsaturated aliphatic heterocyclic group, R.sup.8 is a hydrogen
atom or C.sub.1-4 alkyl, and R.sup.9 is C.sub.1-4 alkyl is
preferable.
[0148] As compound (Ib), a compound wherein
B.sup.b is a benzene ring optionally substituted by halogen;
C.sup.b is a phenyl group optionally substituted by 1 to 5
substituents selected from halogen, optionally halogenated
C.sub.1-4 alkyl and cyano; R.sup.1b is (i) a hydrogen atom, or (ii)
a C.sub.2-4 alkenyl group optionally substituted by hydroxy;
R.sup.2b is
[0149] (i) a C.sub.1-8 alkyl group optionally substituted by
substituent(s) selected from (a) halogen, (b) hydroxy, (c)
C.sub.1-4 alkyloxy, (d) --O--(CH.sub.2).sub.n--OH, (e)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (f)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH,
(g) --NR.sup.6R.sup.7 and
(h) --NR.sup.8--(CH.sub.2)--OH,
[0150] wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are
the same or different and each is a hydrogen atom or a C.sub.1-4
alkyl group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl
group, (ii) a C.sub.6-18 aryl-C.sub.1-4 alkyl group optionally
substituted by substituent(s) selected from (a) C.sub.1-4 alkyl
optionally having hydroxy, (b) carboxy, (c) C.sub.1-4
alkoxy-carbonyl, (d) 5- to 8-membered heterocycle-carbonyl having 1
to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and
a sulfur atom, which optionally has substituent(s) selected from
hydroxy and C.sub.1-4 alkyl, and (e) C.sub.1-4 alkyl-carbamoyl
optionally having substituent(s) selected from hydroxy and
carbamoyl, (iii) a C.sub.6-18 aryl-carbonyl group optionally
substituted by C.sub.1-4 alkoxy, (iv) a C.sub.6-18 aryl-sulfonyl
group optionally substituted by C.sub.1-4 alkoxy, or (v) a 5- to
8-membered heterocycle-C.sub.1-4 alkyl group having 1 to 3 hetero
atoms selected from a nitrogen atom, an oxygen atom and a sulfur
atom, which is optionally substituted by substituent(s) selected
from (a) carboxy, and (b) C.sub.1-4 alkoxy-carbonyl; R.sup.3b is a
hydrogen atom or a C.sub.1-6 alkyl group; or R.sup.2b and R.sup.3b
are optionally bonded to form C.sub.2-4 alkylene; and Z.sup.b is a
C.sub.1-3 alkylene group is preferable.
[0151] Moreover, as compound (Ib), a compound wherein
B.sup.b is a benzene ring optionally substituted by halogen;
C.sup.b is a phenyl group optionally substituted by 1 to 5
substituents selected from halogen and optionally halogenated
C.sub.1-4 alkyl; R.sup.1b is a hydrogen atom; R.sup.2b is a
C.sub.1-8 alkyl group optionally substituted by substituent(s)
selected from (a) hydroxy, (b) --O--(CH.sub.2).sub.n--OH, (c)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH,
(e) --NR.sup.6R.sup.7, and
[0152] (f) --NR.sup.8--(CH.sub.2).sub.n--OH, wherein n is an
integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.8
is a hydrogen atom or a C.sub.1-4 alkyl group; R.sup.3b is a
hydrogen atom or a C.sub.1-6 alkyl group; and Z.sup.b is a
C.sub.1-3 alkylene group is preferable.
[0153] Particularly, as compound (Ib), a compound wherein
B.sup.b is a benzene ring optionally substituted by halogen;
C.sup.b is a phenyl group optionally substituted by 1 to 5
substituents selected from halogen and optionally halogenated
C.sub.1-4 alkyl; R.sup.1b is a hydrogen atom; R.sup.2b is a
C.sub.1-8 alkyl group substituted by substituent(s) selected from
(a) --O--(CH.sub.2).sub.n--OH, (b)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, and (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, wherein n is an integer of 1
to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group;
R.sup.3b is a hydrogen atom or a C.sub.1-6 alkyl group; and Z.sup.b
is a methylene group is preferable.
[0154] As R.sup.8, a hydrogen atom, methyl, ethyl and the like are
preferable, and a hydrogen atom is particularly preferable.
[Compound (Ic)]
[0155] A compound represented by the formula:
##STR00035##
wherein R.sup.10 is a hydrogen atom or an optionally substituted
group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
R.sup.2c is an optionally substituted group bonded via a carbon
atom or a sulfur atom, or R.sup.1c and R.sup.2c, or R.sup.2c and
R.sup.3c are optionally bonded to form an optionally substituted
ring structure, R.sup.3c is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3c is optionally
bonded to a carbon atom of the adjacent phenyl group to form an
optionally substituted ring structure, B.sup.c is an optionally
substituted benzene ring, and cc is an optionally substituted
heterocyclic group, or a salt thereof.
[0156] As the "optionally substituted group bonded via a carbon
atom, a nitrogen atom or an oxygen atom" for R.sup.10, those
similar to the "optionally substituted group bonded via a carbon
atom, a nitrogen atom or an oxygen atom" for R.sup.1 can be
used.
[0157] As the "optionally substituted group bonded via a carbon
atom or a sulfur atom" for R.sup.2c, those similar to the
"optionally substituted group bonded via a carbon atom or a sulfur
atom" for R.sup.2 can be used.
[0158] As the "optionally substituted ring structure" formed by
R.sup.1c and R.sup.2c, or R.sup.2c and R.sup.3c bonded to each
other, those similar to the "optionally substituted ring structure"
formed by R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3 bonded to
each other can be used.
[0159] As the "optionally substituted aliphatic hydrocarbon group"
for R.sup.3c, those similar to the "optionally substituted
aliphatic hydrocarbon group" for R.sup.3 can be used.
[0160] As the "optionally substituted ring structure" formed by
R.sup.3c and a carbon atom of the adjacent phenyl group, those
similar to the "optionally substituted ring structure" formed by
R.sup.3 and a carbon atom of the adjacent phenyl group can be
used.
[0161] As the "optionally substituted benzene ring" for BC, those
similar to the "optionally substituted benzene ring" for B.sup.a
can be used.
[0162] As the "heterocyclic group" of the "optionally substituted
heterocyclic group" for C.sup.c, the aforementioned "heterocyclic
group" can be used, and a 5- to 8-membered heterocyclic group
having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen
atom and an optionally oxidized sulfur atom can be particularly
preferably used. Specifically, 5 or 6-membered aromatic monocyclic
heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl and the like, 3- to 8-membered
(preferably 5- or 6-membered) saturated or unsaturated (preferably
saturated) aliphatic heterocyclic groups such as oxiranyl,
azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,
thiomorpholinyl, piperazinyl, dihydro-1,2,4-oxadiazolyl and the
like can be used, and particularly, pyridyl, pyrimidinyl, piperidyl
(particularly, 4-piperidyl) and the like are preferable.
[0163] As the "substituent" of the "optionally substituted
heterocyclic group" for C.sup.c, those similar to the "substituent"
of the "optionally substituted C.sub.6-18 aryl group" for C.sup.a
can be used.
[0164] As R.sup.2, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a carbamoyl group, a C.sub.1-8
alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
(a) halogen, (b) oxo, (c) optionally halogenated C.sub.1-4 alkyl,
(d) --(CH.sub.2).sub.m-Q, (e) --(CH.sub.2).sub.m-Z.sup.1-
(optionally halogenated C.sub.1-4 alkyl), (f)
--(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--,
--SO, SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2), are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2)-- is optionally replaced by
--CH.dbd.CH--, R.sup.6 and R.sup.7 are the same or different and
each is a hydrogen atom or a C.sub.1-4 alkyl group, or R.sup.6 and
R.sup.7 are bonded to form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group,
R.sup.8 is a hydrogen atom or C.sub.1-4 alkyl, and R.sup.9 is
C.sub.1-4 alkyl is preferable.
[0165] As compound (Ic), a compound wherein
B.sup.c is a benzene ring optionally substituted by 1 to 4
substituents selected from halogen and optionally halogenated
C.sub.1-4 alkyl; C.sup.c is a 5- to 8-membered heterocyclic group
having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen
atom and a sulfur atom (e.g., pyridyl, pyrimidyl, 4-piperidyl),
which is optionally substituted by 1 to 5 substituents selected
from (i) halogen, (ii) C.sub.1-4 alkyl, (iii) C.sub.1-4
alkyl-carbonyl, (iv) optionally halogenated C.sub.1-4
alkoxy-carbonyl, (v) C.sub.3-8 cycloalkyl-carbonyl, and (vi) a
carbamoyl group optionally substituted by substituent(s) selected
from (a) optionally halogenated C.sub.1-8 alkyl, (b) C.sub.3-8
cycloalkyl, and (c) C.sub.6-18 aryl optionally substituted by
substituent(s) selected from halogen, C.sub.1-4 alkyl and C.sub.1-4
alkyloxy; R.sup.1c is (i) a hydrogen atom, (ii) a C.sub.2-4 alkenyl
group optionally substituted by hydroxy, or (iii) a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and a sulfur atom;
R.sup.2c is
[0166] (i) a C.sub.1-4 alkyl group optionally substituted by
substituent(s) selected from (a) halogen, (b) hydroxy, (c)
C.sub.1-4 alkyloxy, (d) carboxy, (e) C.sub.1-4 alkoxy-carbonyl, (f)
--O--(CH.sub.2).sub.n--OH, (g) --O--(CH.sub.2)--O--C.sub.1-4 alkyl,
(h) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, and (i)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl wherein
n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, or (ii) a C.sub.6-18 aryl-C.sub.1-4 alkyl
group optionally substituted by C.sub.1-4 alkyl optionally having
hydroxy; and R.sup.3c is a hydrogen atom or a C.sub.1-6 alkyl
group; or R.sup.2c and R.sup.3c are optionally bonded to form
C.sub.2-4 alkylene is preferable.
[0167] Moreover, as compound (Ic), a compound wherein
B.sup.c is a benzene ring optionally substituted by 1 to 4
substituents selected from halogen and C.sub.1-4 alkyl; C.sup.c is
a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom,
which is optionally substituted by 1 to 5 substituents selected
from (i) C.sub.1-4 alkyl, (ii) C.sub.1-4 alkyl-carbonyl, (iii)
optionally halogenated C.sub.1-4 alkoxy-carbonyl, (iv) C.sub.3-8
cycloalkyl-carbonyl, and (v) a carbamoyl group optionally
substituted by substituent(s) selected from (a) optionally
halogenated C.sub.1-8 alkyl, (b) C.sub.3-8 cycloalkyl, and (c)
C.sub.6-18 aryl optionally substituted by halogen; R.sup.1c is a
hydrogen atom; R.sup.2c is a C.sub.1-4 alkyl group optionally
substituted by substituent(s) selected from (a) hydroxy, (b)
C.sub.1-4 alkyloxy, (c) --O--(CH.sub.2).sub.n--OH, (d)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, and (e)
--NR.sup.8--CO(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl wherein n
is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group; and R.sup.3c is a hydrogen atom or a
C.sub.1-6 alkyl group is preferable, particularly, a compound
wherein R.sup.2c is a C.sub.1-4 alkyl group optionally substituted
by substituent(s) selected from (a) --O--(CH.sub.2).sub.n--OH, and
(b) --O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is an
integer of 1 to 4 is preferable.
[Compound (Id)]
[0168] A compound represented by the formula
##STR00036##
wherein R.sup.1d is a hydrogen atom or an optionally substituted
group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
R.sup.2d is an optionally substituted group bonded via a carbon
atom or a sulfur atom, or R.sup.1d and R.sup.2d, or R.sup.2d and
R.sup.3d are optionally bonded to form an optionally substituted
ring structure, R.sup.3d is a hydrogen atom or an optionally
substituted aliphatic hydrocarbon group, or R.sup.3d is optionally
bonded to a carbon atom of the adjacent phenyl group to form an
optionally substituted ring structure, B.sup.d is an optionally
substituted benzene ring, C.sup.d is an optionally substituted
heterocyclic group, and Z.sup.d is an optionally substituted
C.sub.1-3 alkylene group, or a salt thereof.
[0169] As the "optionally substituted group bonded via a carbon
atom, a nitrogen atom or an oxygen atom" for R.sup.1d, those
similar to the "optionally substituted group bonded via a carbon
atom, a nitrogen atom or an oxygen atom" for R.sup.1 can be
used.
[0170] As the "optionally substituted group bonded via a carbon
atom or a sulfur atom" for R.sup.2d, those similar to the
"optionally substituted group bonded via a carbon atom or a sulfur
atom" for R.sup.2 can be used.
[0171] As the "optionally substituted ring structure" formed by
R.sup.1d and R.sup.2d, or R.sup.2d and R.sup.3d bonded to each
other, those similar to the "optionally substituted ring structure"
formed by R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3 bonded to
each other can be used.
[0172] As the "optionally substituted aliphatic hydrocarbon group"
for R.sup.3d, those similar to the "optionally substituted
aliphatic hydrocarbon group" for R.sup.3 can be used.
[0173] As the "optionally substituted ring structure" formed by
R.sup.3d and a carbon atom of the adjacent phenyl group, those
similar to the "optionally substituted ring structure" formed by
R.sup.3 and a carbon atom of the adjacent phenyl group can be
used.
[0174] As the "optionally substituted benzene ring" for B.sup.d,
those similar to the "optionally substituted benzene ring" for
B.sup.a can be used.
[0175] As the "optionally substituted heterocyclic group" for
C.sup.d, those similar to the "optionally substituted heterocyclic
group" for C.sup.c can be used.
[0176] As the "optionally substituted C.sub.1-3 alkylene group" for
Z.sup.d, those similar to the "optionally substituted C.sub.1-3
alkylene group" for Z.sup.b can be used.
[0177] As R.sup.2d, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a carbamoyl group, a C.sub.1-8
alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
(a) halogen, (b) oxo, (c) optionally halogenated C.sub.1-4 alkyl,
(d) --(CH.sub.2).sub.m-Q, (e) --(CH.sub.2).sub.m-Z.sup.1-
(optionally halogenated C.sub.1-4 alkyl), (f)
--(CH.sub.2).sub.f-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.2-(optionally
halogenated C.sub.2-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z-C.sub.3-8 cycloalkyl,
(j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.5--, --C(.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH--, R.sup.6 and R.sup.7 are the same or different and
each is a hydrogen atom, or a C.sub.1-4 alkyl group, or R.sup.6 and
R.sup.7 are bonded to form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group,
R.sup.8 is a hydrogen atom or C.sub.1-4 alkyl, and R.sup.9 is
C.sub.1-4 alkyl, is preferable.
[0178] As compound (Id), a compound wherein
B.sup.d is a benzene ring optionally substituted by halogen;
C.sup.d is a 5- to 8-membered heterocyclic group having 1 to 3
hetero atoms selected from a nitrogen atom, an oxygen atom and a
sulfur atom; R.sup.1d is a hydrogen atom;
R.sup.2d is
[0179] (i) C.sub.1-4 alkyl optionally substituted by substituent(s)
selected from (a) C.sub.1-4 alkyloxy (b) --O--(CH.sub.2).sub.n--OH,
and (c) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl
wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom
or a C.sub.1-4 alkyl group, or (ii) a 5- to 8-membered
heterocycle-C.sub.1-4 alkyl group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom,
which is optionally substituted by substituent(s) selected from (a)
carboxy, and (b) C.sub.1-4 alkoxy-carbonyl; R.sup.3d is a hydrogen
atom or a C.sub.1-6 alkyl group; and Z.sup.d is a C.sub.1-3
alkylene group is preferable.
[0180] Moreover, as compound (Id), a compound wherein
B.sup.d is a benzene ring optionally substituted by halogen;
C.sup.d is a 5- to 8-membered heterocyclic group having 1 to 3
hetero atoms selected from a nitrogen atom, an oxygen atom and a
sulfur atom; R.sup.1d is a hydrogen atom, R.sup.2d is a C.sub.1-4
alkyl group optionally substituted by C.sub.1-4 alkyloxy, R.sup.3d
is a hydrogen atom or a C.sub.1-6 alkyl group; and Z.sup.d is a
methylene group is preferable.
[Compound (Ie)]
[0181] A compound represented by the formula:
##STR00037##
wherein R.sup.2e is an optionally substituted group bonded via a
carbon atom or a sulfur atom, or R.sup.2e and R.sup.3e are
optionally bonded to form an optionally substituted ring structure,
R.sup.3e is a hydrogen atom or an optionally substituted aliphatic
hydrocarbon group, or R.sup.3e is optionally bonded to a carbon
atom of the adjacent phenyl group to form an optionally substituted
ring structure, B.sup.e is an optionally substituted benzene ring,
and C.sup.e is an optionally substituted C.sub.6-18 aryl group, or
a salt thereof.
[0182] As the "optionally substituted group bonded via a carbon
atom or a sulfur atom" for R.sup.2e, those similar to the
"optionally substituted group bonded via a carbon atom or a sulfur
atom" for R.sup.2 can be used.
[0183] As the "optionally substituted ring structure" formed by
R.sup.2e and R.sup.3e bonded to each other, those similar to the
"optionally substituted ring structure" formed by R.sup.2 and
R.sup.3 bonded to each other can be used.
[0184] As the "optionally substituted aliphatic hydrocarbon group"
for R.sup.3e, those similar to the "optionally substituted
aliphatic hydrocarbon group" for R.sup.3 can be used.
[0185] As the "optionally substituted ring structure" formed by
R.sup.3e and a carbon atom of the adjacent phenyl group, those
similar to the "optionally substituted ring structure" formed by
R.sup.3 and a carbon atom of the adjacent phenyl group can be
used.
[0186] As the "optionally substituted benzene ring" for B.sup.e,
those similar to the "optionally substituted benzene ring" for
B.sup.a can be used.
[0187] As the "optionally substituted C.sub.6-18 aryl group" for
C.sup.e, those similar to the "optionally substituted C.sub.6-18
aryl group" for C.sup.a can be used.
[0188] As R.sup.2e, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a carbamoyl group, a C.sub.1-18
alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
(a) halogen, (b) oxo, (c) optionally halogenated C.sub.1-4 alkyl,
(d) --(CH.sub.2).sub.m-Q, (e) --(CH.sub.2).sub.m-Z.sup.1-
(optionally halogenated C.sub.1-4 alkyl), (f)
--(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2)-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-optionally
halogenated C.sub.1-4 alkyl, (i) --(CH.sub.2).sub.m-Z
--(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8 cycloalkyl, (j)
--(CH.sub.2).sub.m-Z.sup.1- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom), (k) (CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and (l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--,
--CO--NR.sup.8--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--,
--NR.sup.8--CO--NH--, --NR.sup.8SO.sub.2--, or
--NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally substituted by
--CH.dbd.CH--, R.sup.6 and R.sup.7 are the same or different and
each is a hydrogen atom, or a C.sub.1-4 alkyl group, or R.sup.6 and
R.sup.7 are bonded to form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group,
R.sup.8 is a hydrogen atom or C.sub.1-4 alkyl, and R.sup.9 is
C.sub.1-4 alkyl is preferable.
[0189] As compound (Ie), a compound wherein
B.sup.e is a benzene ring optionally substituted by halogen;
C.sup.e is a phenyl group optionally substituted by optionally
halogenated C.sub.1-4 alkyl; and R.sup.2e is a C.sub.1-4 alkyl
group optionally substituted by --O--(CH.sub.2).sub.n--OH wherein n
is an integer of 1 to 4 is preferable.
[0190] Moreover, as compound (Ie), a compound wherein
B.sup.e is a benzene ring optionally substituted by halogen;
C.sup.e is a phenyl group optionally substituted by optionally
halogenated C.sub.1-4 alkyl; and R.sup.2e is a C.sub.1-4 alkyl
group substituted by --O--(CH.sub.2).sub.n--OH wherein n is an
integer of 1 to 4 is preferable.
[Compound (If)]
[0191] A compound represented by the formula:
##STR00038##
wherein R.sup.2f is an optionally substituted group bonded via a
carbon atom or a sulfur atom, or R.sup.2f and R.sup.3f are
optionally bonded to form an optionally substituted ring structure,
R.sup.3f is a hydrogen atom or an optionally substituted aliphatic
hydrocarbon group, or R.sup.3f is optionally bonded to a carbon
atom of the adjacent phenyl group to form an optionally substituted
ring structure, B.sup.f is an optionally substituted benzene ring,
C.sup.f is an optionally substituted C.sub.6-18 aryl group, and
Z.sup.f is an optionally substituted C.sub.1-3 alkylene group, or a
salt thereof.
[0192] As the "optionally substituted group bonded via a carbon
atom or a sulfur atom" for R.sup.2, those similar to the
"optionally substituted group bonded via a carbon atom or a sulfur
atom" for R.sup.2 can be used.
[0193] As the "optionally substituted ring structure" formed by
R.sup.2f and R.sup.3f bonded to each other, those similar to the
"optionally substituted ring structure" formed by R.sup.2 and
R.sup.3 bonded to each other can be used.
[0194] As the "optionally substituted aliphatic hydrocarbon group"
for R.sup.3, those similar to the "optionally substituted aliphatic
hydrocarbon group" for R.sup.3 can be used.
[0195] As the "optionally substituted ring structure" formed by
R.sup.3f and a carbon atom of the adjacent phenyl group, those
similar to the "optionally substituted ring structure" formed by
R.sup.3 and a carbon atom of the adjacent phenyl group can be
used.
[0196] As the "optionally substituted benzene ring" for B.sup.f,
those similar to the "optionally substituted benzene ring" for
B.sup.a can be used.
[0197] As the "optionally substituted C.sub.6-18 aryl group" for
C.sup.f, those similar to the "optionally substituted C.sub.6-18
aryl group" for C.sup.a can be used.
[0198] As the "optionally substituted C.sub.1-3 alkylene group" for
Z.sup.f, those similar to the "optionally substituted C.sub.1-3
alkylene group" for Z.sup.b can be used.
[0199] As R.sup.2f, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a carbamoyl group, a C.sub.1-8
alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-14 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
(a) halogen, (b) oxo, (c) optionally halogenated C.sub.1-4 alkyl,
(d) --(CH.sub.2).sub.m-Q, (e) --(CH.sub.2).sub.m-Z.sup.1-
(optionally halogenated C.sub.1-4 alkyl), (f)
--(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z- optionally
halogenated C.sub.1-4 alkyl, (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.6--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O-- --CO--, --C(OH)R.sup.8--, --C((.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2-- or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally substituted by
--CH.dbd.CH--, R.sup.6 and R.sup.7 are the same or different and
each is a hydrogen atom, or a C.sub.1-4 alkyl group, or R.sup.6 and
R.sup.7 are bonded to form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group,
R.sup.8 is a hydrogen atom or C.sub.1-4 alkyl, and R.sup.9 is
C.sub.1-4 alkyl, is preferable.
[0200] As compound (If), a compound wherein
B.sup.f is a benzene ring optionally substituted by halogen;
C.sup.f is a phenyl group optionally substituted by halogen;
R.sup.2f is
[0201] (i) a C.sub.1-4 alkyl group optionally substituted by 1 to 5
substituents selected from the group consisting of (a) hydroxy, (b)
--O--(CH.sub.2).sub.n--OH, (c)
--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--(CH.sub.2).sub.n-heterocyclic group (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom), and (e)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, wherein n
is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, (ii) a C.sub.6-18 aryl group optionally
substituted by 1 to 5 substituents selected from the group
consisting of (a) C.sub.1-4 alkyl optionally substituted by
substituent(s) selected from hydroxy,
--NR.sup.8--(CH.sub.2).sub.n--OH,
--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl,
--NR.sup.8--(CH.sub.2).sub.n-heterocyclic group (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom) and
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, and (b)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.e is a hydrogen atom or a C.sub.1-4
alkyl group, or (iii) a C.sub.6-18 aryl-C.sub.1-4 alkyl group
optionally substituted by 1 to 5 substituents selected from the
group consisting of (a) carboxy, (b) C.sub.1-4 alkoxy-carbonyl, and
(c) --CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n
is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, R.sup.3f is a hydrogen atom or a C.sub.1-6
alkyl group; and Z.sup.f is a C.sub.1-3 alkylene group; or R.sup.2f
and R.sup.3f are optionally bonded to form C.sub.2-4 alkylene is
preferable.
[0202] As R.sup.e, a hydrogen atom, methyl, ethyl and the like are
preferably, and a hydrogen atom is particularly preferable.
[0203] Moreover, as compound (If), a compound wherein
B.sup.f is a benzene ring optionally substituted by halogen;
C.sup.f is a phenyl group optionally substituted by halogen;
R.sup.2f is a C.sub.1-4 alkyl group optionally substituted by 1 to
5 substituents selected from the group consisting of (a) hydroxy,
and (b) --O--(CH.sub.2).sub.n--OH wherein n is an integer of 1 to
4; R.sup.3f is a hydrogen atom or a C.sub.1-6 alkyl group; Z.sup.f
is methylene is preferable, and particularly, a compound wherein
R.sup.2f is a C.sub.1-4 alkyl group substituted by
--O--(CH.sub.2).sub.n--OH wherein n is an integer of 1 to 4 is
preferable.
[Compound (Ig)]
[0204] A compound represented by the formula:
##STR00039##
wherein R.sup.2g is an optionally substituted group bonded via a
carbon atom or a sulfur atom, or R.sup.2g and R.sup.3g are
optionally bonded to form an optionally substituted ring structure,
R.sup.3g is a hydrogen atom or an optionally substituted aliphatic
hydrocarbon group, or R.sup.3g is optionally bonded to a carbon
atom of the adjacent phenyl group to form an optionally substituted
ring structure, B.sup.g is an optionally substituted benzene ring,
and C.sup.g is an optionally substituted heterocyclic group, or a
salt thereof.
[0205] As the "optionally substituted group bonded via a carbon
atom or a sulfur atom" for R.sup.29, those similar to the
"optionally substituted group bonded via a carbon atom or a sulfur
atom" for R.sup.2 can be used.
[0206] As the "optionally substituted ring structure" formed by
R.sup.29 and R.sup.39 bonded to each other, those similar to the
"optionally substituted ring structure" formed by R.sup.2 and
R.sup.3 bonded to each other can be used.
[0207] As the "optionally substituted aliphatic hydrocarbon group"
for R.sup.3g, those similar to the "optionally substituted
aliphatic hydrocarbon group" for R.sup.3 can be used.
[0208] As the "optionally substituted ring structure" formed by
R.sup.3g and a carbon atom of the adjacent phenyl group, those
similar to the "optionally substituted ring structure" formed by
R.sup.3 and a carbon atom of the adjacent phenyl group can be
used.
[0209] As the "optionally substituted benzene ring" for B.sup.g,
those similar to the "optionally substituted benzene ring" for
B.sup.a can be used.
[0210] As the "optionally substituted heterocyclic group" for
C.sup.g, those similar to the "optionally substituted heterocyclic
group" for C.sup.c can be used.
[0211] As R.sup.2g, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.2-8 alkynyl group, a carbamoyl group, a C.sub.1-8
alkyl-carbonyl group, a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-18 aryl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl group, a C.sub.6-18 aryl-carbonyl group, a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, a C.sub.6-18
aryl-sulfonyl group, a heterocyclic group, a heterocycle-C.sub.1-4
alkyl group, a heterocycle-carbonyl group or a
heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted by 1 to 5 substituents selected from
(a) halogen, (b) oxo, (c) optionally halogenated C.sub.1-4 alkyl,
(d) --(CH.sub.2).sub.m-Q, (e) --(CH.sub.2).sub.m-Z.sup.1-
(optionally halogenated C.sub.1-4 alkyl), (f)
--(CH.sub.2).sub.m-Z.sup.1-C.sub.3-8 cycloalkyl, (g)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Q, (h)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1- (optionally
halogenated C.sub.1-4 alkyl), (i)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-C.sub.3-8
cycloalkyl, (j) --(CH.sub.2).sub.m-Z.sup.1- (optionally substituted
heterocyclic group) (preferably, said heterocyclic group is a 5- to
8-membered heterocyclic group having 1 to 3 hetero atoms selected
from a nitrogen atom, an oxygen atom and an optionally oxidized
sulfur atom), (k) --(CH.sub.2).sub.m-Z.sup.2-C.sub.1-4 alkoxy, and
(l)
--(CH.sub.2).sub.m-Z.sup.2-(CH.sub.2).sub.n-Z.sup.1-(CH.sub.2).sub.n-Z.su-
p.1-C.sub.1-4 alkyl wherein m is an integer of 0 to 4, n is an
integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro,
--NR.sup.6R.sup.7, --CONR.sup.6R.sup.7 or
--SO.sub.2NR.sup.6R.sup.7, Z.sup.1 is --O--, --CO--,
--C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--, --SO--,
--SO.sub.2--, --N(COR.sup.8)--, --N(CO.sub.2R.sup.9)--,
--N(SO.sub.2R.sup.9)--, --CO--O--, --O--CO--, --CO--NR.sup.8--,
--NR.sup.8--CO--, --NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--SO.sub.2--, or --NR.sup.8--C(.dbd.NH)--NH--, Z.sup.2 is
--O--, --CO--, --C(OH)R.sup.8--, --C(.dbd.N--OR.sup.8)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.8--, --N(COR.sup.8)--,
--N(CO.sub.2R.sup.9)--, --N(SO.sub.2R.sup.9)--, --CO--O--,
--O--CO--, --CO--NR.sup.8--, --NR.sup.8--CO--,
--NR.sup.8--CO.sub.2--, --NR.sup.8--CO--NH--,
--NR.sup.8--C(.dbd.NH)--NH--, --NR.sup.8--SO.sub.2--, or
--SO.sub.2--NR.sup.8--, (CH.sub.2).sub.m and (CH.sub.2).sub.n are
optionally substituted by 1 to 5 substituents selected from
halogen, optionally halogenated C.sub.1-4 alkyl and hydroxy, and
when m or n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2).sub.m and (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH--. R.sup.6 and R.sup.7 are the same or different and
each is a hydrogen atom, or a C.sub.1-4 alkyl group, or R.sup.6 and
R.sup.7 are bonded to form, together with a nitrogen atom, a 3- to
8-membered saturated or unsaturated aliphatic heterocyclic group,
R.sup.8 is a hydrogen atom or C.sub.1-4 alkyl, and R.sup.9 is
C.sub.1-4 alkyl, is preferable.
[0212] As compound (Ig), a compound wherein
B.sup.g is a benzene ring optionally substituted by C.sub.1-4
alkyl; C.sup.g is a 5- to 8-membered heterocyclic group having 1 to
3 hetero atoms selected from a nitrogen atom, an oxygen atom and a
sulfur atom, which is optionally substituted by C.sub.1-4 alkyl
R.sup.2g is
[0213] (i) a C.sub.1-4 alkyl group optionally substituted by
hydroxy, (ii) a C.sub.6-18 aryl group optionally substituted by
substituent(s) selected from (a) nitro, (b) amino, (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl,
(e) --NR.sup.8CO--(CH.sub.2)--NR.sup.6R.sup.7,
[0214] (f) --NR.sup.8--CO--(CH.sub.2).sub.n--COOH, (g)
--NR.sup.8CO(CH.sub.2).sub.n--CO.sub.2--C.sub.1-4 alkyl, and (h)
--NR.sup.8--CO--(CH.sub.2).sub.m--O
--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein m is an integer of
0 to 4, n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
or (iii) a C.sub.6-18 aryl-C.sub.1-4 alkyl group optionally
substituted by substituent(s) selected from (a) carboxy, (b)
C.sub.1-4 alkoxy-carbonyl, and (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group; R.sup.3g is a hydrogen atom or a C.sub.1-6 alkyl
group; or R.sup.2g and R.sup.3g are optionally bonded to form
C.sub.2-4 alkylene is preferable.
[0215] As compound (Ig), a compound wherein
R.sup.2g is
[0216] (i) a C.sub.6-18 aryl group optionally substituted by
substituent(s) selected from (a) nitro, (b) amino, (c)
--CO--NR.sup.8--(CH.sub.2)--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (e)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, (f)
--NR.sup.8--CO--(CH.sub.2).sub.n--COOH, (g)
--NR.sup.8--CO--(CH.sub.2).sub.n--CO.sub.2--C.sub.1-4 alkyl, and
(h) --NR.sup.8--CO--(CH.sub.2).sub.m--O
--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein m is an integer of
0 to 4, n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
or (ii) a C.sub.6-18 aryl-C.sub.1-4 alkyl group substituted by
substituent(s) selected from (a) carboxy, (b) C.sub.1-4
alkoxy-carbonyl, and (c) --CO--NR.sup.8--(CH.sub.2)--O--C.sub.1-4
alkyl, wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen
atom or a C.sub.1-4 alkyl group, is preferable.
[0217] As R.sup.8, a hydrogen atom, methyl, ethyl and the like are
preferable, and a hydrogen atom is particularly preferable.
[Compound (Ih)]
[0218] A compound (I) selected from the following (A) to (H).
(A) A compound (I) wherein W is CR.sup.1; A is a
phenyloxy-C.sub.6-18 aryl group wherein the phenyloxy moiety is
optionally substituted by 1 to 5 substituents selected from (i)
halogen, (ii) optionally halogenated C.sub.1-4 alkyl, (iii)
hydroxy-C.sub.1-4 alkyl, (iv) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl, triazolyl and the like), (v) optionally
halogenated C.sub.1-4 alkyloxy, (vi) C.sub.1-4 alkyl-carbonyl,
(vii) cyano, (viii) carbamoyl optionally substituted by C.sub.1-8
alkyl, and (ix) C.sub.1-4 alkoxy-carbonyl, and the C.sub.6-18 aryl
moiety is optionally further substituted by 1 to 4 substituents
selected from halogen, C.sub.1-4 alkyl, hydroxy-C.sub.1-4 alkyl,
C.sub.1-4 alkyloxy, carboxy and C.sub.1-4 alkoxy-carbonyl; X.sup.1
is --NR.sup.3'-- wherein R.sup.3' is a hydrogen atom or a C.sub.1-6
alkyl group;
R.sup.1 is
[0219] (i) a hydrogen atom, (ii) a cyano group, or (iii) a
C.sub.1-4 alkyl group or a C.sub.2-4 alkenyl group, each of which
is optionally substituted by
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7 wherein n is an
integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, R.sup.8 is
a hydrogen atom or a C.sub.1-4 alkyl group, and when n is not less
than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--; R.sup.2 is (i) a hydrogen
atom or (ii) a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group or
a C.sub.2-8 alkynyl group, each of which is optionally substituted
by substituent(s) selected from (a) hydroxy, (b) carboxy, (c)
cyano, (d) optionally halogenated C.sub.1-4 alkyloxy, (e)
--O--(CH.sub.2).sub.n--OH, (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g) --O--(CH.sub.2)--O--
(optionally halogenated C.sub.1-4 alkyl), (h)
--O--(CH.sub.2)--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (i) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (j)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2)--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (m) --O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (n) --CO--NR.sup.8
(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4
alkyl,
(q) --NR.sup.6R.sup.7,
[0220] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (v)
--NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, (x)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (z) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc)
--NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(dd) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(ii) --S-- (CH.sub.2).sub.n--OH, (jj) --SO--(CH.sub.2).sub.n--OH,
(kk) --SO.sub.2--(CH.sub.2).sub.n--OH, and (ll) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--O--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like)
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
(CH.sub.2).sub.n is optionally substituted by optionally
halogenated C.sub.1-4 alkyl or hydroxy, and when n is not less than
2, and a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--; or R.sup.1 and R.sup.2 are
optionally bonded to form
##STR00040##
[0221] R.sup.2 and R.sup.3' are optionally bonded to form C.sub.2-4
alkylene optionally substituted by an imino group, particularly
preferably, R.sup.2a is a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group or a C.sub.2-8 alkynyl group (particularly, C.sub.1-8
alkyl group), each of which is optionally substituted by
substituent(s) selected from
(a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated
C.sub.1-4 alkyloxy, (e) --O--(CH.sub.2).sub.n--OH (wherein
(CH.sub.2).sub.n is optionally substituted by hydroxy), (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (h) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (i)
--O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (j)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2)--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (m) --O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (n)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4
alkyl,
(q) --NR.sup.6R.sup.7,
[0222] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by optionally halogenated C.sub.1-4 alkyl or
hydroxy), (v) --NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7 (when n is not less
than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--), (x)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (z) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (wherein (CH.sub.2).sub.n
is optionally substituted by C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc)
--NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(dd) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl, (ii)
--S-- (CH.sub.2).sub.n--OH,
(jj) --SO--(CH.sub.2)--OH,
[0223] (kk) --SO.sub.2--(CH.sub.2).sub.n--OH, and (ll)
--NR.sup.8--CO-- (optionally substituted heterocyclic group)
(preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--O--C.sub.1-4 alkyl,
--CO--NH--C.sub.1-4 alkyl, --CONH.sub.2, --SO.sub.2--C.sub.1-4
alkyl, --SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the
like) wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are
the same or different and each is a hydrogen atom or a C.sub.1-4
alkyl group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl
group. (B) A compound (I) wherein W is CR.sup.1; A is a
phenyl-C.sub.1-3 alkyloxy-C.sub.6-18 aryl group wherein the phenyl
moiety is optionally substituted by 1 to 5 substituents selected
from halogen, optionally halogenated C.sub.1-4 alkyl and cyano, and
the C.sub.6-18 aryl moiety is optionally further substituted by 1
to 4 substituents selected from halogen, C.sub.1-4 alkyl optionally
having hydroxy and C.sub.1-4 alkyloxy; X.sup.1 is --NR.sup.3'
wherein R.sup.3' is a hydrogen atom or a C.sub.1-6 alkyl group;
R.sup.1 is (i) a hydrogen atom, or (ii) a C.sub.1-4 alkyl group or
a C.sub.2-4 alkenyl group, each of which is optionally substituted
by substituent(s) selected from (a) hydroxy, (b) amino, and
(c) --NR.sup.8--CO--(CH.sub.2)--NR.sup.6R.sup.7,
[0224] wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are
the same or different and each is a hydrogen atom or a C.sub.1-4
alkyl group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl
group, (iii) a C.sub.6-18 aryl group optionally substituted by
substituent(s) selected from (a) amino, (b) carboxy, (c)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, and (d)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group, and when n is not less than 2, a subset
--CH.sub.2--CH.sub.2 of (CH.sub.2).sub.n is optionally replaced by
--CH.dbd.CH--, or (iv) a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom; R.sup.2 is (i) a hydrogen atom, (ii) a C.sub.1-8
alkyl group optionally substituted by substituent(s) selected from
(a) halogen, (b) hydroxy, (c) C.sub.1-4 alkyloxy, (d)
--O--(CH.sub.2).sub.n--OH, (e) --O--(CH.sub.2).sub.n--O--C.sub.1-4
alkyl, (f) --CO--NR.sup.8--(CH.sub.2).sub.n--OH,
(g) --NR.sup.6R.sup.7, and
[0225] (h) --NR.sup.8--(CH.sub.2).sub.n--OH, wherein n is an
integer of 1 to 4, R.sup.6 and R.sup.7 are the same or different
and each is a hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.8
is a hydrogen atom or a C.sub.1-4 alkyl group, (iii) a C.sub.6-18
aryl-C.sub.1-4 alkyl group optionally substituted by substituent(s)
selected from (a) C.sub.1-4 alkyl optionally having hydroxy, (b)
carboxy, (c) C.sub.1-4 alkoxy-carbonyl, (d) 5- to 8-membered
heterocycle-carbonyl having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and a sulfur atom, which optionally
has substituent(s) selected from hydroxy and C.sub.1-4 alkyl, and
(e) C.sub.1-4 alkyl-carbamoyl optionally having substituent(s)
selected from hydroxy and carbamoyl, (iv) a C.sub.6-18
aryl-carbonyl group optionally substituted by C.sub.1-4 alkoxy, (v)
a C.sub.6-18 aryl-sulfonyl group optionally substituted by
C.sub.1-4 alkoxy, or (vi) a 5- to 8-membered heterocycle-C.sub.1-4
alkyl group having 1 to 3 hetero atoms selected from a nitrogen
atom, an oxygen atom and a sulfur atom, which is optionally
substituted by substituent(s) selected from (a) carboxy, and (b)
C.sub.1-4 alkoxy-carbonyl; or R.sup.2 and R.sup.3-- are optionally
bonded to form C.sub.2-4 alkylene. (C) A compound (I) wherein W is
CR.sup.1; A is a 5- to 8-membered heterocycleoxy-C.sub.6-18 aryl
group containing 1 to 3 hetero atoms selected from a nitrogen atom,
an oxygen atom and a sulfur atom, wherein the heterocycleoxy moiety
is optionally substituted by 1 to 5 substituents selected from (i)
halogen, (ii) C.sub.1-4 alkyl, (iii) C.sub.1-4 alkyl-carbonyl, (iv)
optionally halogenated C.sub.1-4 alkoxy-carbonyl, (v) C.sub.3-8
cycloalkyl-carbonyl, and (vi) a carbamoyl group optionally
substituted by substituent(s) selected from (a) optionally
halogenated C.sub.1-8 alkyl, (b) C.sub.3-8 cycloalkyl, and (c)
C.sub.6-18 aryl optionally substituted by substituent(s) selected
from halogen, C.sub.1-4 alkyl and C.sub.1-4 alkyloxy, and the
C.sub.6-18 aryl moiety is optionally further substituted by 1 to 4
substituents selected from halogen and optionally halogenated
C.sub.1-4 alkyl;
[0226] X.sup.1 is --NR.sup.3'-- wherein R.sup.3' is a hydrogen atom
or a C.sub.1-6 alkyl group;
R.sup.1 is (i) a hydrogen atom, (ii) a C.sub.1-4 alkyl group or a
C.sub.2-4 alkenyl group, each of which is optionally substituted by
substituent(s) selected from (a) hydroxy, (b) amino,
(c) --NR.sup.8--CO-- (CH.sub.2)--NR.sup.6R.sup.7, and
[0227] (d) --NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl,
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, and
when n is not less than 2, a subset --CH.sub.2CH.sub.2-- of
(CH.sub.2), is optionally replaced by --CH.dbd.CH--, (iii) a
C.sub.6-18 aryl group optionally substituted by substituent(s)
selected from (a) C.sub.1-4 alkyl optionally substituted by
substituent(s) selected from hydroxy,
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl and
--NR.sup.8--CO--(CH.sub.2)--O--C.sub.1-4 alkyl, (b) amino, (c)
C.sub.1-4 alkyloxy, (d) carboxy, and (e)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group, or (iv) a 5- to 8-membered heterocyclic group having 1
to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and
a sulfur atom; R.sup.2 is (i) a hydrogen atom, (ii) a C.sub.1-4
alkyl group optionally substituted by substituent(s) selected from
(a) halogen, (b) hydroxy, (c) C.sub.1-4 alkyloxy, (d) carboxy, (e)
C.sub.1-4 alkoxy-carbonyl,
(f) --O--(CH.sub.2)--OH,
[0228] (g) --O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl,
(h) --CO--NR.sup.8--(CH.sub.2)--OH, and
[0229] (i) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen
atom or a C.sub.1-4 alkyl group, or (iii) a C.sub.6-18
aryl-C.sub.1-4 alkyl group optionally substituted by C.sub.1-4
alkyl optionally having hydroxy; or R.sup.2 and R.sup.3' are
optionally bonded to form C.sub.2-4 alkylene. (D) A compound (I)
wherein W is CR.sup.1; A is 5- to 8-membered heterocycle-C.sub.1-3
alkyloxy-C.sub.6-18 aryl group containing 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom;
wherein the C.sub.6-18 aryl moiety is optionally further
substituted by halogen; X.sup.1 is --NR.sup.3'-- wherein R.sup.3'
is a hydrogen atom or a C.sub.1-6 alkyl group; R.sup.1 is (i) a
hydrogen atom or (ii) a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom; R.sup.2 is (i) a hydrogen atom, (ii) C.sub.1-4
alkyl optionally substituted by substituent(s) selected from (a)
C.sub.1-4 alkyloxy, (b) --O--(CH.sub.2).sub.n--OH, and (c)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
wherein n is an integer of 1 to 4, and R.sup.8 is a hydrogen atom
or a C.sub.1-4 alkyl group, or (iii) a 5- to 8-membered
heterocycle-C.sub.1-4 alkyl group having 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom,
which is optionally substituted by substituent(s) selected from (a)
carboxy, and (b) C.sub.1-4 alkoxy-carbonyl. (E) A compound (I)
wherein W is N; A is a phenyloxy-C.sub.6-18 aryl group wherein the
phenyloxy moiety is optionally substituted by 1 to 5 substituents
selected from optionally halogenated C.sub.1-4 alkyl and cyano, and
the C.sub.6-18 aryl moiety is optionally further substituted by 1
to 4 substituents selected from halogen and C.sub.1-4 alkyl;
X.sup.1 is --NR.sup.3' wherein R.sup.3' is a hydrogen atom or a
C.sub.1-6 alkyl group; R.sup.2 is (i) a hydrogen atom or (ii) a
C.sub.1-4 alkyl group optionally substituted by
--O--(CH.sub.2).sub.n--OH wherein n is an integer of 1 to 4. (F) A
compound (I) wherein W is N; A is a phenyl-C.sub.1-3
alkyloxy-C.sub.6-18 aryl group wherein the phenyl moiety is
optionally substituted by 1 to 5 substituents selected from halogen
and cyano, and the C.sub.6-18 aryl moiety is optionally further
substituted by 1 to 5 substituents selected from halogen and
C.sub.1-4 alkyl; X.sup.1 is --NR.sup.3'-- wherein R.sup.3' is a
hydrogen atom or a C.sub.1-6 alkyl group; R.sup.2 is (i) a hydrogen
atom, (ii) a C.sub.1-4 alkyl group optionally substituted by 1 to 5
substituents selected from the group consisting of (a) hydroxy, (b)
--O--(CH.sub.2).sub.n--OH, (c)
--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--(CH.sub.2).sub.n-heterocyclic group (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom), and (e)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, wherein n
is an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a
C.sub.1-4 alkyl group, (iii) a C.sub.6-18 aryl group optionally
substituted by C.sub.1-4 alkyl optionally substituted by
substituent(s) selected from hydroxy,
--NR.sup.8--(CH.sub.2).sub.n--OH,
--NR.sup.8--(CH.sub.2).sub.n-heterocyclic group (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and a sulfur atom) and --NR.sup.8--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, or (iv) a C.sub.6-18 aryl-C.sub.1-4 alkyl group optionally
substituted by 1 to 5 substituents selected from the group
consisting of (a) carboxy, (b) C.sub.1-4 alkoxy-carbonyl, and (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group; or R.sup.2 and R.sup.3 are optionally bonded to form
C.sub.2-4 alkylene. (G) A compound (I) wherein W is N; A is a 5- to
8-membered heterocycleoxy-C.sub.6-18 aryl group containing 1 to 3
hetero atoms selected from a nitrogen atom, an oxygen atom and a
sulfur atom, wherein the heterocycleoxy moiety is optionally
substituted by C.sub.1-4 alkyl, and the C.sub.6-18 aryl moiety is
optionally further substituted by C.sub.1-4 alkyl; X.sup.1 is
--NR.sup.3'-- wherein R.sup.3' is a hydrogen atom or a C.sub.1-6
alkyl group; R.sup.2 is (i) a hydrogen atom, (ii) a C.sub.1-4 alkyl
group optionally substituted by hydroxy, (iii) a C.sub.6-18 aryl
group optionally substituted by substituent(s) selected from (a)
nitro, (b) amino, (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (d)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (e)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7, (f)
--NR.sup.8--CO--(CH.sub.2).sub.n--COOH, (g)
--NR.sup.8--CO--(CH.sub.2)--CO.sub.2--C.sub.1-4 alkyl, and (h)
--NR.sup.8--CO--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--O--C.sub.1-4
alkyl, wherein m is an integer of 0 to 4, n is an integer of 1 to
4, R.sup.6 and R.sup.7 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.8 is a hydrogen
atom or a C.sub.1-4 alkyl group, or (iv) a C.sub.6-19
aryl-C.sub.1-4 alkyl group optionally substituted by substituent(s)
selected from (a) carboxy, (b) C.sub.1-4 alkoxy-carbonyl, and (c)
--CO--NR.sup.8--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, wherein n is
an integer of 1 to 4, and R.sup.8 is a hydrogen atom or a C.sub.1-4
alkyl group; and R.sup.2 and R.sup.3' are optionally bonded to form
C.sub.2-4 alkylene. (H) A compound (I) wherein W is CH; A is a
C.sub.6-18 aryl group optionally substituted by substituent(s)
selected from (a) carboxy, (b) C.sub.1-4 alkoxy-carbonyl, (c) a 5-
to 8-membered heterocycle-carbonyl group containing 1 to 3 hetero
atoms selected from a nitrogen atom, an oxygen atom and a sulfur
atom (preferably, a 5- to 8-membered cyclic amino-carbonyl group
optionally having 1 or 2 hetero atoms selected from a nitrogen
atom, an oxygen atom and a sulfur atom), which is optionally
substituted by C.sub.6-18 aryl-C.sub.1-4 alkyl, (d) a carbamoyl
group optionally substituted by C.sub.6-18 aryl-C.sub.1-4 alkyl,
and (e) a ureido group optionally substituted by C.sub.6-18
aryl-C.sub.1-4 alkyl; X.sup.1 is --NR.sup.3'-- wherein R.sup.3 is a
hydrogen atom or a C.sub.1-6 alkyl group; and R.sup.2 is a hydrogen
atom.
[Compound (Ii)]
[0230] A compound (I) wherein A is a C.sub.6-18 aryl group
substituted by substituent(s) selected from
(i) a phenyloxy group substituted by 1 to 5 substituents selected
from (a) halogen, (b) optionally halogenated C.sub.1-4 alkyl, (c)
hydroxy-C.sub.1-4 alkyl, (d) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl, triazolyl and the like), (e) optionally
halogenated C.sub.1-4 alkyloxy, (f) C.sub.1-4 alkyl-carbonyl, (g)
cyano, (h) carbamoyl optionally substituted by C.sub.1-8 alkyl, and
(i) C.sub.1-4 alkoxy-carbonyl, (ii) a phenyl-C.sub.1-3 alkyloxy
group substituted by 1 to 5 substituents selected from (a) halogen,
(b) optionally halogenated C.sub.1-4 alkyl, (c) hydroxy-C.sub.1-4
alkyl, (d) heterocycle-C.sub.1-4 alkyl (preferably, 5- to
8-membered heterocycle-C.sub.1-4 alkyl, said 5- to 8-membered
heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom,
an oxygen atom and an optionally oxidized sulfur atom, such as
imidazolyl, triazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) C.sub.1-4 alkyl-carbonyl, (g) cyano, (h)
carbamoyl optionally substituted by C.sub.1-8 alkyl, and (i)
C.sub.1-4 alkoxy-carbonyl, (iii) a 5- to 8-membered heterocycleoxy
group containing 1 to 3 hetero atoms selected from a nitrogen atom,
an oxygen atom and a sulfur atom, which is substituted by 1 to 5
substituents selected from (a) halogen, (b) optionally halogenated
C.sub.1-4 alkyl, (c) hydroxy-C.sub.1-4 alkyl, (d)
heterocycle-C.sub.1-4 alkyl (preferably, 5- to 8-membered
heterocycle-C.sub.1-4 alkyl, said 5- to 8-membered heterocycle has
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, such as imidazolyl,
triazolyl and the like), (e) optionally halogenated C.sub.1-4
alkyloxy, (f) C.sub.1-4 alkyl-carbonyl, (g) cyano, (h) carbamoyl
optionally substituted by C.sub.1-8 alkyl, and (i) C.sub.1-4
alkoxy-carbonyl, and (iv) 5- to 8-membered heterocycle-C.sub.1-3
alkyloxy containing 1 to 3 hetero atoms selected from a nitrogen
atom, an oxygen atom and a sulfur atom, which is substituted by 1
to 5 substituents selected from (a) halogen, (b) optionally
halogenated C.sub.1-4 alkyl, (c) hydroxy-C.sub.1-4 alkyl, (d)
heterocycle-C.sub.1-4 alkyl (preferably, 5- to 8-membered
heterocycle-C.sub.1-4 alkyl, said 5- to 8-membered heterocycle has
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, such as imidazolyl,
triazolyl and the like), (e) optionally halogenated C.sub.1-4
alkyloxy, (f) C.sub.1-4 alkyl-carbonyl, (g) cyano, (h) carbamoyl
optionally substituted by C.sub.1-8 alkyl, and (i) C.sub.1-4
alkoxy-carbonyl; wherein the C.sub.6-18 aryl group is optionally
further substituted by 1 to 4 substituents selected from halogen
and optionally halogenated C.sub.1-4 alkyl; R.sup.1 is a hydrogen
atom; R.sup.2 is a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group
or a C.sub.2-8 alkynyl group, each of which is substituted by
substituent(s) selected from (a) hydroxy, (b) carboxy, (c) cyano,
(d) optionally halogenated C.sub.1-4 alkyloxy, (e)
--O--(CH.sub.2).sub.n--OH, (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (h) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (i)
--O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (j)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1--
4 alkyl, (m) --O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (n)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4
alkyl,
(q) --NR.sup.6R.sup.7,
[0231] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (v)
--NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2).sub.n, --NR.sup.6R.sup.7, (x)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (z) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc)
--NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(dd) --NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(ii) --S--(CH.sub.2).sub.n--OH, (jj) --SO--(CH.sub.2).sub.n--OH,
(kk) --SO.sub.2--(CH.sub.2).sub.n--OH, and (ll) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--O--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
(CH.sub.2).sub.n is optionally substituted by optionally
halogenated C.sub.1-4 alkyl or hydroxy, and when n is not less than
2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is optionally
replaced by --CH.dbd.CH--; R.sup.3 is a hydrogen atom or a
C.sub.1-6 alkyl group; or R.sup.1 and R.sup.2 are optionally bonded
to form
##STR00041##
R.sup.2 and R.sup.3 are optionally bonded to form C.sub.2-4
alkylene optionally substituted by an imino group, particularly
preferably, R.sup.2 is a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group or a C.sub.2-8 alkynyl group (particularly, C.sub.1-8 alkyl
group), each of which is optionally substituted by substituent(s)
selected from (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally
halogenated C.sub.1-4 alkyloxy, (e) --O--(CH.sub.2).sub.n--OH
(wherein (CH.sub.2) n is optionally substituted by hydroxy), (f)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (g) --O--(CH.sub.2)--O--
(optionally halogenated C.sub.1-4 alkyl), (h)
--O--(CH.sub.2).sub.n--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (i) --O--(CH.sub.2)--SO.sub.2--C.sub.6-18 aryl, (j)
--O--(CH.sub.2)--SO.sub.2--(CH.sub.2).sub.n--OH, (k)
--O--(CH.sub.2)--NR.sup.8--CO--C.sub.1-4 alkyl, (l)
--O--(CH.sub.2).sub.n--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.1--
4 alkyl, (m) --O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (n)
--CO--NR.sup.8--(CH.sub.2).sub.n--OH, (o)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (p) --CO--NR.sup.8--O--C.sub.1-4
alkyl,
(q) --NR.sup.6R.sup.7,
[0232] (r) --NR.sup.8--(CH.sub.2).sub.n--OH, (s)
--NR.sup.8--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl, (t)
--NR.sup.8--CO-- (optionally halogenated C.sub.1-4 alkyl), (u)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by optionally halogenated C.sub.1-4 alkyl or
hydroxy), (v) --NR.sup.8--CO--(CH.sub.2).sub.n--CN, (w)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.6R.sup.7 (when n is not
less than 2, a subset --CH.sub.2CH.sub.2-- of (CH.sub.2).sub.n is
optionally replaced by --CH.dbd.CH--), (x)
--NR.sup.8CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (y)
--NR.sup.8--CO--(CH.sub.2)--SO-- (optionally halogenated C.sub.1-4
alkyl), (z) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl) (wherein (CH.sub.2) is
optionally substituted by C.sub.1-4 alkyl), (aa)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(bb)
--NR.sup.8--CO--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2--C.sub.1-4
alkyl, (cc) --NR.sup.8--CO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-14
alkyl, (dd)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(ee) --NR.sup.8--CO--NH--O--C.sub.1-4 alkyl, (ff)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (gg)
--NR.sup.8--C(.dbd.NH)--NH--C.sub.1-4 alkyl, (hh)
--NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(ii) --S-- (CH.sub.2).sub.n--OH,
(jj) --SO--(CH.sub.2)--OH,
[0233] (kk) --SO.sub.2--(CH.sub.2).sub.n--OH, and (ll)
--NR.sup.8--CO-- (optionally substituted heterocyclic group)
(preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--O--C.sub.1-4 alkyl,
--CO--NH--C.sub.1-4 alkyl, --CONH.sub.2, --SO.sub.2--C.sub.1-4
alkyl, --SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the
like), wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are
the same or different and each is a hydrogen atom or a C.sub.1-4
alkyl group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl
group.
[Compound (Ij)]
[0234] A compound (I) wherein
A is a C.sub.6-18 aryl group substituted by substituent(s) selected
from (i) a phenyloxy group substituted by 1 to 5 substituents
selected from (a) halogen, (b) optionally halogenated C.sub.1-4
alkyl, (c) hydroxy-C.sub.1-4 alkyl, (d) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted
by C.sub.1-8 alkyl, and (h) C.sub.1-4 alkoxy-carbonyl, (ii) a
phenyl-C.sub.1-3 alkyloxy group substituted by 1 to 5 substituents
selected from (a) halogen, (b) optionally halogenated C.sub.1-4
alkyl, (c) hydroxy-C.sub.1-4 alkyl, (d) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted
by C.sub.1-8 alkyl, and (h) C.sub.1-4 alkoxy-carbonyl, (iii) a 5-
to 8-membered heterocycleoxy group containing 1 to 3 hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom,
which is substituted by 1 to 5 substituents selected from (a)
halogen, (b) optionally halogenated C.sub.1-4 alkyl, (c)
hydroxy-C.sub.1-4 alkyl, (d) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl, said 5-
to 8-membered heterocycle has 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, such as imidazolyl and the like), (e) optionally halogenated
C.sub.1-4 alkyloxy, (f) cyano, (g) carbamoyl optionally substituted
by C.sub.1-8 alkyl, and (h) C.sub.1-4 alkoxy-carbonyl, and (iv) 5-
to 8-membered heterocycle-C.sub.1-3 alkyloxy containing 1 to 3
hetero atoms selected from a nitrogen atom, an oxygen atom and a
sulfur atom, which is substituted by 1 to 5 substituents selected
from (a) halogen, (b) optionally halogenated C.sub.1-4 alkyl, (c)
hydroxy-C.sub.1-4 alkyl, (d) heterocycle-C.sub.1-4 alkyl
(preferably, 5- to 8-membered heterocycle-C.sub.1-4 alkyl having 1
to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and
an optionally oxidized sulfur atom, such as imidazolyl and the
like), (e) optionally halogenated C.sub.1-4 alkyloxy, (f) cyano,
(g) carbamoyl optionally substituted by C.sub.1-8 alkyl, and (h)
C.sub.1-4 alkoxy-carbonyl; wherein the C.sub.6-18 aryl group is
optionally further substituted by 1 to 4 substituents selected from
halogen and optionally halogenated C.sub.1-4 alkyl; R.sup.1 is a
hydrogen atom; R.sup.2 is a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group or a C.sub.2-8 alkynyl group, each of which is
substituted by substituent(s) selected from (a) hydroxy, (b)
optionally halogenated C.sub.1-4 alkyloxy,
(c) --O--(CH.sub.2)--OH,
[0235] (d) --O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (e)
--O--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (f)
--O--(CH.sub.2)--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (g) --O--(CH.sub.2)--SO.sub.2--C.sub.6-18 aryl, (h)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (i)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (j) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (k)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl),
(l) --NR.sup.6R.sup.7,
[0236] (m) --NR.sup.8--(CH.sub.2).sub.n--OH, (n)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (p)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (q)
--NR.sup.8--CO--(CH.sub.2)--SO-- (optionally halogenated C.sub.1-4
alkyl), (r) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (s)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(t) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (u)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(v) --NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (w) --S-- (CH.sub.2).sub.n--OH, (x)
--SO--(CH.sub.2).sub.n--OH, (y) --SO.sub.2--(CH.sub.2).sub.n--OH,
and (z) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, and
(CH.sub.2).sub.n is optionally substituted by C.sub.1-4 alkyl or
hydroxy; R.sup.3 is a hydrogen atom or a C.sub.1-6 alkyl group; or
R.sup.1 and R.sup.2 are optionally bonded to form
##STR00042##
R.sup.2 and R.sup.3 are optionally bonded to form C.sub.2-4
alkylene.
[0237] Particularly preferably, R.sup.2 is a C.sub.1-8 alkyl group,
a C.sub.2-8 alkenyl group or a C.sub.2-8 alkynyl group
(particularly, a C.sub.1-8 alkyl group), each of which is
substituted by substituent(s) selected from
(a) hydroxy, (b) optionally halogenated C.sub.1-4 alkyloxy, (c)
--O--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is optionally
substituted by hydroxy),
(d) --O--(CH.sub.2)--O--CO--NH.sub.2,
[0238] (e) --O--(CH.sub.2)--O--C.sub.1-4 alkyl, (f)
--O--(CH.sub.2)--SO.sub.2-- (optionally halogenated C.sub.1-4
alkyl), (g) --O--(CH.sub.2).sub.n--SO.sub.2--C.sub.618 aryl, (h)
--O--(CH.sub.2).sub.n--SO.sub.2--(CH.sub.2).sub.n--OH, (i)
--O--(CH.sub.2)--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (j) --CO--NR.sup.8-- (CH.sub.2).sub.n--OH, (k)
--CO--NR.sup.8--(CH.sub.2)--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl),
(l) --NR.sup.6R.sup.7,
[0239] (m) --NR.sup.8--(CH.sub.2).sub.n--OH, (n)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by C.sub.1-4 alkyl), (p)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (q)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (r) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl) (wherein (CH.sub.2), is
optionally substituted by C.sub.1-4 alkyl), (s)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(t) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (u) --NR.sup.8--CO--NH--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (v) --NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4
alkyl, (w) --S--(CH.sub.2).sub.n--OH, (x)
--SO--(CH.sub.2).sub.n--OH, (y) --SO.sub.2--(CH.sub.2).sub.n--OH,
and (z) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, R.sup.6 and R.sup.7 are the same
or different and each is a hydrogen atom or a C.sub.1-4 alkyl
group, and R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group,
and the like is preferable.
[Compound (Ik)]
[0240] A compound (I) wherein
R.sup.2 is (i) a C.sub.5-8 alkyl group substituted by hydroxy, (ii)
a C.sub.1-8 alkyl group substituted by substituent(s) selected from
(a) halogenated C.sub.1-4 alkyloxy, (b) --O--(CH.sub.2).sub.n--OH,
(c) --O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (d)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (e) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (f)
--O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (g)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (h) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (i)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (j)
--NR.sup.8--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl, (k)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH, (l)
--NR.sup.8--CO--(CH.sub.2).sub.n--O--C.sub.1-4 alkyl, (m)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (n) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl), (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(p) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (q)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(r) --NR.sup.8--SO.sub.2--(CH.sub.2)--SO.sub.2--C.sub.1-4 alkyl,
(s) --S-- (CH.sub.2).sub.n--OH, (t) --SO--(CH.sub.2).sub.n--OH, (u)
--SO.sub.2--(CH.sub.2).sub.n--OH, and (v) --NR.sup.8--CO--
(optionally substituted heterocyclic group) (preferably, said
heterocyclic group is a 5- to 8-membered heterocyclic group having
1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom
and an optionally oxidized sulfur atom, which is optionally
substituted by substituent(s) selected from hydroxy, C.sub.1-4
alkyl, optionally oxidized C.sub.1-4 alkylthio, --CO--C.sub.1-4
alkyl, --CO--NH--C.sub.1-4 alkyl, --CONH.sub.2,
--SO.sub.2--C.sub.1-4 alkyl, --SO.sub.2--NH--C.sub.1-4 alkyl,
--SO.sub.2NH.sub.2 and the like), wherein n is an integer of 1 to
4, R.sup.8 is a hydrogen atom or a C.sub.1-4 alkyl group, and
(CH.sub.2).sub.n is optionally substituted by C.sub.1-4 alkyl,
(iii) a C.sub.2-8 alkenyl group optionally substituted by hydroxy,
or (iv) a C.sub.2-8 alkynyl group optionally substituted by
hydroxy.
[0241] Particularly preferably, R.sup.2 is (i) a C.sub.5-8 alkyl
group substituted by hydroxy,
(ii) a C.sub.1-8 alkyl group substituted by substituent(s) selected
from (a) halogenated C.sub.1-4 alkyloxy, (b)
--O--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is optionally
substituted by hydroxy), (c)
--O--(CH.sub.2).sub.n--O--CO--NH.sub.2, (d)
--O--(CH.sub.2).sub.n--O-- (optionally halogenated C.sub.1-4
alkyl), (e) --O--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (f)
--O--(CH.sub.2).sub.n--SO.sub.2--C.sub.6-18 aryl, (g)
--O--(CH.sub.2).sub.n--NR.sup.8--SO.sub.2-- (optionally halogenated
C.sub.1-4 alkyl), (h) --CO--NR.sup.8--(CH.sub.2).sub.n--OH, (i)
--CO--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2-- (optionally
halogenated C.sub.1-4 alkyl), (j)
--NR.sup.8--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl, (k)
--NR.sup.8--CO--(CH.sub.2).sub.n--OH (wherein (CH.sub.2).sub.n is
optionally substituted by C.sub.1-4 alkyl), (l)
--NR.sup.8--CO--(CH.sub.2)--O--C.sub.1-4 alkyl, (m)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO-- (optionally halogenated
C.sub.1-4 alkyl), (n) --NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--
(optionally halogenated C.sub.1-4 alkyl) (wherein (CH.sub.2).sub.n
is optionally substituted by C.sub.1-4 alkyl), (o)
--NR.sup.8--CO--(CH.sub.2).sub.n--SO.sub.2--C.sub.3-8 cycloalkyl,
(p) --NR.sup.8--CO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (q)
--NR.sup.8--CO--NH--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4 alkyl,
(r) --NR.sup.8--SO.sub.2--(CH.sub.2).sub.n--SO.sub.2--C.sub.1-4
alkyl, (s) --S-- (CH.sub.2).sub.n--OH, (t)
--SO--(CH.sub.2).sub.n--OH, (u) --SO.sub.2--(CH.sub.2).sub.n--OH A
and (v) --NR.sup.8--CO-- (optionally substituted heterocyclic
group) (preferably, said heterocyclic group is a 5- to 8-membered
heterocyclic group having 1 to 3 hetero atoms selected from a
nitrogen atom, an oxygen atom and an optionally oxidized sulfur
atom, which is optionally substituted by substituent(s) selected
from hydroxy, C.sub.1-4 alkyl, optionally oxidized C.sub.1-4
alkylthio, --CO--C.sub.1-4 alkyl, --CO--NH--C.sub.1-4 alkyl,
--CONH.sub.2, --SO.sub.2--C.sub.1-4 alkyl,
--SO.sub.2--NH--C.sub.1-4 alkyl, --SO.sub.2NH.sub.2 and the like),
wherein n is an integer of 1 to 4, and R.sup.6 is a hydrogen atom
or a C.sub.1-4 alkyl group, (iii) a C.sub.2-8 alkenyl group
optionally substituted by hydroxy, or (iv) a C.sub.2-8 alkynyl
group optionally substituted by hydroxy.
[0242] As the salts of the compound represented by the formula (I),
for example, metal salt, ammonium salt, salts with organic base,
salts with inorganic acid, salts with organic acid, salts with
basic or acidic amino acid and the like can be mentioned. As
preferable examples of the metal salt, for example, alkali metal
salts such as sodium salt, potassium salt and the like; alkaline
earth metal salts such as calcium salt, magnesium salt, barium salt
and the like; aluminum salt and the like can be mentioned. As
preferable examples of the salts with organic base, for example,
salts with trimethylamine, triethylamine, pyridine, picoline,
2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,
tromethamine [tris(hydroxymethyl)methylamine], t-butylamine,
cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine
and the like can be mentioned. As preferable examples of salts with
inorganic acid, for example, salts with hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and
the like can be mentioned. As preferable examples of the salts with
organic acid, for example, salts with formic acid, acetic acid,
trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid,
tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
and the like can be mentioned. As preferable examples of the salts
with basic amino acid, for example, salts with arginine, lysine,
ornithine and the like can be mentioned, and as preferable examples
of the salts with acidic amino acid, for example, salts with
aspartic acid, glutamic acid and the like can be mentioned.
[0243] Of these, pharmaceutically acceptable salts are preferable.
For example, when a compound contains an acidic functional group,
inorganic salts such as alkali metal salts (e.g., sodium salt,
potassium salt etc.), alkaline earth metal salts (e.g., calcium
salt, magnesium salt, barium salt etc.) and the like, ammonium salt
and the like, and when a compound contains a basic functional
group, for example, salts with inorganic acid such as hydrochloric
acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid
and the like, or salts with organic acid such as acetic acid,
phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic
acid, citric acid, succinic acid, methanesulfonic acid,
p-toluenesulfonic acid and the like can be mentioned.
[0244] As compound (I), preferred is a compound wherein A is an
aryl group substituted by a group of the formula --Y.sup.2--B and
optionally further substituted, wherein Y.sup.2 is a single bond,
--O--, --OCH.sub.2--, --NH-- or --S--, and B is an aryl group, a
heterocyclic group, a C.sub.3-8 cycloalkyl group, a carbamoyl
group, a ureido group, a C.sub.6-18 aryl-carbonyl group or a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted.
[0245] As a preferable embodiment of compound (I), a compound
wherein W is C(R.sup.1);
A is an aryl group substituted by a group of the formula
--Y.sup.2--B, and optionally further substituted, wherein Y.sup.2
is a single bond, --O--, --OCH.sub.2--, --NH-- or --S--, and B is
an aryl group, a heterocyclic group, a C.sub.3-8 cycloalkyl group,
a carbamoyl group, a ureido group, a C.sub.6-18 aryl-carbonyl group
or a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, each of which
is optionally substituted; R.sup.1 is a group of the formula
--X.sup.2--R.sup.4 wherein X.sup.2 is a single bond, --NH-- or
--O--, and R.sup.4 is hydrogen atom or a C.sub.1-8 alkyl group, a
C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a carbamoyl
group, a C.sub.1-8 alkyl-carbonyl group, a C.sub.3-8 cycloalkyl
group, a C.sub.6-18 aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl
group, a C.sub.6-18 aryl-carbonyl group, a C.sub.6-18
aryl-C.sub.1-4 alkyl-carbonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted; R.sup.2 is hydrogen atom or a C.sub.1-8
alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group,
a carbamoyl group, a C.sub.1-18 alkyl-carbonyl group, a C.sub.1-8
alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-18
aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a C.sub.6-18
aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl
group, a C.sub.6-18 aryl-sulfonyl group, a heterocyclic group, a
heterocycle-C.sub.1-4 alkyl group, a heterocycle-carbonyl group or
a heterocycle-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted; and X.sup.1 is --NR.sup.3-- wherein R.sup.3
is a hydrogen atom or an optionally substituted aliphatic
hydrocarbon group can be mentioned.
[0246] As another preferable embodiment of compound (I), a compound
wherein W is N;
X.sup.1 is --NR.sup.3-- wherein R.sup.3 is a hydrogen atom or an
optionally substituted aliphatic hydrocarbon group; A is an aryl
group substituted by a group of the formula --Y.sup.2--B and
optionally further substituted wherein Y.sup.2 is a single bond,
--O--, --OCH.sub.2--, --NH-- or --S--, and B is an aryl group, a
heterocyclic group, a C.sub.3-8 cycloalkyl group, a carbamoyl
group, a ureido group, a C.sub.6-18 aryl-carbonyl group or a
C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, each of which is
optionally substituted; and R.sup.2 is a hydrogen atom or a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a carbamoyl group, a C.sub.1-8 alkyl-carbonyl group,
a C.sub.1-8 alkylsulfonyl group, a C.sub.3-8 cycloalkyl group, a
C.sub.6-18 aryl group, a C.sub.6-18 aryl-C.sub.1-4 alkyl group, a
C.sub.6-18 aryl-carbonyl group, a C.sub.6-18 aryl-C.sub.1-4
alkyl-carbonyl group, a C.sub.6-18 aryl-sulfonyl group, a
heterocyclic group, a heterocycle-C.sub.1-4 alkyl group, a
heterocycle-carbonyl group or a heterocycle-C.sub.1-4
alkyl-carbonyl group, each of which is optionally substituted can
be mentioned.
[0247] As a yet another preferable embodiment of compound (I), a
compound wherein W is N;
X.sup.1 is --NR.sup.3--;
[0248] A is an aryl group substituted by a group of the formula
--Y.sup.2--B and optionally further substituted wherein Y.sup.2 is
a single bond, --O--, --OCH.sub.2--, --NH-- or --S--, and B is an
aryl group, a heterocyclic group, a C.sub.3-8 cycloalkyl group, a
carbamoyl group, a ureido group, a C.sub.6-18 aryl-carbonyl group
or a C.sub.6-18 aryl-C.sub.1-4 alkyl-carbonyl group, each of which
is optionally substituted; and R.sup.2 and R.sup.3 are bonded to
form an optionally substituted ring structure can be mentioned.
[Production Methods]
[0249] The production methods of compound (I) of the present
invention are described in the following.
[0250] The compound (I) of the present invention the present
invention can be obtained by, for example, the method shown by in
the following schemes or a method analogous thereto and the
like.
##STR00043##
[0251] The compounds (II)-(VIII) in the schemes include salts, and
as such salts, for example, those similar to the salts of compound
(I) and the like can be used.
[0252] The compound obtained in each step can be used as a reaction
mixture or as a crude product in the next reaction. In addition,
the compound can be isolated from a reaction mixture according to a
conventional method, and can be easily purified by a separation
means such as recrystallization, distillation, chromatography and
the like.
[0253] A schematic reaction formulas are shown in the following,
wherein each symbol of the compounds is as defined above.
[0254] The compound (I) of the present invention can be produced
by, for example, reacting a compound represented by the
formula:
##STR00044##
wherein L is a leaving group and other symbols are as defined
above, or a salt thereof with a compound represented by the
formula:
G-X.sup.1-A (III)
wherein G is a hydrogen atom or a metal atom, and other symbols are
as defined above, or a salt thereof.
[0255] When X.sup.1 is --NR.sup.3--Y.sup.1--, --O-- or --S--, G is
mainly a hydrogen atom, but may be an alkali metal such as lithium,
sodium, potassium, cesium and the like, or an alkaline earth metal
such as magnesium, calcium and the like. When X.sup.1 is
--CHR.sup.3--, G is preferably a metal such as lithium, halogenated
magnesium, copper, zinc and the like.
[0256] The compound (III) or a salt thereof is preferably used in
an amount of 1-5 equivalents, preferably 1-2 equivalents, relative
to compound (II) and the reaction is preferably carried out in a
solvent. In addition, a base or an ammonium salt may be used in an
amount of about 1-10 equivalents, preferably 1-2 equivalents.
[0257] In the aforementioned formula, as a leaving group
represented by L, a halogen atom such as chlorine, bromine, iodine
and the like, a group of the formula: --S(O).sub.kR.sup.a wherein k
is 0, 1 or 2, and R.sup.a is a lower (C.sub.1-4)alkyl group such as
methyl, ethyl, propyl and the like, benzyl group, a C.sub.6-10 aryl
group such as, phenyl, tolyl and the like, or a group of the
formula: --OR.sup.a wherein R.sup.a is as defined above, and the
like can be used.
[0258] As a solvent in the aforementioned reaction, for example,
halogenated hydrocarbons such as dichloromethane, chloroform,
carbon tetrachloride, 1,2-dichloroethane and the like, aromatic
hydrocarbons such as benzene, toluene, xylene and the like,
alcohols such as methanol, ethanol, isopropanol, t-butanol, phenol
and the like, ethers such as diethyl ether, tetrahydrofuran,
dioxane and the like, acetone, acetonitrile, ethyl acetate,
N,N-dimethylformamide, N,N-dimethylacetamide,
1-methyl-2-pyrrolidone, dimethyl sulfoxide,
hexamethylphosphoramide, water or a mixed solvent thereof and the
like can be used.
[0259] As a base in the aforementioned reaction, an inorganic base,
an organic base and the like can be used. Specifically, for
example, sodium hydroxide, potassium hydroxide, sodium carbonate,
potassium carbonate, sodium hydrogen carbonate, potassium hydrogen
carbonate, triethylamine, N-ethyldiisopropylamine, pyridine,
N,N-dimethylaminopyridine, sodium methoxide, sodium ethoxide,
potassium t-butoxide, sodium hydride, sodium amide,
diazabicycloundecene (DBU) and the like can be used.
[0260] As an ammonium salt in the aforementioned reaction, pyridine
hydrochloride, pyridine hydrobromide, pyridine p-toluenesulfonate,
quinoline hydrochloride, isoquinoline hydrochloride, pyrimidine
hydrochloride, pyrazine hydrochloride, triazine hydrochloride,
trimethylamine hydrochloride, triethylamine hydrochloride,
N-ethyldiisopropylamine hydrochloride and the like can be used.
[0261] The aforementioned reaction can be carried under cooling, at
room temperature or under heating (about 40-200.degree. C.,
preferably about 40-160.degree. C.), the reaction time is generally
about 1-30 hr, preferably about 1-20 hr, more preferably about 1-10
hr.
[0262] A compound (I) wherein X.sup.1 is --SO-- or --SO.sub.2-- can
be produced by subjecting a compound (I) wherein X.sup.1 is --S--
to an oxidation reaction. As an oxidizing agent therefor, for
example, m-chloroperbenzoic acid, hydrogen peroxide, peracetic
acid, t-butyl hydroperoxide, potassium peroxysulfate, potassium
permanganate, sodium perborate, sodium periodate, sodium
hypochlorite, halogen and the like can be used. When a compound (I)
wherein X.sup.1 is --SO-- is produced, an oxidizing agent is used
in an amount of about 1-1.5 equivalents relative to a starting
compound, and when a compound (I) wherein X.sup.1 is --SO.sub.2--
is produced, it is used in an amount of about 2-3 equivalents
relative to a starting compound. The reaction solvent is not
particularly limited as long as it does not react with the
oxidizing agent and, for example, halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane and the like, aromatic hydrocarbons such as
benzene, toluene, xylene and the like, alcohols such as methanol,
ethanol, isopropanol, t-butanol and the like, ethers such as
diethyl ether, tetrahydrofuran, dioxane and the like, carboxylic
acids such as acetic acid, trifluoroacetic acid and the like,
acetonitrile, ethyl acetate, N,N-dimethylformamide,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide,
water or a mixed solvent thereof and the like can be used. The
reaction is carried out under cooling, at room temperature or under
heating, and the reaction time is generally about 1-20 hr,
preferably about 1-10 hr.
[0263] A compound within the scope of the present invention can be
also produced by applying means known per se to the obtained
compound of the present invention (I) for introduction of
substituents and conversion of functional groups. For conversion of
substituents, a known conventional method can be used. For example,
conversion to carboxy group by hydrolysis of ester, conversion to
carbamoyl group by amidation of carboxy group, conversion to
hydroxymethyl group by reduction of carboxy group, conversion to
alcohol compound by reduction or alkylation of carbonyl group,
reductive amination of carbonyl group, oximation of carbonyl group,
acylation of amino group, alkylation of amino group, substitution
and amination of active halogen by amine, alkylation of hydroxy
group, substitution and amination of hydroxy group and the like can
be mentioned. When a reactive substituent that causes non-object
reaction is present during the introduction of substituents and
conversion of functional groups, a protecting group is introduced
in advance as necessary into the reactive substituent by a means
known per se, and the protecting group is removed by a means known
per se after the object reaction, whereby the compound within the
scope of the present invention can be also produced.
[0264] The compound (I), which is a product of the reaction, may be
produced as a single compound or as a mixture.
[0265] The compound (I) of the present invention thus obtained can
be subjected to a means known per se, such as solvent extraction,
concentration, neutralization, filtration, crystallization,
recrystallization, column chromatography, high performance liquid
chromatography and the like, whereby the object compound can be
isolated and purified at high purity from a reaction mixture.
[0266] As the starting compound (III) of this production method, a
commercially available one is used or can be produced by a means
known per se.
[0267] The starting compound (II) of this production method can be
produced by, for example, a method shown by the following scheme.
Here, compounds (IIa), (IIb), (IIc), (IId) and (IIe) are
encompassed in compound (II).
##STR00045##
wherein L.sup.1 and L.sup.2 are halogen atoms, R.sup.a is as
defined above and t is 1 or 2.
[0268] As Method A, compound (IIa) can be produced by reacting
compound (IV) with a halogenating agent. As Method B, compound (IV)
is reacted with an thionating agent to give compound (V), which is
then reacted with a compound represented by R.sup.aL.sup.2 in the
presence of a base to give compound (IIb), which is further
subjected to an oxidation reaction to give compound (IIc). As
Method C, compound (IIa) is reacted with a compound represented by
R.sup.aOH in the presence of a base to give compound (IId).
[0269] As the halogenating agent in Method A, for example, about
1-100 equivalents of phosphorus oxychloride, phosphorus
pentachloride, phosphorus trichloride, thionyl chloride, sulfuryl
chloride, phosphorus tribromide and the like can be used. In this
case, the reaction may be carried out in the presence of a base
such as diethylaniline, dimethylaniline, pyridine and the like.
While the reaction may be carried out without solvent, as a
reaction solvent, for example, halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane and the like, aromatic hydrocarbons such as
benzene, toluene, xylene and the like, ethers such as diethyl
ether, tetrahydrofuran, dioxane and the like, acetonitrile, ethyl
acetate and the like may be used. The reaction is carried out under
cooling, at room temperature or under heating, and the reaction
time is generally about 1-20 hr, preferably about 1-10 hr.
[0270] As the thionating agent used in the production step from
compound (IV) to compound (V) in Method B, for example, about 1-5
equivalents of a Lawesson reagent, phosphorus pentasulfide and the
like can be used. As the reaction solvent, for example, halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane and the like, aromatic
hydrocarbons such as benzene, toluene, xylene and the like, ethers
such as diethyl ether, tetrahydrofuran, dioxane and the like, and
the like can be used. The reaction is carried out at room
temperature or under heating, and the reaction time is generally
about 1-20 hr, preferably about 1-10 hr.
[0271] As R.sup.aL.sup.2 in the production step from compound (V)
to compound (IIb) in Method B, for example, about 1-5 equivalents
of methyl iodide, benzyl chloride, benzyl bromide and the like can
be used, and as the base, for example, sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen
carbonate, potassium hydrogen carbonate, triethylamine,
N-ethyldiisopropylamine, pyridine, N,N-dimethylaminopyridine,
sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium
hydride, sodium amide, diazabicycloundecene (DBU) and the like can
be used. As the reaction solvent, for example, halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane and the like, aromatic
hydrocarbons such as benzene, toluene, xylene and the like,
alcohols such as methanol, ethanol, isopropanol, t-butanol and the
like, ethers such as diethyl ether, tetrahydrofuran, dioxane and
the like, acetone, acetonitrile, ethyl acetate,
N,N-dimethylformamide, N,N-dimethylacetamide,
1-methyl-2-pyrrolidone, dimethyl sulfoxide,
hexamethylphosphoramide, water or a mixed solvent thereof and the
like can be used. The reaction is carried out under cooling, at
room temperature or under heating, and the reaction time is
generally about 1-20 hr, preferably about 1-10 hr.
[0272] As the oxidizing agent in the production step from compound
(IIb) to compound (IIc) in Method B, for example,
m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, t-butyl
hydroperoxide, potassium peroxysulfate, potassium permanganate,
sodium perborate, sodium periodate, sodium hypochlorite, halogen
and the like can be used. When compound (IIc) wherein t=1 is
produced, an oxidizing agent is used in about 1-1.5 equivalents
relative to compound (IIb), and when compound (IIc) wherein t=2 is
produced, it is used in about 2-3 equivalents relative to compound
(IIb). The reaction solvent is not particularly limited as long as
it does not react with the oxidizing agent and, for example,
halogenated hydrocarbons such as dichloromethane, chloroform,
carbon tetrachloride, 1,2-dichloroethane and the like, aromatic
hydrocarbons such as benzene, toluene, xylene and the like,
alcohols such as methanol, ethanol, isopropanol, t-butanol and the
like, ethers such as diethyl ether, tetrahydrofuran, dioxane and
the like, carboxylic acids such as acetic acid, trifluoroacetic
acid and the like, acetonitrile, ethyl acetate,
N,N-dimethylformamide, N,N-dimethylacetamide,
1-methyl-2-pyrrolidone, dimethyl sulfoxide, water or a mixed
solvent thereof and the like can be used. The reaction is carried
out under cooling, at room temperature or under heating, and the
reaction time is generally about 1-20 hr, preferably about 1-10
hr.
[0273] As R.sup.aOH in the production step from compound (IIa) to
compound (IId) in Method C, for example, about 1-10 equivalents of
methanol, ethanol, phenol and the like can be used, and as a base,
for example, sodium hydroxide, potassium hydroxide, sodium
carbonate, potassium carbonate, sodium hydrogen carbonate,
potassium hydrogen carbonate, triethylamine,
N-ethyldiisopropylamine, pyridine, N,N-dimethylaminopyridine,
sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium
hydride, sodium amide, diazabicycloundecene (DBU) and the like can
be used. As a reaction solvent, for example, halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane and the like, aromatic
hydrocarbons such as benzene, toluene, xylene and the like, ethers
such as diethyl ether, tetrahydrofuran, dioxane and the like,
acetone, acetonitrile, ethyl acetate, N,N-dimethylformamide,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide,
hexamethylphosphoramide, water or a mixed solvent thereof and the
like can be used. The reaction is carried out under cooling, at
room temperature or under heating, and the reaction time is
generally about 1-20 hr, preferably about 1-10 hr.
[0274] Furthermore, compound (IV) can be produced by, for example,
a method shown by the following formula:
##STR00046##
wherein R.sup.10 is a C.sub.1-4 alkyl group, and other symbols are
as defined above.
[0275] That is, compound (VI) is reacted in the presence of about
1-4 equivalents of formamidine or a salt thereof, whereby compound
(IV) can be produced. As the reaction solvent, for example,
alcohols such as methanol, ethanol, isopropanol, t-butanol and the
like, halogenated hydrocarbons such as dichloromethane, chloroform,
carbon tetrachloride, 1,2-dichloroethane and the like, aromatic
hydrocarbons such as benzene, toluene, xylene and the like, ethers
such as diethyl ether, tetrahydrofuran, dioxane and the like,
acetone, acetonitrile, ethyl acetate, N,N-dimethylformamide,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide,
hexamethylphosphoramide, water or a mixed solvent thereof and the
like can be used. The reaction is carried out under cooling, at
room temperature or under heating, and the reaction time is
generally about 1-20 hr, preferably about 1-10 hr.
[0276] When W is C(R.sup.1), compound (II) can be also produced by,
for example, a method shown by the following formula:
##STR00047##
wherein L.sup.3 is a halogen atom, and other symbols are as defined
above.
[0277] For a step in this method to produce compound (VIII) from
compound (VII), a reaction generally known as a Sonogashira
reaction or a reaction analogous thereto can be used and generally,
compound (VIII) can be produced by reacting compound (VII) with
about 1-3 equivalents of a compound represented by the formula
##STR00048##
in the presence of a base, about 0.01-1 equivalent of a palladium
catalyst and copper iodide. As the base, for example,
triethylamine, N-ethyldiisopropylamine, diisopropylamine, pyridine,
N,N-dimethylaminopyridine, diazabicycloundecene (DBU), sodium
carbonate, potassium carbonate, sodium hydrogen carbonate,
potassium hydrogen carbonate and the like can be used. As the
palladium catalyst, for example,
dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,
palladium(II) diacetate, bis(benzonitrile)dichloropalladium(II) and
the like can be used. This reaction may be carried out in the
co-presence of a tertiary phosphine compound such as
triphenylphosphine, tributylphosphine and the like as a ligand. As
the reaction solvent, for example, halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane and the like, aromatic hydrocarbons such as
benzene, toluene, xylene and the like, alcohols such as methanol,
ethanol, isopropanol, t-butanol and the like, ethers such as
diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and
the like, acetone, acetonitrile, ethyl acetate,
N,N-dimethylformamide, N,N-dimethylacetamide,
1-methyl-2-pyrrolidone, dimethyl sulfoxide,
hexamethylphosphoramide, water or a mixed solvent thereof and the
like can be used. This reaction is carried out at room temperature
or under heating and the reaction time is generally about 1-50 hr,
preferably about 1-20 hr.
[0278] For a step in this method to produce compound (IIe) from
compound (VIII), generally, cyclization reaction is conducted in
the presence of about 1-3 equivalents of base or about 0.01-1
equivalent of copper iodide to give compound (IIe). As the base,
for example, potassium t-butoxide, sodium t-butoxide, cesium
t-butoxide, sodium ethoxide, potassium hydride, sodium hydride,
cesium hydroxide, sodium hydroxide, potassium hydroxide, sodium
carbonate, potassium carbonate, sodium hydrogen carbonate,
potassium hydrogen carbonate, triethylamine,
N-ethyldiisopropylamine, diisopropylamine, pyridine,
N,N-dimethylaminopyridine, diazabicycloundecene (DBU) and the like
can be used. As the reaction solvent, for example, halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane and the like, aromatic
hydrocarbons such as benzene, toluene, xylene and the like,
alcohols such as methanol, ethanol, isopropanol, t-butanol and the
like, ethers such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane and the like, acetone, acetonitrile, ethyl
acetate, N,N-dimethylformamide, N,N-dimethylacetamide,
1-methyl-2-pyrrolidone, dimethyl sulfoxide,
hexamethylphosphoramide, water or a mixed solvent thereof and the
like can be used. The reaction is carried out at low temperature,
at room temperature or under heating and the reaction time is
generally about 1-50 hr, preferably about 1-20 hr.
[0279] Depending on the kind of the substituent of starting
compound (II), a starting compound (II) having a different
substituent can be produced by substituent conversion from, as a
starting material, a compound produced by the above-mentioned
production method. For the substituent conversion, a known general
method can be used. For example, conversion to carbamoyl group by
hydrolysis and amidation of ester, conversion to hydroxymethyl
group by reduction of carboxy group, conversion to alcohol compound
by reduction or alkylation of carbonyl group, reductive amination
of carbonyl group, oximation of carbonyl group, acylation of amino
group, alkylation of amino group, substitution and amination of
active halogen by amine, alkylation of hydroxy group, substitution
and amination of hydroxy group and the like can be mentioned. When
a reactive substituent that causes non-object reaction is present
during the introduction of substituents and conversion of
functional groups, a protecting group is introduced in advance as
necessary into the reactive substituent by a means known per se,
and the protecting group is removed by a means known per se after
the object reaction, whereby the starting compound (II) can be also
produced.
[0280] Thus-obtained compound (I) can be isolated and purified by a
separation means known per se, such as concentration, concentration
under reduced pressure, solvent extraction, crystallization,
recrystallization, phase transfer, chromatography and the like.
[0281] If compound (I) is obtained as a free form, it can be
converted into a desired salt by a method known per se or a
modification thereof; conversely, if compound (I) is obtained as a
salt, it can be converted into a free form or another desired salt
by a method known per se or a modification thereof.
[0282] When compound (I) has isomers such as optical isomer,
stereoisomer, positional isomer, rotational isomer and the like,
and any isomers and mixtures are encompassed in the compound (I).
For example, when compound (I) has an optical isomer, an optical
isomer separated from a racemate is also encompassed in the
compound (I). These isomers can be obtained as independent products
by a synthesis means or a separation means (concentration, solvent
extraction, column chromatography, recrystallization and the like)
known per se.
[0283] The compound (I) may be a crystal, and both a single crystal
and crystal mixtures are encompassed in the compound (I). Crystals
can be produced by crystallization according to crystallization
methods known per se.
[0284] The compound (I) may be a solvate (e.g., hydrate etc.) or a
non-solvate, both of which are encompassed in the compound (I).
[0285] A compound labeled with an isotope (e.g., .sup.3H, .sup.14C,
.sup.35S, .sup.125I and the like) is also encompassed in the
compound (I).
[0286] A prodrug of the compound (I) or a salt thereof (hereinafter
referred to as compound (I)) means a compound which is converted to
the compound (I) with a reaction due to an enzyme, an gastric acid,
etc. under the physiological condition in the living body, that is,
a compound which is converted to the compound (I) with oxidation,
reduction, hydrolysis, etc. according to an enzyme; a compound
which is converted to the compound (I) by hydrolysis etc. due to
gastric acid, etc. A prodrug for compound (I) may be a compound
obtained by subjecting an amino group in compound (I) to an
acylation, alkylation or phosphorylation (e.g., a compound obtained
by subjecting an amino group in compound (I) to an eicosanoylation,
alanylation, pentylaminocarbonylation,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,
tetrahydrofuranylation, pyrrolidylmethylation,
pivaloyloxymethylation and tert-butylation, etc.); a compound
obtained by subjecting a hydroxy group in compound (I) to an
acylation, alkylation, phosphorylation or boration (e.g., a
compound obtained by subjecting an hydroxy group in compound (1) to
an acetylation, palmitoylation, propanoylation, pivaloylation,
succinylation, fumarylation, alanylation,
dimethylaminomethylcarbonylation, etc.); a compound obtained by
subjecting a carboxyl group in compound (I) to an esterification or
amidation (e.g., a compound obtained by subjecting a carboxyl group
in compound (I) to an ethyl esterification, phenyl esterification,
carboxymethyl esterification, dimethylaminomethyl esterification,
pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl
esterification, phthalidyl esterification,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,
cyclohexyloxycarbonylethyl esterification and methylamidation,
etc.) and the like. Any of these compounds can be produced from
compound (I) by a method known per se.
[0287] A prodrug for compound (I) may also be one which is
converted into compound (I) under a physiological condition, such
as those described in IYAKUHIN no KAIHATSU (Development of
Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198,
Published by HIROKAWA SHOTEN (1990).
[0288] The compound (I) of the present invention, or a salt thereof
or a prodrug thereof (hereinafter referred to as the compound of
the present invention) possesses tyrosine kinase-inhibiting
activity and can be used for the prophylaxis or treatment of treat
tyrosine kinase-dependent diseases in mammals. Tyrosine
kinase-dependent diseases include diseases characterized by
increased cell proliferation due to abnormal tyrosine kinase enzyme
activity. Furthermore, the compound of the present invention
specifically inhibits HER2 kinase and/or EGFR kinase and is
therefore also useful as a therapeutic agent for suppressing the
growth of HER2 and/or EGFR kinase-expressing cancer, or a
preventive agent for preventing the transition of hormone-dependent
cancer to hormone-independent cancer. In addition, the compound is
useful as a pharmaceutical agent because it shows low toxicity
(e.g., acute toxicity, chronic toxicity, genetic toxicity,
reproductive toxicity, cardiotoxicity, drug interaction,
carcinogenicity and the like), high water solubility, and is
superior in stability, pharmacokinetics (absorption, distribution,
metabolism, excretion and the like) and efficacy expression.
[0289] Accordingly, the compound of the present invention can be
used as a safe agent for the prophylaxis or treatment of diseases
due to abnormal cell proliferation such as various cancers
(particularly breast cancer, prostate cancer, pancreatic cancer,
gastric cancer, lung cancer, colon cancer, rectal cancer, esophagus
cancer, duodenal cancer, cancer of the tongue, cancer of pharynx,
cerebral tumor, neurilemoma, non-small cell lung cancer, small cell
lung cancer, liver cancer, kidney cancer, cancer of the bile duct,
cancer of the uterine body, cancer of the uterine cervix, ovarian
cancer, urinary bladder cancer, skin cancer, hemangioma, malignant
lymphoma, malignant melanoma, thyroid cancer, bone tumors, vascular
fibroma, retinoblastoma, penile cancer, solid cancer in childhood,
Kaposi's sarcoma, Kaposi's sarcoma derived from AIDS, maxillary
tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma,
leukemia, etc.), atherosclerosis, angiogenesis (e.g., angiogenesis
associated with growth of solid cancer and sarcoma, angiogenesis
associated with tumor metastasis, and angiogenesis associated with
diabetic retinopathy, etc.), and viral diseases (HIV infection
etc.).
[0290] Tyrosine kinase-dependent diseases further include
cardiovascular diseases associated with abnormal tyrosine kinase
enzyme activity. The compound of the present invention can
therefore be used as an agent for prophylaxis or treatment of
cardiovascular diseases such as restenosis.
[0291] The compound of the present invention is useful as an
anticancer agent for the prophylaxis or treatment of cancer,
especially e.g., breast cancer, prostate cancer, pancreatic cancer,
gastric cancer, lung cancer, colon cancer, colorectal cancer,
kidney cancer and the like.
[0292] The compound of the present invention shows low toxicity and
can be used as a pharmaceutical agent as it is, or as a
pharmaceutical composition in admixture with a commonly known
pharmaceutically acceptable carrier etc. in mammals (e.g., humans,
horses, bovines, dogs, cats, rats, mice, rabbits, pigs, monkeys,
and the like).
[0293] In addition to the compound of the present invention, said
pharmaceutical composition may contain other active ingredients,
e.g., the following hormonal therapeutic agents, anticancer agent
(e.g., chemotherapeutic agents, immunotherapeutic agents, or
pharmaceutical agents inhibiting the action of cell growth factors
or cell growth factor receptors), and the like.
[0294] As a pharmaceutical agent for mammals such as humans, the
compound of the present invention can be administered orally in the
form of, for example, tablets, capsules (including soft capsules
and microcapsules), powders, granules and the like, or parenterally
in the form of injections, suppositories, pellets and the like.
Examples of the "parenteral administration route" include
intravenous, intramuscular, subcutaneous, intra-tissue, intranasal,
intradermal, instillation, intracerebral, intrarectal,
intravaginal, intraperitoneal, intratumoral, juxtaposition of tumor
and administration directly to the lesion.
[0295] The dose of the compound of the present invention varies
depending on the route of administration, symptoms, etc. For
example, when it is administered orally as an anticancer agent to a
patient (body weight 40 to 80 kg) with breast cancer or prostate
cancer, its dose is, for example, 0.5 to 100 mg/kg body weight per
day, preferably 1 to 50 mg/kg body weight per day, and more
preferably 1 or 25 mg/kg body weight per day. This amount may be
administered once or in 2 to 3 divided portions daily.
[0296] The compound of the present invention can be safely
administered orally or parenterally (e.g., topical, rectal,
intravenous administrations etc.) as a single agent, or a
pharmaceutical composition containing a pharmacologically
acceptable carrier according to a conventional method (e.g., a
method described in the Japanese Pharmacopoeia etc.), such as
tablet (including sugar-coated tablet, film-coated tablet), powder,
granule, capsule, liquid, emulsion, suspension, injection,
suppository, sustained release preparation, plaster and the
like.
[0297] And a combination of (1) administering an effective amount
of a compound of the present invention and (2) 1 to 3 selected from
the group consisting of (i) administering an effective amount of
other anticancer agents, (ii) administering an effective amount of
hormonal therapeutic agents and (iii) non-drug therapy can prevent
and/or treat cancer more effectively. As the non-drug therapy, for
example, surgery, radiotherapy, gene therapy, thermotherapy,
cryotherapy, laser cauterization, and the like are exemplified and
two or more of these may be combined.
[0298] For example, the compound of the present invention can be
administered to the same subject simultaneously with hormonal
therapeutic agents, anticancer agents (e.g., chemotherapeutic
agents, immunotherapeutic agents, or pharmaceutical agents
inhibiting the action of cell growth factors or cell growth factor
receptors) (hereafter, these are referred to as a concomitant
drug).
[0299] Although the compound of the present invention exhibits
excellent anticancer action even when used as a simple agent, its
effect can be enhanced by using it in combination with one or more
of the concomitant drug(s) mentioned above (multi-agent
co-administration).
[0300] As examples of said "hormonal therapeutic agents," there may
be mentioned fosfestrol, diethylstylbestrol, chlorotrianisene,
medroxyprogesterone acetate, megestrol acetate, chlormadinone
acetate, cyproterone acetate, danazol, dienogest, asoprisnil,
allylestrenol, gestrinone, nomegestrol, Tadenan, mepartricin,
raloxifene, ormeloxifene, levormeloxifene, anti-estrogens (e.g.,
tamoxifen citrate, toremifene citrate, and the like), ER down
regulator (e.g., fulvestrant, and the like), human menopausal
gonadotrophin, follicle stimulating hormone, pill preparations,
mepitiostane, testrolactone, aminoglutethimide, LH-RH agonists
(e.g., goserelin acetate, buserelin, leuprorelin, and the like),
droloxifene, epitiostanol, ethinylestradiol sulfonate, aromatase
inhibitors (e.g., fadrozole hydrochloride, anastrozole, retrozole,
exemestane, vorozole, formestane, and the like), anti-androgens
(e.g., flutamide, bicartamide, nilutamide, and the like),
5.alpha.-reductase inhibitors (e.g., finasteride, dutasteride,
epristeride, and the like), adrenocorticohormone drugs (e.g.,
dexamethasone, prednisolone, betamethasone, triamcinolone, and the
like), androgen synthesis inhibitors (e.g., abiraterone, and the
like), retinoid and drugs that retard retinoid metabolism (e.g.,
liarozole, and the like), etc. and LH-RH agonists (e.g., goserelin
acetate, buserelin, leuprorelin) are preferable.
[0301] As examples of said "chemotherapeutic agents", there may be
mentioned alkylating agents, antimetabolites, anticancer
antibiotics, plant-derived anticancer agents, and the like.
[0302] As examples of "alkylating agents", there may be mentioned
nitrogen mustard, nitrogen mustard-N-oxide hydrochloride,
chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone,
improsulfan tosylate, busulfan, nimustine hydrochloride,
mitobronitol, melphalan, dacarbazine, ranimustine, sodium
estramustine phosphate, triethylenemelamine, carmustine, lomustine,
streptozocin, pipobroman, etoglucid, carboplatin, cisplatin,
miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine,
dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa,
ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin
stimalamer, adozelesin, cystemustine, bizelesin, and the like.
[0303] As examples of "antimetabolites", there may be mentioned
mercaptopurine, 6-mercaptopurine riboside, thioinosine,
methotrexate, enocitabine, cytarabine, cytarabine ocfosfate,
ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur,
UFT, doxifluridine, carmofur, gallocitabine, emmitefur, and the
like), aminopterine, leucovorin calcium, tabloid, butocine,
folinate calcium, levofolinate calcium, cladribine, emitefur,
fludarabine, gemcitabine, hydroxycarbamide, pentostatin,
piritrexim, idoxuridine, mitoguazone, thiazophrine, ambamustine,
and the like.
[0304] As examples of "anticancer antibiotics", there may be
mentioned actinomycin-D, actinomycin-C, mitomycin-C,
chromomycin-A3, bleomycin hydrochloride, bleomycin sulfate,
peplomycin sulfate, daunorubicin hydrochloride, doxorubicin
hydrochloride, aclarubicin hydrochloride, pirarubicin
hydrochloride, epirubicin hydrochloride, neocarzinostatin,
mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin
hydrochloride, mitoxantrone hydrochloride, idarubicin
hydrochloride, and the like.
[0305] As examples of "plant-derived anticancer agents", there may
be mentioned etoposide, etoposide phosphate, vinblastine sulfate,
vincristine sulfate, vindesine sulfate, teniposide, paclitaxel,
docetaxel, vinorelbine, and the like.
[0306] As examples of said "immunotherapeutic agents (BRM)", there
may be mentioned picibanil, krestin, sizofuran, lentinan, ubenimex,
interferons, interleukins, macrophage colony-stimulating factor,
granulocyte colony-stimulating factor, erythropoietin, lymphotoxin,
BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K,
procodazole, and the like.
[0307] The "growth factor" in said "pharmaceutical agents
inhibiting the action of cell growth factors or cell growth factor
receptors", there may be mentioned any substances that promote cell
proliferation, which are normally peptides having a molecular
weight of not more than 20,000 that are capable of exhibiting their
activity at low concentrations by binding to a receptor, including
(1) EGF (epidermal growth factor) or substances possessing
substantially the same activity as it [e.g., EGF, heregulin (HER2
ligand), and the like], (2) insulin or substances possessing
substantially the same activity as it [e.g., insulin, IGF
(insulin-like growth factor)-1, IGF-2, and the like], (3) FGF
(fibroblast growth factor) or substances possessing substantially
the same activity as it [e.g., acidic FGF, basic FGF, KGF
(keratinocyte growth factor), FGF-10, and the like], (4) other cell
growth factors [e.g., CSF (colony stimulating factor), EPO
(erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor),
PDGF (platelet-derived growth factor), TGF.beta. (transforming
growth factor .beta.), HGF (hepatocyte growth factor), VEGF
(vascular endothelial growth factor), and the like], and the
like.
[0308] As examples of said "growth factor receptors", there may be
mentioned any receptors capable of binding to the aforementioned
growth factors, including EGF receptor, heregulin receptor (HER2),
insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2,
and the like.
[0309] As examples of said "pharmaceutical agents inhibiting the
action of cell growth factor", there may be mentioned trastuzumab
(Herceptin (trade mark): HER2 antibody), imatinib mesilate, ZD1839
or cetuximab, antibody to VEGF (e.g., bevacizumab), antibody to
VEGF receptor, gefitinib, erlotinib, and the like.
[0310] In addition to the aforementioned drugs, L-asparaginase,
aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt
complex salt, mercuric hematoporphyrin-sodium, topoisomerase I
inhibitors (e.g., irinotecan, topotecan, and the like),
topoisomerase II inhibitors (e.g., sobuzoxane, and the like),
differentiation inducers (e.g., retinoid, vitamin D, and the like),
angiogenesis inhibitors (e.g., thalidomide, SU11248, and the like),
.alpha.-blockers (e.g., tamsulosin hydrochloride, naftopidil,
urapidil, alfuzosin, terazosin, prazosin, silodosin, and the like),
serine/threonine kinase inhibitor, endothelin receptor antagonist
(e.g., atrasentan, and the like), proteasome inhibitor (e.g.,
bortezomib, and the like), Hsp 90 inhibitor (e.g., 17-AAG, and the
like), spironolactone, minoxidil, 11.alpha.-hydroxyprogesterone,
bone resorption inhibiting/metastasis suppressing agent (e.g.,
zoledronic acid, alendronic acid, pamidronic acid, etidronic acid,
ibandronic acid, clodronic acid) and the like can be used.
[0311] Of those mentioned above, LH-RH agonist (e.g., goserelin
acetate, buserelin, leuprorelin, and the like), trastuzumab (HER2
antibody) and the like are preferable as concomitant drugs.
[0312] In combination of the compound of the present invention and
the concomitant drug, the administration time of the compound of
the present invention and the concomitant drug is not restricted,
and the compound of the present invention and the concomitant drug
can be administered to the administration subject simultaneously,
or may be administered at different times. The dosage of the
concomitant drug may be determined according to the administration
amount clinically used, and can be appropriately selected depending
on the administration subject, administration route, disease,
combination and the like.
[0313] The administration mode of the compound of the present
invention and the concomitant drug is not particularly restricted,
and it is sufficient that the compound of the present invention and
the concomitant drug are combined in administration. Examples of
such administration mode include the following methods:
[0314] (1) The compound of the present invention and the
concomitant drug are simultaneously produced to give a single
preparation which is administered. (2) The compound of the present
invention and the concomitant drug are separately produced to give
two kinds of preparations which are administered simultaneously by
the same administration route. (3) The compound of the present
invention and the concomitant drug are separately produced to give
two kinds of preparations which are administered by the same
administration route only at the different times. (4) The compound
of the present invention and the concomitant drug are separately
produced to give two kinds of preparations which are administered
simultaneously by different administration routes. (5) The compound
of the present invention and the concomitant drug are separately
produced to give two kinds of preparations which are administered
by different administration routes at different times (for example,
the compound of the present invention and the concomitant drug are
administered in this order, or in the reverse order).
EXAMPLES
[0315] The present invention is explained in detail by way of the
following Reference Examples, Examples, Formulation Examples and
Experimental Examples but these do not limit the present
invention.
[0316] The elution in column chromatography in Reference Examples
and Examples was performed under observation by TLC (thin-layer
chromatography). In the TLC observation, Kieselgel 60F.sub.254
plate (Merck) or NH TLC plate manufactured by Fuji Silysia Chemical
Ltd. was used as a TLC plate, the solvent used as an elution
solvent in the column chromatography was used as a developing
solvent, and the means of detection used was an UV detector. As
silica gel for column, Kieselgel 60F.sub.254 (70-230 mesh)
manufactured by Merck or Chromatorex NH DM1020 (basic silica gel,
100-200 mesh) manufactured by Fuji Silysia Chemical Ltd. was used.
The ratio of solvents in silica gel chromatography is a volume
ratio of the solvents mixed. In addition, % means percentage by
weight unless otherwise specified.
[0317] NMR spectra are shown by proton NMR with tetramethylsilane
as the internal standard, using VARIAN Gemini-200 (200 MHz type
spectrometer) or Gemini-300 (300 MHz type spectrometer) or BRUKER
AVANCE300 (300 MHz type spectrometer); 6 values are expressed in
ppm.
[0318] The abbreviations used in Reference Examples and Examples
mean the following:
s: singlet, br: broad, d: doublet, t: triplet, q: quartet, dd:
double doublet, m: multiplet, J: coupling constant, Hz: hertz,
DMSO: dimethyl sulfoxide
[0319] Genetic manipulation methods described in Experimental
Examples below are based on the methods described in Maniatis et
al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989, and
the appended protocol.
Reference Example 1
Production of 2-[(2-chloro-4-nitrophehoxy)methyl]benzonitrile
[0320] To a solution of 2-chloro-4-nitrophenol (3.5 g) and
2-(bromomethyl)benzonitrile (4.0 g) in N,N-dimethylformamide (50
mL) was added potassium carbonate (3.7 g), and the mixture was
stirred at room temperature for 30 min. After the completion of the
reaction, water (50 mL) was added, and the mixture was stirred for
10 min. The resultant pale-yellow solid was collected by
filtration. The residue was washed with diisopropyl ether, and
dried to give the title compound (5.04 g) as pale-yellow
crystals.
[0321] .sup.1H-NMR (CDCl.sub.3) .delta. 5.44 (2H, s), 7.13 (1H, d,
J=9.0 Hz), 7.51 (1H, dt, J=1.2, 7.2 Hz), 7.68-7.80 (3H, m), 8.19
(1H, dd, J=2.7, 9.0 Hz), 8.35 (1H, d, J=2.7 Hz).
Reference Example 2
Production of 2-[(4-amino-2-chlorophenoxy)methyl]benzonitrile
[0322] To a solution of
2-[(2-chloro-4-nitrophenoxy)methyl]benzonitrile (2.0 g) in
ethanol/water (9:1, 40 mL) was added calcium chloride (90%, 427
mg), and the mixture was stirred at 100.degree. C. for 10 min.
Reduced iron (90%, 2.6 g) was added at room temperature, and the
mixture was stirred at 100.degree. C. for 3 hrs. After the
completion of the reaction, the reaction mixture was filtered
(celite), and the filtrate was concentrated under reduced pressure.
Water was added to the residue and the mixture was diluted with
ethyl acetate and washed with water and saturated brine. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane:ethyl acetate:methylene
chloride=2:1:1) to give the title compound (1.2 g) as a white
solid.
[0323] .sup.1H-NMR (CDCl.sub.3) .delta. 3.53 (2H, br s), 5.23 (2H,
s), 6.54 (1H, dd, J=2.7, 8.7 Hz), 6.76 (1H, d, J=2.7 Hz), 6.88 (1H,
d, J=8.7 Hz), 7.42 (1H, dt, J=0.9, 7.8 Hz), 7.62-7.70 (2H, m), 7.81
(1H, d, J=7.8 Hz).
Reference Example 3
Production of 2-[(2-methyl-4-nitrophenoxy)methyl]benzonitrile
[0324] The title compound (8.2 g) was obtained as a pale-yellow
solid by the reaction in the same manner as in Reference Example 1
using 2-methyl-4-nitrophenol (5.0 g) and
2-(bromomethyl)benzonitrile (6.4 g).
[0325] .sup.1H-NMR (CDCl.sub.3) .delta. 2.37 (3H, s), 5.36 (2H, s),
6.97 (1H, d, J=8.4 Hz), 7.50 (1H, m), 7.65-7.69 (2H, m), 7.76 (1H,
td, J=0.9, 7.5 Hz), 8.09-8.14 (2H, m).
Reference Example 4
Production of 2-[(4-amino-2-methylphenoxy)methyl]benzonitrile
[0326] The title compound (3.7 g) was obtained as a white solid by
the reaction in the same manner as in Reference Example 2 using
2-[(2-methyl-4-nitrophenoxy)methyl]benzonitrile (6.0 g), calcium
chloride (90%, 1.3 g) and reduced iron (90%, 8.3 g).
[0327] .sup.1H-NMR (CDCl.sub.3) .delta. 2.24 (3H, s), 3.41 (2H, br
s), 5.17 (2H, s), 6.48 (1H, dd, J=3.0, 8.4 Hz), 6.56 (1H, d, J=3.0
Hz), 6.73 (1H, d, J=8.4 Hz), 7.40 (1H, dt, J=1.2, 7.5 Hz),
7.59-7.71 (3H, m).
Reference Example 5
Production of 3-(2-chloro-4-nitrophenoxy)benzonitrile
[0328] To a solution of 2-chloro-1-fluoro-4-nitrobenzene (3.7 g)
and 3-hydroxybenzonitrile (2.5 g) in N,N-dimethylformamide (50 mL)
was added potassium carbonate (4.4 g), and the mixture was stirred
at 60.degree. C. for 4 hrs. After the completion of the reaction,
water (50 mL) was added, and the mixture was stirred for 10 min.
The resultant pale-yellow solid was collected by filtration, washed
with diisopropyl ether, and dried to give the title compound (5.3
g) as pale-yellow crystals.
[0329] .sup.1H-NMR (CDCl.sub.3) .delta. 7.03 (1H, d, J=9.0 Hz),
7.27-7.33 (2H, m), 7.55-7.56 (2H, m), 8.15 (1H, dd, J=2.7, 9.0 Hz),
8.42 (1H, d, J=2.7 Hz).
Reference Example 6
Production of 3-(4-amino-2-chlorophenoxy)benzonitrile
[0330] To a solution of 3-(2-chloro-4-nitrophenoxy)benzonitrile
(2.0 g) in ethanol/water (9:1, 40 mL) was added calcium chloride
(90%, 449 mg), and the mixture was stirred at 100.degree. C. for 10
min. Reduced iron (90%, 2.7 g) was added at room temperature, and
the mixture was stirred at 100.degree. C. for 5 hrs. After the
completion of the reaction, the reaction mixture was filtered
(celite), and the filtrate was concentrated under reduced pressure.
Water was added to the residue and the mixture was diluted with
ethyl acetate and washed with water and saturated brine. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane:ethyl acetate=3:1) to
give the title compound (1.25 g) as a white solid.
[0331] .sup.1H-NMR (CDCl.sub.3) .delta. 3.75 (2H, br s), 6.60 (1H,
dd, J=2.7, 8.4 Hz), 6.80 (1H, d, J=2.7 Hz), 6.92 (1H, d, J=8.4 Hz),
7.06 (1H, m), 7.14 (1H, m), 7.30 (1H, td, J=1.2, 7.5 Hz), 7.37 (1H,
d, J=7.5 Hz).
Reference Example 7
Production of ethyl 2-fluoro-5-nitrobenzoate
[0332] Under ice-cooling, thionyl chloride (8.02 mL) was added
dropwise to ethanol (200 mL), and 2-fluoro-5-nitrobenzoic acid
(13.81 g) was added. This mixture was stirred at 80.degree. C. for
4 hrs. and concentrated under reduced pressure. A saturated aqueous
sodium hydrogen carbonate solution was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced
pressure to give the title compound (15.77 g) as a pale-yellow
oil.
[0333] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (3H, t, J=7.2 Hz),
4.46 (2H, q, J=7.2 Hz), 7.32 (1H, t, J=9.1 Hz), 8.41 (1H, ddd,
J=9.1, 4.3, 3.0 Hz), 8.85 (1H, dd, J=6.1, 3.0 Hz)
Reference Example 8
Production of ethyl 5-amino-2-phenoxybenzoate
[0334] A mixture of ethyl 2-fluoro-5-nitrobenzoate (1.07 g), phenol
(565 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide
(20 mL) was stirred at 80.degree. C. for 4 hrs. The reaction
mixture was concentrated under reduced pressure. Water was added to
the residue and the mixture was extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced
pressure, and the obtained residue was purified by silica gel
column chromatography (eluent, ethyl
acetate:hexane=20:80.fwdarw.30:70). The object fraction was
concentrated under reduced pressure and ethanol (20 mL) and 10%
palladium on carbon (1.5 g) were added to the residue (1.54 g). The
mixture was stirred overnight under a hydrogen stream. The catalyst
was filtered off, and the filtrate was concentrated. The obtained
residue was purified by silica gel column chromatography (eluent,
ethyl acetate:hexane=20:80.fwdarw.50:50) and recrystallized from
diisopropyl ether-hexane to give the title compound (1.07 g) as a
pale-brown powder.
[0335] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (3H, t, J=7.2 Hz),
3.71 (2H, s), 4.17 (2H, q, J=7.2 Hz), 6.80-6.87 (3H, m), 6.91 (1H,
d, J=8.5 Hz), 6.97 (1H, t, J=7.3 Hz), 7.21-7.30 (3H, m).
Reference Example 9
Production of methyl
4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate
and methyl
4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoat-
e
[0336] To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine
(400 mg) in N,N-dimethylformamide (8 mL) was added 60% sodium
hydride (98 mg) under ice-cooling, and the mixture was stirred at
room temperature for 10 min. Then, methyl 4-(bromomethyl)benzoate
(606 mg) was added under ice-cooling, and the mixture was stirred
at room temperature for 30 min. After the completion of the
reaction, the mixture was diluted with ethyl acetate and washed
with saturated aqueous sodium hydrogen carbonate and saturated
brine. The organic layer was concentrated under reduced pressure,
and the residue was subjected to silica gel column chromatography
(hexane:ethyl acetate=2:1.fwdarw.1:2) to give methyl
4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate
(251 mg) and methyl
4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate
(450 mg) both as pale-yellow solids.
methyl
4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoat-
e: .sup.1H-NMR (CDCl.sub.3) .delta. 2.71 (3H, s), 3.89 (3H, s),
5.93 (2H, s), 7.22 (2H, d, J=8.1 Hz), 7.98 (2H, d, J=8.1 Hz), 8.23
(1H, s), 8.80 (1H, s). methyl
4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate:
.sup.1H-NMR (CDCl.sub.3) .delta. 2.73 (3H, s), 3.92 (3H, s), 5.69
(2H, s), 7.34 (2H, d, J=8.4 Hz), 8.03 (2H, d, J=8.4 Hz), 8.04 (1H,
s), 8.73 (1H, s).
Reference Example 10
Production of
2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate
and 2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl
benzoate
[0337] To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine
(300 mg) and 2-iodoethyl benzoate (548 mg) in N,N-dimethylformamide
(10 mL) was added potassium carbonate (374 mg), and the mixture was
stirred at 60.degree. C. for 1 hr. After the completion of the
reaction, water was added to the reaction mixture. The mixture was
diluted with ethyl acetate and washed with water and saturated
brine. The organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=3:2) to give
2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate
(266 mg) and
2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate
(191 mg) both as pale-yellow solids.
2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate:
.sup.1H-NMR (CDCl.sub.3) .delta. 2.66 (3H, s), 4.78 (2H, t, J=5.4
Hz), 5.06 (2H, t, J=5.4 Hz), 7.27-7.40 (2H, m), 7.53 (1H, m),
7.85-7.89 (2H, m), 8.20 (1H, s), 8.79 (1H, s).
2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate:
.sup.1H-NMR (CDCl.sub.3) .delta. 2.73 (3H, s), 4.80-4.86 (4H, m),
7.40-7.46 (2H, m), 7.58 (1H, m), 7.94-7.97 (2H, m), 8.20 (1H, s),
8.73 (1H, s).
Reference Example 11
Production of
3-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propyl benzoate
and 3-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl
benzoate
[0338] 3-[7-(Methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propyl
benzoate (623 mg) and
3-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl benzoate
(556 mg) were obtained both as pale-yellow solids by the reaction
in the same manner as in Reference Example 10 using
7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (600 mg), 3-iodopropyl
benzoate (1.15 g) and potassium carbonate (748 mg).
3-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propyl benzoate:
.sup.1H-NMR (CDCl.sub.3) .delta. 2.40-2.47 (2H, m), 2.66 (3H, s),
4.42 (2H, t, J=5.7 Hz), 4.88 (2H, t, J=7.2 Hz), 7.42-7.46 (2H, m),
7.57 (1H, m), 7.98-8.02 (2H, m), 8.15 (1H, s), 8.73 (1H, s).
3-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl benzoate:
.sup.1H-NMR (CDCl.sub.3) .delta. 2.52-2.58 (2H, m), 2.72 (3H, s),
4.39 (2H, t, J=6.0 Hz), 4.65 (2H, t, J=6.9 Hz), 7.40-7.46 (2H, m),
7.57 (1H, m), 7.96-8.02 (2H, m), 8.14 (1H, s), 8.71 (1H, s).
Example 1
##STR00049##
[0339] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-a-
mine hydrochloride
[0340] 4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (770 mg) and
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (2.52 g) were dissolved in
1-methyl-2-pyrrolidone (10 mL), and the mixture was stirred with
heating at 140.degree. C. for 2.5 hrs. After cooling to room
temperature, the mixture was diluted with ethyl acetate (300 mL),
and stirred at room temperature for 1 hr. The precipitated powder
was collected by filtration, washed with ethyl acetate (30 mL), and
dried under reduced pressure to give the title compound (1.62
g).
[0341] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 5.27 (2H, s), 6.63 (1H,
d, J=3 Hz), 7.0-7.5 (5H, m), 7.78 (1H, dd, J=3 Hz, 9 Hz), 8.00 (1H,
m), 8.15 (1H, d, J=3 Hz), 8.79 (1H, s), 11.79 (1H, br s).
Example 2
##STR00050##
[0342] Production of
(4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]p-
yrimidin-5-yl]methyl}phenyl)methanol
(i) Production of
{4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol
[0343] 4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) was dissolved
in N,N-dimethylformamide (2 mL), potassium carbonate (304 mg) was
added, and the mixture was stirred at room temperature for 30 min.
4-Hydroxymethylbenzyl chloride (377 mg) was added, and the mixture
was stirred at room temperature for 16 hrs. After diluting with
water (30 mL), the mixture was extracted with ethyl
acetate/tetrahydrofuran (3:1, 80 mL.times.2).
[0344] The organic layer was dried over magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.0:100) to give the title compound (383 mg) as
a powder.
[0345] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.15 (1H, br s), 4.69 (2H,
d, J=4 Hz), 5.71 (2H, s), 6.76 (1H, m), 7.06 (2H, d, J=8 Hz), 7.34
(2H, d, J=8 Hz), 7.50 (1H, d, J=3 Hz), 8.69 (1H, s).
(ii) Production of
(4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]p-
yrimidin-5-yl]methyl}phenyl)methanol
[0346]
{4-[(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methano-
l (354 mg) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (488 mg)
were dissolved in 1-methyl-2-pyrrolidone (2.58 mL), and the mixture
was stirred with heating at 140.degree. C. for 2 hrs. After cooling
to room temperature, the reaction mixture was diluted with ethyl
acetate (80 mL) and partitioned with saturated aqueous sodium
hydrogen carbonate (30 mL). The organic layer was washed with
saturated brine (30 mL), dried over magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.0:100) to give the title compound (588 mg) as
a powder.
[0347] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.77 (2H, s), 5.07 (2H,
s), 5.52 (2H, s), 6.26 (2H, s), 6.64 (1H, d, J=3 Hz), 6.81 (1H, d,
J=9 Hz), 6.9-7.4 (8H, m), 7.49 (2H, d, J=8 Hz), 8.44 (1H, s).
Example 3
##STR00051##
[0348] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3,4-dimethoxybenzoyl)-5H-py-
rrolo[3,2-d]pyrimidin-4-amine
[0349] Under ice-cooling, to a suspension of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-a-
mine hydrochloride (150 mg) and potassium carbonate (102 mg) in
N,N-dimethylformamide (1.5 mL) was added 3,4-dimethoxybenzoyl
chloride (82 mg), and the mixture was stirred under ice-cooling,
for 1 hr. The mixture was partitioned between ethyl acetate (50 mL)
and water (30 mL). The organic layer was washed with saturated
brine (30 mL), dried over magnesium sulfate and concentrated under
reduced pressure. The residue was separated and purified by silica
gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.ethyl acetate:methanol=80:20), and
crystallized from diisopropyl ether to give the title compound (104
mg).
[0350] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.97 (3H, s), 4.01 (3H,
s), 5.14 (2H, s), 6.72 (1H, d, J=3 Hz), 6.9-7.6 (10H, m), 7.88 (2H,
d, J=3 Hz), 8.63 (1H, s), 9.75 (1H, br s).
Example 4
##STR00052##
[0351] Production of
(4-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]methyl}phenyl)methanol
[0352] The title compound (242 mg) was obtained as crystals by the
reaction in the same manner as in Example 2 (ii) using
{4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol
(200 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (235 mg)
and 1-methyl-2-pyrrolidone (1.46 mL).
[0353] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.14 (3H, s), 2.50 (3H,
s), 3.01 (1H, br s), 4.75 (2H, s), 5.53 (2H, s), 6.38 (1H, br s),
6.64 (1H, d, J=3 Hz), 6.75 (1H, d, J=9 Hz), 6.8-7.2 (6H, m), 7.34
(2H, d, J=3 Hz), 7.47 (1H, d, J=9 Hz), 8 09 (1H, m), 8.46 (1H,
s).
Example 5
##STR00053##
[0354] Production of
N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimid-
in-4-amine
[0355] The title compound (283 mg) was obtained as crystals by the
reaction in the same manner as in Example 2 (ii) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg),
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (418 mg) and
1-methyl-2-pyrrolidone (2.6 mL).
[0356] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.16 (3H, s), 2.51 (3H,
s), 6.56 (1H, d, J=3 Hz), 6.80 (1H, d, J=9 Hz), 7.0-7.6 (5H, m), 8
17 (1H, m), 8.59 (1H, s), 8.76 (1H, br s), 11.08 (1H, br s).
Example 6
##STR00054##
[0357] Production of methyl
4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoate
(i) Production of methyl
4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate
[0358] The title compound (1.0 g) was obtained as a powder by the
reaction in the same manner as in Example 2 (i) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (710 mg), methyl
4-(bromomethyl)benzoate (1.27 g), potassium carbonate (703 mg) and
N,N-dimethylformamide (9.2 mL).
[0359] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.90 (3H, s), 5.77 (2H,
s), 6.83 (1H, d, J=3 Hz), 7.08 (2H, d, J=8 Hz), 7.53 (1H, d, J=3
Hz), 8.00 (2H, d, J=8 Hz), 8.73 (1H, s).
(ii) Production of methyl
4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoate
[0360] The title compound (1.35 g) was obtained as a powder by the
reaction in the same manner as in Example 2 (ii) using methyl
4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate (1.0
g), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.25 g) and
1-methyl-2-pyrrolidone (6.63 mL).
[0361] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.93 (3H, s), 5.07 (2H,
s), 5.57 (2H, s), 6.10 (2H, br s), 6.68 (1H, d, J=3 Hz), 6.7-7.4
(10H, m), 8.11 (2H, d, J=9 Hz), 8.47 (1H, s).
Example 7
##STR00055##
[0362] Production of
4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoic acid
[0363] Methyl
4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoate (850 mg) was dissolved in a mixed
solvent of ethanol (3.29 mL)/tetrahydrofuran (3.29 mL), 1N aqueous
sodium hydroxide solution (3.29 mL) was added, and the mixture was
stirred at room temperature for 20 hrs. 1N Hydrochloric acid (3.29
mL) was added to the reaction mixture and the mixture was diluted
with water (20 mL). The precipitated crystals were collected by
filtration, washed with water (10 mL), and dried under reduced
pressure to give the title compound (738 mg).
[0364] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 5.21 (2H, s), 5.94 (2H,
s), 6.62 (1H, d, J=3 Hz), 7.0-7.6 (9H, m), 7.84 (2H, d, J=9 Hz),
7.91 (1H, d, J=3 Hz), 8.40 (1H, s), 8.81 (1H, br s), 12.88 (1H, br
s).
Example 8
##STR00056##
[0365] Production of
1-(4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d-
]pyrimidin-5-yl]methyl}benzoyl)piperidin-4-ol
[0366] To a mixture of
4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoic acid (150 mg), 4-hydroxypiperidine
(33.2 mg) and 1-hydroxybenzotriazole monohydrate (60 mg) in
N,N-dimethylformamide (3 mL) were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg)
and triethylamine (0.208 mL) at room temperature and the mixture
was stirred overnight at room temperature. The mixture was
partitioned between ethyl acetate (50 mL) and water (30 mL). The
organic layer was washed with saturated brine (30 mL), dried over
magnesium sulfate, and concentrated under reduced pressure. The
residue was separated and purified by basic silica gel column
chromatography (eluent, ethyl acetate:methanol=100:0.fwdarw.ethyl
acetate:methanol=80:20), and crystallized from diisopropyl ether to
give the title compound (168 mg).
[0367] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.4-2.1 (5H, m), 3.0-3.7
(3H, m), 3.97 (1H, m), 4.16 (1H, m), 5.08 (2H, s), 5.55 (2H, s),
6.33 (1H, br s), 6.66 (1H, d, J=3 Hz), 6.82 (1H, d, J=9 Hz),
6.9-7.5 (11H, m), 8.47 (1H, s).
Example 9
##STR00057##
[0368] Production of
6-(3-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine
(i) Production of
6-chloro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-nitropyrimidi-
n-4-amine hydrochloride
[0369] 4,6-Dichloro-5-nitropyrimidine (9.7 g) was dissolved in
1-methyl-2-pyrrolidone (25.7 mL), a solution of
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (5.35 g) in
1-methyl-2-pyrrolidone (10 mL) was added dropwise under cooling at
-15.degree. C., and the mixture was stirred at -10.degree. C. to
0.degree. C. for 1 hr. The mixture was diluted with ethyl acetate
(100 mL) and stirred at 0.degree. C. for 15 min. The precipitated
crystals were collected by filtration, washed with ethyl acetate
(30 mL), and dried under reduced pressure to give the title
compound (7.34 g).
[0370] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.20 (3H, s), 2.67 (3H,
s), 7.0-8.0 (5H, m), 8.44 (1H, m), 8.55 (1H, s), 10.14 (1H, br
s).
(ii) Production of
6-chloro-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5--
diamine
[0371]
6-Chloro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-nitropy-
rimidin-4-amine hydrochloride (2.04 g) was suspended in diethyl
ether (9.45 mL) and a solution of tin(IV) chloride dihydrate (9.1
g) in conc. hydrochloric acid (20.17 mL) was added under
ice-cooling. After stirring at room temperature for 3 hrs, the
reaction mixture was poured into ice water (400 mL). A 50% aqueous
sodium hydroxide solution (18 mL) was added dropwise to adjust pH
to 8. Ethyl acetate (300 mL) was added and the mixture was filtered
through celite. The organic layer was dried over magnesium sulfate
and concentrated under reduced pressure to give the title compound
(1.30 g).
[0372] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.23 (3H, s), 2.52 (3H,
s), 6.85 (1H, d, J=9 Hz), 7.0-7.5 (4H, m), 8.16 (1H, s), 8.21 (1H,
d, J=3 Hz).
(iii) Production of
6-iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-di-
amine hydriodide
[0373]
6-Chloro-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidin-
e-4,5-diamine (400 mg) was suspended in 55% hydriodic acid (6.16
mL), sodium iodide (878 mg) was added, and the mixture was stirred
with heating at 70.degree. C. for 10 min. After cooling to room
temperature, water (40 mL)/ethyl acetate (30 mL) was added. After
adjusting its pH to not less than 7 with aqueous sodium hydrogen
carbonate, and the mixture was stirred at room temperature for 15
min. The organic layer was dried over magnesium sulfate and
concentrated under reduced pressure to give the title compound (626
mg).
[0374] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.19 (3H, s), 2.52 (3H,
s), 4.23 (2H, br s), 6.81 (1H, d, J=9 Hz), 7.0-7.5 (5H, m), 7.97
(1H, s), 8.18 (1H, d, J=3 Hz).
(iv) Production of
6-[(3-aminophenyl)ethynyl]-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phen-
yl}pyrimidine-4,5-diamine
[0375]
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine--
4,5-diamine hydriodide (200 mg) was dissolved in a mixed solvent of
acetonitrile (7.6 mL)/triethylamine (5.72 mL), 3-ethynylaniline
(0.0574 mL), trans-dichlorobis(triphenylphosphine)palladium(II)
(15.4 mg) and copper(I) iodide (5.3 mg) were sequentially added,
and the mixture was stirred under a nitrogen stream at room
temperature for 1.5 hrs. The reaction mixture was concentrated
under reduced pressure and the residue was separated and purified
by silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20-4 ethyl acetate:methanol=80:20) to give the title
compound (157 mg).
[0376] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.19 (3H, s), 2.51 (3H,
s), 3.65 (2H, br s), 4.37 (2H, br s), 6.6-7.5 (9H, m), 7.50 (1H, br
s), 8.19 (1H, d, J=3 Hz), 8.29 (1H, s).
(v) Production of
6-(3-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine
[0377]
6-[(3-Aminophenyl)ethynyl]-4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy-
]phenyl}pyrimidine-4,5-diamine (140 mg) was dissolved in
N,N-dimethylformamide (0.82 mL), copper(I) iodide (6.3 mg) was
added and the mixture was stirred under a nitrogen stream with
heating at 110.degree. C. for 16 hrs. After cooling to room
temperature, the reaction mixture was diluted with dichloromethane
(20 mL), and filtered through celite. The filtrate was concentrated
under reduced pressure, and the residue was separated and purified
by basic silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.85:15) and crystallized from
diisopropyl ether to give the title compound (76 mg).
[0378] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.22 (3H, s), 2.44 (3H,
s), 5.32 (2H, br s), 6.65 (1H, d, J=7 Hz), 6.76 (1H, d, J=2 Hz),
6.9-7.3 (6H, m), 7.75 (1H, dd, J=3 Hz, 9 Hz), 7.83 (1H, d, J=2 Hz),
8.18 (1H, d, J=3 Hz), 8.34 (1H, s), 9.14 (1H, br s), 11.47 (1H, br
s).
Example 10
##STR00058##
[0379] Production of
6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine
(i) Production of
6-[(4-aminophenyl)ethynyl]-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phen-
yl}pyrimidine-4,5-diamine
[0380]
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine--
4,5-diamine hydriodide (270 mg) was dissolved in a mixed solvent of
acetonitrile (10.3 mL)/triethylamine (7.72 mL), and
4-ethynylaniline (80.3 mg),
trans-dichlorobis(triphenylphosphine)palladium(II) (20.8 mg) and
copper(I) iodide (7.16 mg) were sequentially added. The title
compound (134 mg) was obtained as a powder by the reaction in the
same manner as in Example 9 (iv).
[0381] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.20 (3H, s), 2.51 (3H,
s), 4.00 (4H, br s), 6.60 (2H, d, J=9 Hz), 6.83 (1H, d, J=9 Hz),
7.0-7.5 (6H, m), 8.21 (1H, m), 8.29 (1H, s).
(ii) Production of
6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine
[0382] The title compound (68 mg) was obtained as a powder by the
reaction in the same manner as in Example 9 (v) using
6-[(4-aminophenyl)ethynyl]-N-4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phe-
nyl}pyrimidine-4,5-diamine (160 mg) and copper(I) iodide (7.2
mg).
[0383] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.21 (3H, s), 2.44 (3H,
s), 5.58 (2H, br s), 6.70 (2H, d, J=9 Hz), 6.99 (1H, d, J=2 Hz),
7.20 (2H, m), 7.56 (1H, d, J=9 Hz), 7.75 (1H, dd, J=2 Hz, 9 Hz),
7.81 (1H, d, J=2 Hz), 8.18 (1H, d, J=2 Hz), 8.32 (1H, s), 9.12 (1H,
br s), 11.38 (1H, br s).
Example 11
##STR00059##
[0384] Production of
2-methoxy-N-{4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5-
H-pyrrolo[3,2-d]pyrimidin-6-yl]phenyl}acetamide
[0385] To a mixture of
6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine (40 mg), methoxyacetic acid (0.0145
mL) and 1-hydroxybenzotriazole monohydrate (38 mg) in
N,N-dimethylformamide (1.9 mL) were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg)
and triethylamine (0.079 mL) at room temperature. After stirring
overnight at room temperature, the reaction mixture was diluted
with dichloromethane (10 mL). The residue was separated and
purified by basic silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=85:15) and
crystallized from diisopropyl ether to give the title compound (24
mg).
[0386] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.21 (3H, s), 2.43 (3H,
s), 3.39 (3H, s) 4.04 (2H, s), 6.91 (1H, d, J=2 Hz), 6.99 (1H, d,
J=9 Hz), 7.20 (2H, m), 7.7-7.9 (6H, m), 8.17 (1H, d, J=3 Hz), 8.33
(1H, s), 9.07 (1H, br s), 9.97 (1H, br s), 11.52 (1H, br s).
Example 12
##STR00060##
[0387] Production of
6-(4-methoxyphenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-p-
yrrolo[3,2-d]pyrimidin-4-amine hydrochloride
(i) Production of
6-(4-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol
[0388] Ethyl 3-amino-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate
(7.2 g) was dissolved in tetrahydrofuran (16 mL)/ethanol (32 mL),
formamidine (3.46 g) was added, and the mixture was stirred at
90.degree. C. for 16 hrs. After cooling to room temperature,
tetrahydrofuran was evaporated under reduced pressure. The residue
was diluted with ethanol (20 mL), and the precipitated powder was
collected by filtration, washed with ethanol (15 mL) and dried
under reduced pressure to give the title compound (769 mg).
[0389] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.80 (3H, s), 6.76 (1H,
s), 6.9-7.1 (3H, m) 7.7-8.0 (2H, m), 11.83 (1H, br s).
(ii) Production of
4-chloro-6-(4-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine
[0390] 6-(4-Methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol (500 mg)
was suspended in N,N-diethylaniline (1.11 mL)/1,2-dichloroethane
(3.73 mL), phosphorus oxychloride (2.29 mL) was added, and the
mixture was stirred with heating at 110.degree. C. for 2 hrs. After
cooling to room temperature, the reaction mixture was treated with
ice water (20 mL), and adjusted to pH 7 or above with aqueous
ammonia. After diluting with tetrahydrofuran (500 mL), the mixture
was washed with saturated brine (50 mL). The organic layer was
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was separated and purified by silica gel
column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.20:80) to give the title compound (25 mg).
[0391] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.90 (3H, s), 6.92 (1H,
s), 7.05 (2H, d, J=9 Hz), 7.71 (2H, d, J=9 Hz), 8.73 (1H, s).
(iii) Production of
6-(4-methoxyphenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-p-
yrrolo[3,2-d]pyrimidin-4-amine hydrochloride
[0392] The title compound (11 mg) was obtained as crystals by the
reaction in the same manner as in Example 1 using
4-chloro-6-(4-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine (13 mg),
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (16 mg) and
1-methyl-2-pyrrolidone (0.2 mL).
[0393] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.24 (3H, s), 2.46 (3H,
s), 3.86 (3H, s), 7.02 (1H, s), 7.14 (2H, d, J=9 Hz), 7.26 (2H, m),
7.80 (1H, dd, J=3 Hz, 9 Hz), 7.90 (1H, d, J=3 Hz), 8.11 (2H, d, J=9
Hz), 8.22 (1H, d, J=3 Hz), 8.72 (1H, s), 11.54 (1H, br s).
Example 13
##STR00061##
[0394] Production of
(2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-6-yl]-2-propen-1-ol
(i) Production of
(2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)py-
rimidin-4-yl]-2-penten-4-yn-1-ol
[0395]
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine--
4,5-diamine hydriodide (507 mg) was dissolved in a mixed solvent of
acetonitrile (19.4 mL)/triethylamine (14.5 mL), 2-penten-4-yn-1-ol
(106 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (38.8
mg) and copper(I) iodide (13.4 mg) were sequentially added. The
title compound (373 mg) was obtained as a powder by the reaction in
the same manner as in Example 9 (iv).
[0396] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.17 (3H, s), 2.43 (3H,
s), 4.12 (2H, m), 5.52 (2H, br s), 6.05 (1H, dt, J=2 Hz, 16 Hz),
6.53 (1H, dt, J=5 Hz, 16 Hz), 6.93 (1H, d, J=9 Hz), 7.20 (2H, m),
7.63 (2H, m), 7.96 (1H, s), 8.15 (1H, d, J=3 Hz), 8.57 (1H, br
s).
(ii) Production of (2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)
oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol
[0397] The title compound (59 mg) was obtained by the reaction in
the same manner as in Example 9 (v) using
(2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)
oxy]phenyl}amino)pyrimidin-4-yl]-2-penten-4-yn-1-ol (200 mg),
copper(I) iodide (9.8 mg) and N,N-dimethylformamide (1.29 mL), and
crystallization from diisopropyl ether.
[0398] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.20 (3H, s), 2.43 (3H,
s), 4.22 (2H, d, J=3 Hz), 6.45 (1H, m), 6.50 (1H, s), 6.67 (1H, dt,
J=16 Hz), 6.98 (1H, d, J=9 Hz), 7.19 (2H, m), 7.72 (1H, dd, J=3 Hz,
9 Hz), 7.80 (1H, d, J=2 Hz), 8.17 (1H, d, J=2 Hz), 8.30 (1H, s),
9.02 (1H, br s), 11.30 (1H, br s).
Example 14
##STR00062##
[0399] Production of
6-[3-(aminomethyl)phenyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl-
}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of tert-butyl
3-{[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimi-
din-4-yl]ethynyl}benzylcarbamate
[0400]
6-Iodo-N-4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-
-4,5-diamine hydriodide (500 mg) was dissolved in a mixed solvent
of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl
3-ethynylbenzylcarbamate (247 mg),
trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and
copper(I) iodide (10.2 mg) were sequentially added. The title
compound (376 mg) was obtained as a powder by the reaction in the
same manner as in Example 9 (iv).
[0401] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.47 (9H, s), 2.24 (3H,
s), 2.53 (3H, s), 4.00 (2H, br s), 4.32 (2H, d, J=6 Hz), 5.04 (1H,
br s), 6.87 (1H, d, J=9 Hz), 7.01 (1H, br s), 7.09-7.5 (9H, m),
8.22 (1H, d, J=2 Hz), 8.34 (1H, s).
(ii) Production of tert-butyl
3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-
-d]pyrimidin-6-yl]benzylcarbamate
[0402] The title compound (287 mg) was obtained as a powder by the
reaction in the same manner as in Example 9 (v) using tert-butyl
3-{[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimi-
din-4-yl]ethynyl}benzylcarbamate (363 mg) and copper(I) iodide
(12.9 mg).
[0403] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.49 (9H, s), 2.17 (3H,
s), 2.51 (3H, s) 4.23 (2H, br s), 5.67 (1H, br s), 6.72 (1H, s),
6.82 (1H, d, J=8 Hz), 6.9-7.7 (8H, m), 8.16 (1H, br s), 8.60 (1H,
s), 8.66 (1H, br s), 10.64 (1H, br s).
(iii) Production of
6-[3-(aminomethyl)phenyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl-
}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0404] tert-Butyl
3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-
-d]pyrimidin-6-yl]benzylcarbamate (230 mg) was suspended in
tetrahydrofuran (2.3 mL), 2N hydrochloric acid (2.3 mL) was added,
and the mixture was stirred with heating at 60.degree. C. for 3
hrs. After cooling to room temperature, 1N aqueous sodium hydroxide
solution (4.6 mL) was added, and the mixture was stirred at room
temperature for 5 min. The solvent was removed by decantation, and
the residue was dissolved in tetrahydrofuran (30 mL), dried over
potassium carbonate, and concentrated under reduced pressure. The
residue was triturated with diisopropyl ether, collected by
filtration and dried under reduced pressure to give the title
compound (164 mg).
[0405] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.18 (3H, s), 2.41 (3H,
s), 3.92 (2H, br s), 4.86 (2H, br s), 6.9-8.2 (11H, m), 8.33 (1H,
s), 9.62 (1H, br s), 12.13 (1H, br s).
Example 15
##STR00063##
[0406] Production of
2-methoxy-N-{3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5-
H-pyrrolo[3,2-d]pyrimidin-6-yl]benzyl}acetamide
[0407] The title compound (56 mg) was obtained by the reaction in
the same manner as in Example 11 using
6-[3-(aminomethyl)phenyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl-
}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (50 mg), methoxyacetic acid
(0.01055 mL), 1-hydroxybenzotriazole monohydrate (23.2 mg),
N,N-dimethylformamide (2.3 ml),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32.9
mg) and triethylamine (0.080 mL).
[0408] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.27 (3H, s), 2.52 (3H,
s), 3.44 (3H, s), 3.98 (2H, s), 4.56 (2H, d, J=6 Hz), 6.65 (1H, s),
6.82 (1H, d, J=2 Hz), 6.93 (1H, d, J=8 Hz), 7.11 (2H, m), 7.3-7.9
(6H, m), 8.22 (1H, m), 8.47 (1H, s), 8.82 (1H, br s), 11.26 (1H, br
s).
Example 16
##STR00064##
[0409] Production of
6-(aminomethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrro-
lo[3,2-d]pyrimidin-4-amine
(i) Production of tert-butyl
3-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimid-
in-4-yl]-2-propynylcarbamate
[0410]
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine--
4,5-diamine hydriodide (500 mg) was dissolved in a mixed solvent of
acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl
2-propynylcarbamate (166 mg),
trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and
copper(I) iodide (10.2 mg) were sequentially added. The title
compound (303 mg) was obtained as a powder by the reaction in the
same manner as in Example 9 (iv).
[0411] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46 (9H, s), 2.22 (3H,
s), 2.52 (3H, s), 4.06 (2H, br s), 4.17 (2H, d, J=6 Hz), 5.09 (1H,
br s), 6.84 (1H, d, J=9 Hz), 7.0-7.5 (4H, m), 8.20 (1H, d, J=3 Hz),
8.25 (1H, s).
(ii) Production of tert-butyl
[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d-
]pyrimidin-6-yl]methylcarbamate
[0412] The title compound (212 mg) was obtained as a powder by the
reaction in the same manner as in Example 9 (v) using tert-butyl
3-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)pyrimid-
in-4-yl]-2-propynylcarbamate (286 mg) and copper(I) iodide (11.8
mg).
[0413] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (9H, s), 2.20 (3H,
s), 2.52 (3H, s), 4.30 (2H, d, J=6 Hz), 5.38 (1H, t, J=6 Hz), 6.32
(1H, br s), 6.83 (1H, d, J=9 Hz), 7.07 (1H, d, J=9 Hz), 7.1-7.4
(4H, m), 7.84 (1H, br s), 8.20 (1H, d, J=2 Hz), 8.50 (1H, s), 9.95
(1H, br s).
(iii) Production of
6-(aminomethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrro-
lo[3,2-d]pyrimidin-4-amine
[0414] The title compound (160 mg) was obtained as a powder by the
reaction in the same manner as in Example 14 (iii) using tert-butyl
[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d-
]pyrimidin-6-yl]melhylcarbamate (165 mg), 2N hydrochloric acid
(1.92 mL) and tetrahydrofuran (1.92 mL).
[0415] .sup.1H-NMR. (DMSO-d.sub.6) .delta.: 2.17 (3H, s), 2.42 (3H,
s), 3.59 (2H, t, J=6 Hz), 3.95 (2H, s), 6.25 (1H, s), 6.86 (1H, s),
6.94 (1H, d, J=8 Hz), 7.1-7.3 (2H, m), 7.78 (2H, m), 8.14 (1H, d,
J=3 Hz), 8.26 (1H, s), 9.46 (1H, br s), 11.50 (1H, br s).
Example 17
##STR00065##
[0416] Production of
(2E)-4-(dimethylamino)-N-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phen-
yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl}-2-butenamide
[0417] The title compound (32 mg) was obtained by the reaction in
the same manner as in Example 11 using
6-(aminomethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrro-
lo[3,2-d]pyrimidin-4-amine (40 mg),
(2E)-4-(dimethylamino)-2-butenoic acid hydrochloride (22 mg),
1-hydroxybenzotriazole monohydrate (22.5 mg), N,N-dimethylformamide
(2.2 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (31.9 mg) and triethylamine (0.0928 mL).
[0418] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.15 (6H, s), 2.19 (3H,
s), 2.43 (3H, s), 3.01 (2H, d, J=5 Hz), 4.55 (2H, d, J=5 Hz), 6.12
(1H, d, J=16 Hz), 6.36 (1H, d, J=1 Hz), 6.68 (1H, m), 6.96 (1H, d,
J=8 Hz), 7.18 (2H, m), 7.74 (2H, m), 8.16 (1H, d, J=3 Hz), 8.30
(1H, s), 8.70 (1H, t, J=5 Hz), 9.30 (1H, br s), 11.03 (1H, br
s).
Example 18
##STR00066##
[0419] Production of
6-[(1E)-3-amino-1-propen-1-yl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]p-
henyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of tert-butyl
(2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)py-
rimidin-4-yl]-2-penten-4-yn-1-ylcarbamate
[0420]
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine--
4,5-diamine hydriodide (500 mg) was dissolved in a mixed solvent of
acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl
(2E)-2-penten-4-yn-1-ylcarbamate (194 mg),
trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and
copper(I) iodide (10.2 mg) were sequentially added. The title
compound (199 mg) was obtained as a powder by the reaction in the
same manner as in Example 9 (iv).
[0421] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46 (9H, s), 2.20 (3H,
s), 2.52 (3H, s), 3.85 (2H, m), 4.22 (2H, br s), 5.02 (1H, br s),
5.84 (1H, d, J=16 Hz), 6.29 (1H, m), 6.84 (1H, d, J=9 Hz), 7.0-7.5
(5H, m), 8.19 (1H, d, J=2 Hz), 8.26 (1H, s).
(ii) Production of tert-butyl
(2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-6-yl]-2-propenylcarbamate
[0422] The title compound (66 mg) was obtained as a powder by the
reaction in the same manner as in Example 9 (v) using tert-butyl
(2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)py-
rimidin-4-yl]-2-penten-4-yn-1-ylcarbamate (195 mg) and copper(I)
iodide (7.63 mg).
[0423] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (9H, s), 2.12 (3H,
s), 2.49 (3H, s) 3.82 (2H, br s), 5.53 (1H, br s), 6.00 (1H, d,
J=16 Hz), 6.36 (1H, m), 6.77 (1H, d, J=9 Hz), 7.0-7.5 (4H, m), 8.09
(1H, s), 8.43 (1H, br s), 8.51 (1H, br s), 11.00 (1H, br s).
(iii) Production of
6-[(1E)-3-amino-1-propen-1-yl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]p-
henyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0424] The title compound (41 mg) was obtained as a powder by the
reaction in the same manner as in Example 14 (iii) using tert-butyl
(2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-6-yl]-2-propenylcarbamate (65 mg), 2N
hydrochloric acid (0.755 mL) and tetrahydrofuran (0.755 mL).
[0425] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.17 (3H, s), 2.42 (3H,
s), 3.41 (2H, m), 6.40 (1H, s), 6.62 (2H, m), 6.96 (1H, d, J=8 Hz),
7.17 (2H, m), 7.95 (2H, m), 8.16 (1H, d, J=3 Hz), 8.28 (1H, s),
10.09 (1H, br s), 12.43 (1H, br s).
Example 19
##STR00067##
[0426] Production of
2-methoxy-N-{(2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}ami-
no)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propenyl}acetamide
[0427] The title compound (15 mg) was obtained by the reaction in
the same manner as in Example 11 using
6-[(1E)-3-aminopropen-1-yl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phen-
yl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (50 mg), methoxyacetic acid
(0.0119 mL), 1-hydroxybenzotriazole monohydrate (26.2 mg),
N,N-dimethylformamide (2.56 mL),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.2
mg) and triethylamine (0.090 mL).
[0428] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.20 (3H, s), 2.43 (3H,
s), 3.36 (3H, s), 3.88 (2H, s), 3.97 (2H, t, J=5 Hz), 6.32 (1H, m),
6.49 (1H, d, J=1 Hz), 6.56 (1H, d, J=17 Hz), 6.97 (1H, d, J=9 Hz),
7.19 (2H, m), 7.75 (2H, m), 8.15 (1H, d, J=2 Hz), 8.24 (1H, t, J=5
Hz), 8.29 (1H, s), 9.04 (1H, br s), 11.33 (1H, br s).
Example 20
##STR00068##
[0429] Production of
(2E)-3-[5-ethyl-4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5-
H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol
(i) Production of 4-iodo-6-phenoxypyrimidin-5-amine
[0430] 4,6-Diiodopyrimidin-5-amine (2.2 g) was dissolved in
1-methyl-2-pyrrolidone (11.5 mL), phenol (656 mg) and potassium
carbonate (964 mg) were added, and the mixture was stirred at
100.degree. C. for 16 hrs. After cooling to room temperature, the
mixture was diluted with ethyl acetate (200 mL) and washed
successively with water (100 mL) and saturated brine (100 mL).
[0431] The organic layer was dried over magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.20:80) to give the title compound (2.0 g) as
an oil.
[0432] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.34 (2H, br s), 7.1-7.5
(5H, m), 7.87 (1H, s).
(ii) Production of
4-((3E)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-penten-1-ynyl)-6-phenoxypyri-
midin-5-amine
[0433] 4-Iodo-6-phenoxypyrimidin-5-amine (1.0 g) was dissolved in a
mixed solvent of acetonitrile (53 mL)/triethylamine (39 mL), and
tert-butyl(dimethyl)[(2E)-2-penten-4-ynyloxy]silane (753 mg),
trans-dichlorobis(triphenylphosphine)palladium(II) (112 mg) and
copper(I) iodide (36.5 mg) were sequentially added. The title
compound (1.07 g) was obtained as crystals by the reaction in the
same manner as in Example 9 (iv).
[0434] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.09 (6H, s), 0.93 (9H,
s), 4.32 (2H, m), 4.42 (2H, br s), 6.08 (1H, dt, J=16 Hz, 3 Hz),
6.48 (1H, dt, J=16 Hz, 4 Hz), 7.1-7.5 (5H, m), 8.11 (1H, s).
(iii) Production of
6-((1E)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propenyl)-4-phenoxy-5H-pyrro-
lo[3,2-d]pyrimidine
[0435] The title compound (409 mg) was obtained as a powder by the
reaction in the same manner as in Example 9 (v) using
4-((3E)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-penten-1-ynyl)-6-phenoxypyri-
midin-5-amine (950 mg) and copper(I) iodide (47.4 mg).
[0436] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.12 (6H, s), 0.95 (9H,
s), 4.39 (2H, m), 6.44 (1H, dt, J=16 Hz, 4 Hz), 6.67 (2H, m),
7.1-7.5 (5H, m), 8.48 (1H, s), 9.07 (1H, br s).
(iv) Production of
6-((1E)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propenyl)-5-ethyl-4-phenoxy--
5H-pyrrolo[3,2-d]pyrimidine
[0437]
6-((1E)-3-{[tert-Butyl(dimethyl)silyl]oxy}-1-propenyl)-4-phenoxy-5H-
-pyrrolo[3,2-d]pyrimidine (100 mg) was dissolved in
N,N-dimethylformamide (0.786 mL), cesium carbonate (102.6 mg) was
added, and the mixture was stirred at room temperature for 20 min.
Iodoethane (0.0231 mL) was added and the mixture was stirred at
room temperature for 2 hrs and at 40.degree. C. for 4 hrs. After
cooling to room temperature, the reaction mixture was diluted with
ethyl acetate (50 mL) and washed successively with water (30 mL)
and saturated brine (30 mL). The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was separated and purified by silica gel column
chromatography (eluent, hexane:ethyl acetate=80:20.fwdarw.50:50) to
give the title compound (79 mg) as an oil.
[0438] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.14 (6H, s), 0.97 (9H,
s), 1.44 (3H, t, J=7 Hz), 4.44 (2H, m), 4.52 (2H, q, J=7 Hz), 6.58
(1H, dt, J=15 Hz, 4 Hz), 6.74 (1H, s), 6.78 (1H, m), 7.2-7.5 (5H,
m), 8.41 (1H, s).
(v) Production of
(2E)-3-[5-ethyl-4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5-
H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol
[0439] A mixture of
6-((1E)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propenyl)-5-ethyl-4-phenoxy--
5H-pyrrolo[3,2-d]pyrimidine (78 mg),
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (61.2 mg), pyridine
hydrochloride (26 mg) and phenol (122 mg) was stirred with heating
at 120.degree. C. for 16 hrs. After cooling to room temperature,
the mixture was diluted with dichloromethane (30 mL), and washed
with saturated aqueous sodium hydrogen carbonate (20 mL). The
organic layer was dried over magnesium sulfate and concentrated
under reduced pressure. The residue was separated and purified by
basic silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.80:20) to give the title compound (32
mg) as a powder.
[0440] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46 (3H, t, J=7 Hz), 2.24
(3H, s), 2.53 (3H, s), 4.31 (2H, q, J=7 Hz), 4.42 (1H, dd, J=5 Hz,
2 Hz), 6.54 (1H, dt, J=15 Hz, 5 Hz), 6.66 (1H, s), 6.70 (1H, d,
J=15 Hz), 6.88 (1H, d, J=8 Hz), 7.0-7.4 (4H, m), 8.20 (1H, d, J=2
Hz), 8.46 (1H, s).
Example 21
##STR00069##
[0441] Production of
[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrim-
idin-6-yl]methanol hydrochloride
(i) Production of
3-(5-amino-6-phenoxypyrimidin-4-yl)-2-propyn-1-ol
[0442] 4-Iodo-6-phenoxypyrimidin-5-amine (3.0 g) was dissolved in a
mixed solvent of acetonitrile (159 mL)/triethylamine (117 mL), and
2-propyn-1-ol (0.669 mL),
trans-dichlorobis(triphenylphosphine)palladium(II) (336 mg) and
copper(I) iodide (109.5 mg) were sequentially added. The title
compound (2.02 g) was obtained as crystals by the reaction in the
same manner as in Example 9 (iv).
[0443] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.53 (1H, br s), 4.52 (2H,
br s), 4.63 (2H, br s), 7.1-7.5 (5H, m), 8.09 (1H, s).
(ii) Production of
(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanol
[0444] The title compound (1.31 g) was obtained as crystals by the
reaction in the same manner as in Example 9 (v) using
3-(5-amino-6-phenoxypyrimidin-4-yl)-2-propyn-1-ol (1.98 g) and
copper(I) iodide (156 mg).
[0445] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.67 (2H, d, J=5 Hz),
5.45 (1H, t, J=5 Hz), 6.50 (1H, s), 7.2-7.5 (5H, m), 8.26 (1H, s),
12.15 (1H, br s).
(iii) Production of
[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrim-
idin-6-yl]methanol hydrochloride
[0446] The title compound (142 mg) was obtained as crystals by the
reaction in the same manner as in Example 1 using
(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanol (100 mg),
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (156 mg), pyridine
hydrochloride (56.7 mg) and 1-methyl-2-pyrrolidone (0.828 mL).
[0447] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.76 (2H, s), 5.27 (2H,
s), 6.50 (1H, d, J=2 Hz), 7.1-7.6 (5H, m), 7.73 (1H, dd, J=3 Hz, 9
Hz), 8.12 (1H, d, J=3 Hz), 8.77 (1H, s), 11.50 (1H, br s).
Example 22
##STR00070##
[0448] Production of
(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5-methyl-5H-pyr-
rolo[3, 2-d]pyrimidin-6-yl]-2-propen-1-ol
(i) Production of
(2E)-5-(5-amino-6-phenoxypyrimidin-4-yl)-2-penten-4-yn-1-ol
[0449] 4-Iodo-6-phenoxypyrimidin-5-amine (3.5 g) was dissolved in a
mixed solvent of acetonitrile (185 mL)/triethylamine (136 mL), and
2-penten-4-yn-1-ol (1.1 g),
trans-dichlorobis(triphenylphosphine)palladium(II) (392 mg) and
copper(I) iodide (127 mg) were sequentially added. The title
compound (1.79 g) was obtained as a powder by the reaction in the
same manner as in Example 9 (iv).
[0450] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.48 (1H, br s), 4.33 (2H,
dd, J=5 Hz, 2 Hz), 4.45 (2H, br s), 6.12 (1H, dt, J=2 Hz, 16 Hz),
6.54 (1H, dt, J=16 Hz, 5 Hz), 7.1-7.5 (5H, m), 8.11 (1H, s).
(ii) Production of
(2E)-3-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propen-1-ol
[0451] The title compound (1.25 g) was obtained as crystals by the
reaction in the same manner as in Example 9 (v) using
(2E)-5-(5-amino-6-phenoxypyrimidin-4-yl)-2-penten-4-yn-1-ol (1.7 g)
and copper(I) iodide (268 mg).
[0452] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.38 (1H, br s), 4.41 (2H,
d, J=4 Hz), 6.58 (1H, dt, J=3 Hz, 16 Hz), 6.66 (1H, s), 6.75 (1H,
d, J=16 Hz), 7.2-7.5 (5H, m), 8.48 (1H, s), 9.73 (1H, br s).
(iii) Production of
(2E)-3-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl
benzoate
[0453]
(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propen-1-ol
(1.0 g) was suspended in tetrahydrofuran (20 mL), and triethylamine
(0.651 mL) and benzoyl chloride (0.86 mL) were sequentially added
under ice-cooling. The mixture was stirred under ice-cooling for 2
hrs, diluted with ethyl acetate (200 mL) and washed with water (50
mL). The organic layer was dried over magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by basic silica gel column chromatography (eluent,
hexane:ethyl acetate=80:20.fwdarw.0:100) to give the title compound
(1.08 g) as crystals.
[0454] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.03 (2H, d, J=6 Hz), 6.52
(1H, m), 6.72 (1H, dt, J=16 Hz, 2 Hz), 6.80 (1H, d, J=16 Hz),
7.1-7.7 (8H, m), 8.08 (2H, m), 8.50 (1H, s), 9.27 (1H, br s).
(iv) Production of
(2E)-3-(5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl
benzoate
[0455]
(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl
benzoate (500 mg) was dissolved in N,N-dimethylformamide (4 mL),
and potassium carbonate (279 mg) and iodomethane (0.1 mL) were
sequentially added. After stirring at room temperature for 4 hrs,
water (30 mL) was added to the reaction mixture and the mixture was
extracted with ethyl acetate (100 mL), dried over magnesium sulfate
and concentrated under reduced pressure. The residue was separated
and purified by basic silica gel column chromatography (eluent,
hexane:ethyl acetate=80:20.fwdarw.50:50) to give the title compound
(301 mg) as crystals.
[0456] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.14 (3H, s), 5.08 (2H,
dd, J=6 Hz, 1 Hz), 6.66 (1H, m), 6.84 (1H, s), 6.85 (1H, d, J=16
Hz), 7.2-7.7 (8H, m), 8.10 (2H, d, J=9 Hz), 8.42 (1H, s).
(v) Production of
(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5-methyl-5H-pyr-
rolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol
[0457] A mixture of
(2E)-3-(5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl
benzoate (100 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (130
mg), pyridine hydrochloride (36 mg) and 1-methyl-2-pyrrolidone
(0.518 mL) was stirred with heating at 140.degree. C. for 4 hrs.
After cooling to room temperature, aqueous sodium hydrogen
carbonate (20 mL) was added to the reaction mixture and the mixture
was extracted with ethyl acetate (100 mL). The organic layer was
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was dissolved in tetrahydrofuran (0.518
mL)/ethanol (0.518 mL), 1N aqueous sodium hydroxide solution (0.518
mL) was added, and the mixture was stirred at room temperature for
2 hrs. Tetrahydrofuran/ethyl acetate (1:1, 50 mL) and saturated
brine (30 mL) were added, and the mixture was extracted. The
organic layer was dried over magnesium sulfate and concentrated
under reduced pressure. The residue was separated and purified by
basic silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.85:15) to give the title compound (45
mg) as crystals.
[0458] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.00 (3H, s), 4.21 (2H,
t, J=4 Hz), 5.07 (1H, t, J=5 Hz), 5.23 (2H, s), 6.58 (1H, m), 6.68
(1H, s), 6.80 (1H, d, J=16 Hz), 7.1-7.8 (7H, m), 8.21 (1H, s), 8.49
(1H, br s).
Example 23
##STR00071##
[0459] Production of
(2E)-3-[5-methyl-4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)--
5H-pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-1-ol
[0460] The title compound (60 mg) was obtained as crystals by the
reaction in the same manner as in Example 22 (v) using
(2E)-3-(5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl
benzoate (100 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline
(111 mg), pyridine hydrochloride (36 mg) and 1-methyl-2-pyrrolidone
(0.518 mL).
[0461] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.16 (3H, s), 2.43 (3H,
s), 4.02 (3H, s) 4.22 (2H, br s), 5.07 (1H, t, J=5 Hz), 6.60 (1H,
m), 6.69 (1H, s), 6.80 (1H, d, J=16 Hz), 6.93 (1H, d, J=9 Hz),
7.1-7.6 (5H, m), 8.16 (1H, d, J=2 Hz), 8.23 (1H, s), 8.54 (1H, br
s).
Example 24
##STR00072##
[0462] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[(3,4-dimethoxyphenyl)sulfon-
yl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0463]
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimid-
in-4-amine hydrochloride (150 mg) was dissolved in
N,N-dimethylformamide (1.5 mL), and potassium carbonate (102 mg)
and (3,4-dimethoxyphenyl)sulfonyl chloride (96.9 mg) were
sequentially added under ice-cooling. The mixture was stirred under
ice-cooling for 2 hrs, and at room temperature for 1 hr. The
mixture was diluted with ethyl acetate (50 mL) and washed twice
with water (30 mL). The organic layer was dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
separated and purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=80:20.fwdarw.0:100) to give the title compound
(95 mg) as a powder.
[0464] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.68 (3H, s), 3.86 (3H,
s), 5.16 (2H, s), 6.76 (1H, d, J=4 Hz), 6.82 (1H, d, J=9 Hz), 6.97
(1H, d, J=9 Hz), 7.02 (1H, m), 7.1-7.4 (5H, m), 7.55 (1H, dd, J=9
Hz. 3 Hz), 7.79 (1H, d, J=4 Hz), 7.94 (1H, d, J=3 Hz), 8.52 (1H,
s), 9.39 (1H, br s).
Example 25
##STR00073##
[0465] Production of ethyl
5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}-2-furoate
(i) Production of ethyl
5-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate
[0466] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500
mg) in N,N-dimethylformamide (6.5 mL) was added potassium carbonate
(541 mg) under ice-cooling, and the mixture was stirred for 15 min.
while warming to room temperature. Ethyl 5-(chloromethyl)-2-furoate
(737 mg) was added to the reaction mixture, and the mixture was
stirred at room temperature for 16 hrs. The reaction mixture was
diluted with water (20 mL), and extracted with a mixed solvent (40
mL.times.3) of ethyl acetate/tetrahydrofuran (1/1). The organic
layer was washed with saturated brine (20 mL.times.3) and dried
over anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure, and the obtained residue was subjected to silica
gel column chromatography (silica gel, eluent:hexane/ethyl
acetate=80/20.fwdarw.10/90). The object fraction was concentrated
under reduced pressure and dried to give the title compound (825
mg) as a pale-yellow solid.
[0467] .sup.1H-NMR (CDCl.sub.3) .delta. 1.37 (3H, t, J=7.2 Hz),
4.36 (2H, q, J=7.2 Hz), 5.75 (2H, s), 6.30 (1H, ddd, J=0.9, 2.1,
2.7 Hz), 6.80 (1H, t, J=3.9 Hz), 7.10 (1H, t, J=3.3 Hz), 7.63 (1H,
dd, J=2.7, 3.3 Hz), 8.73 (1H, d, J=3.9 Hz).
(ii) Production of ethyl
5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}-2-furoate
[0468] To a solution of ethyl
5-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (200
mg) in 1-methyl-2-pyrrolidone (1.3 mL) was added
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (247 mg), and the mixture
was heated to 140.degree. C. and stirred for 2 hrs. The reaction
mixture was allowed to cool to room temperature, diluted with 5%
aqueous sodium hydrogen carbonate solution (20 mL) and extracted
with ethyl acetate (20 mL.times.3). The organic layer was washed
with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography (silica
gel, eluent:ethyl acetate/methanol=10/0.fwdarw.8/2). The object
fraction was concentrated under reduced pressure and dried to give
the title compound (307 mg) as a pale-yellow solid.
[0469] .sup.1H-NMR (CDCl.sub.3) .delta. 1.34 (3H, t, J=7.2 Hz),
4.38 (2H, q, J=7.2 Hz), 5.14 (2H, s), 5.49 (2H, s), 6.45 (1H, d,
J=3.4 Hz), 6.63 (1H, d, J=3.0 Hz), 6.94 (1H, d, J=8.8 Hz), 7.03
(1H, d, J=9.6 Hz), 7.26-7.38 (6H, m), 7.43 (1H, dd, J=2.6, 8.8 Hz),
7.65 (1H, d, J=3.0 Hz), 8.50 (1H, s).
Example 26
##STR00074##
[0470] Production of
5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}-2-furancarboxylic acid
[0471] To a solution of ethyl
5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}-2-furoate (280 mg) in a mixed solvent of
tetrahydrofuran (1.34 mL) and ethanol (1.34 mL) was added 1N
aqueous sodium hydroxide solution (1.34 mL) and the mixture was
stirred at room temperature for 14 hrs. 1N Hydrochloric acid (1.34
mL) and water (10 mL) were added to the reaction mixture and the
mixture was stirred at room temperature for 30 min. The resultant
precipitate was collected by filtration, washed with water (10
mL.times.3) and diisopropyl ether (10 mL.times.3) and dried under
reduced pressure (80.degree. C.) to give the title compound (178
mg) as a white powder.
[0472] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.24 (2H, s), 5.89 (2H,
s), 6.37 (1H, d, J=3.3 Hz), 6.54 (1H, d, J=2.7 Hz), 7.10 (1H, d,
J=3.3 Hz), 7.21 (2H, d, J=9.0 Hz), 7.32 (2H, t, J=6.6 Hz), 7.48
(2H, t, J=8.1 Hz), 7.73 (2H, d, J=9.6 Hz), 8.29 (1H, s), 8.57 (1H,
br s).
Example 27
##STR00075##
[0473] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-{4-[(cis-3,5-dimethylpiperaz-
in-1-yl)carbonyl]benzyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0474] To a solution of
4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoic acid (120 mg) in N,N-dimethylformamide
(2.4 mL) were added cis-2,6-dimethylpiperazine (95 mg) and
1H-1,2,3-benzotriazol-1-ol (65 mg), and the mixture was stirred at
room temperature for 15 min.
N-[3-(Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (92
mg) and triethylamine (0.2 mL) were added, and the mixture was
stirred at room temperature for 12 hrs. The reaction mixture was
diluted with water (20 mL) and extracted with ethyl acetate (25
mL.times.3). The organic layer was washed with saturated brine (20
mL.times.3) and dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure, and the obtained residue was
subjected to silica gel column chromatography (basic silica gel,
eluent:ethyl acetate/methanol=10/0.fwdarw.9/1). The object fraction
was concentrated under reduced pressure. Chloroform/diisopropyl
ether (3/7) was added to the residue and the resultant precipitate
was collected by filtration and dried under reduced pressure to
give the title compound (85 mg) as white powder crystals.
[0475] .sup.1H-NMR (CDCl.sub.3) .delta. 1.13 (6H, d, J=6.6 Hz),
1.66 (4H, br s), 2.69 (2H, br), 3.41 (1H, brd, J=6.6 Hz), 4.60 (1H,
brd, J=13.5 Hz), 5.08 (2H, s), 5.56 (2H, s), 6.28 (1H, s), 6.68
(1H, dd, J=2.1, 5.4 Hz), 6.82 (1H, d, J=9.3 Hz), 7.00 (2H, dt,
J=2.1, 8.7 Hz), 7.15-7.21 (4H, m), 7.25 (1H, d, J=2.4 Hz),
7.30-7.38 (4H, m), 7.48 (2H, d, J=8.4 Hz), 8.48 (1H, s).
Example 28
##STR00076##
[0476] Production of
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-a-
mine
[0477] To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (63
mg) in 1-methyl-2-pyrrolidone (0.8 mL), was added
3-chloro-4-(pyridin-2-ylmethoxy)aniline (149 mg), and the mixture
was heated to 140.degree. C. and stirred for 2 hrs. The reaction
mixture was allowed to cool to room temperature, diluted with 5%
aqueous sodium hydrogen carbonate solution (20 mL) and extracted
with a mixed solvent (25 mL.times.3) of ethyl
acetate/tetrahydrofuran (1/1). The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography (basic
silica gel, eluent:ethyl acetate/methanol=10/0.fwdarw.8/2). The
object fraction was concentrated under reduced pressure.
Chloroform/diisopropyl ether (1/9) was added to the residue, and
the resultant precipitate was collected by filtration and dried
under reduced pressure to give the title compound (112 mg) as
pale-yellow powder crystals.
[0478] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.27 (2H, s), 6.48 (1H,
d, J=2.4 Hz), 7.25 (1H, d, J=8.7 Hz), 7.37 (1H, dd, J=5.1, 7.5 Hz),
7.55-7.60 (2H, m), 7.66 (1H, s), 7.89 (1H, t, J=7.5 Hz), 8.20 (1H,
dd, J=1.5, 2.4 Hz), 8.35 (1H, d, J=1.5 Hz), 8.60 (1H, dd, J=0.6,
4.8 Hz), 9.25 (1H, s), 12.78 (1H, s).
Example 29
##STR00077##
[0479] Production of ethyl
5-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)methyl]-2-furoate
[0480] To a solution of ethyl
5-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (300
mg) in 1-methyl-2-pyrrolidone (2.0 mL) was added
3-chloro-4-(pyridin-2-ylmethoxy)aniline (360 mg), and the mixture
was heated to 140.degree. C. and stirred for 1.5 hrs. The reaction
mixture was allowed to cool to room temperature, diluted with 5%
aqueous sodium hydrogen carbonate solution (30 mL) and extracted
with a mixed solvent (45 mL.times.3) of ethyl
acetate/tetrahydrofuran (1/1). The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography (basic
silica gel, eluent:ethyl acetate/methanol=10/0.fwdarw.8/2). The
object fraction was concentrated under reduced pressure.
Chloroform/diisopropyl ether (1/9) was added to the residue, and
the resultant precipitate was collected by filtration and dried
under reduced pressure to give the title compound (440 mg) as
pale-yellow powder crystals.
[0481] .sup.1H-NMR (CDCl.sub.3) .delta. 1.37 (3H, t, J=7.2 Hz),
4.36 (2H, q, J=7.2 Hz), 5.33 (2H, s), 5.91 (2H, s), 6.39 (1H, d,
J=3.4 Hz), 6.57 (1H, d, J=2.6 Hz), 7.12 (1H, d, J=3.4 Hz), 7.23
(1H, d, J=9.0 Hz), 7.43 (1H, dd, J=4.8, 7.8 Hz), 7.50 (1H, dd,
J=2.2, 9.2 Hz), 7.61 (1H, d, J=7.8 Hz), 7.75 (2H, s), 7.90 (1H, dt,
J=1.2, 7.8 Hz), 8.14 (1H, d, J=4.8 Hz), 8.30 (1H, s), 8.55 (1H, br
s).
Example 30
##STR00078##
[0482] Production of
5-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)methyl]-2-furancarboxylic acid
[0483] To a solution of ethyl
5-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)methyl]-2-furoate (440 mg) in a mixed solvent of
tetrahydrofuran (2.0 mL) and ethanol (2.0 mL) was added 1N aqueous
sodium hydroxide solution (2.0 mL), and the mixture was stirred at
room temperature for 5 hrs. 1N Hydrochloric acid (2.0 mL) and water
(25 mL) were added to the reaction mixture, and the mixture was
stirred at room temperature for 30 min. The resultant precipitate
was collected by filtration, washed with water (10 mL.times.3) and
diisopropyl ether (10 mL.times.3), and dried under reduced pressure
(80.degree. C.) to give the title compound (310 mg) as white powder
crystals.
[0484] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.27 (2H, s), 5.88 (2H,
s), 6.35 (1H, d, J=3.4 Hz), 6.53 (1H, d, J=2.6 Hz), 7.08 (1H, d,
J=3.4 Hz), 7.20 (1H, d, J=9.0 Hz), 7.37 (1H, dd, J=4.8, 7.8 Hz),
7.47 (1H, dd, J=2.2, 9.2 Hz), 7.58 (1H, d, J=7.8 Hz), 7.73 (2H, s),
7.88 (1H, t, J=1.2, 7.8 Hz), 8.27 (1H, s), 8.53 (1H, br s), 8.59
(1H, d, J=4.8 Hz).
Example 31
##STR00079##
[0485] Production of ethyl
2-(3,5-dichlorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate
[0486] To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (61
mg) in 1-methyl-2-pyrrolidone (0.8 mL), was added ethyl
5-amino-2-(3,5-dichlorophenoxy)benzoate (186 mg), and the mixture
was heated to 140.degree. C. and stirred for 2.5 hrs. The reaction
mixture was allowed to cool to room temperature, diluted with 5%
aqueous sodium hydrogen carbonate solution (20 mL), and extracted
with a mixed solvent (25 mL.times.3) of ethyl
acetate/tetrahydrofuran (1/1). The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography (basic
silica gel, eluent:hexane/ethyl acetate=8/2.fwdarw.0/10). The
object fraction was concentrated under reduced pressure. Ethyl
acetate was added to the residue, and the resultant precipitate was
collected by filtration and dried under reduced pressure to give
the title compound (149 mg) as pale-yellow powder crystals.
[0487] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.10 (3H, t, J=7.2 Hz),
4.18 (2H, q, J=7.2 Hz), 6.52 (1H, d, J=2.8 Hz), 6.90 (2H, t, J=3.0
Hz), 7.28 (1H, dd, J=1.8, 2.8 Hz), 7.33 (1H, dd, J=8.8 Hz), 7.71
(1H, d, J=2.8 Hz), 8.36 (2H, d, J=8.8 Hz), 8.39 (1H, d, J=1.8 Hz),
9.60 (1H, s), 11.15 (1H, s).
Example 32
##STR00080##
[0488] Production of
2-(3,5-dichlorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic
acid
[0489] To a solution of ethyl
2-(3,5-dichlorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate
(100 mg) in a mixed solvent of tetrahydrofuran (0.68 mL) and
ethanol (0.68 mL) was added 1N aqueous sodium hydroxide solution
(0.68 mL), and the mixture was stirred at room temperature for 16
hrs. 1N Hydrochloric acid (0.68 mL) and water (5 mL) were added to
the reaction mixture, and the mixture was stirred at room
temperature for 30 min. The resultant precipitate was collected by
filtration, washed with water (10 mL.times.3) and diisopropyl ether
(10 mL.times.3) and dried under reduced pressure (80.degree. C.) to
give the title compound (76 mg) as white powder crystals.
[0490] .sup.1H-NMR (DMSO-d.sub.6) .delta. 6.52 (1H, d, J=1.2 Hz),
6.90 (2H, t, J=1.2 Hz), 7.28 (2H, dt, J=3.0, 5.1 Hz), 7.71 (1H, t,
J=2.7 Hz), 8.29 (1H, dd, J=2.7, 8.7 Hz), 8.37 (1H, d, J=2.7 Hz),
8.40 (1H, d, J=1.2 Hz), 9.59 (1H, s), 11.18 (1H, br s).
Example 33
##STR00081##
[0491] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-ethyl-5H-pyrrolo[3,2-d]pyrim-
idin-4-amine
(i) Production of 4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine
[0492] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200
mg) in N,N-dimethylformamide (1.3 mL) was added potassium carbonate
(269 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min.
[0493] Iodoethane (305 mg) was added to the reaction mixture, and
the mixture was stirred at room temperature for 3 hrs. The reaction
mixture was diluted with water (20 mL) and extracted with ethyl
acetate (30 mL.times.3). The organic layer was washed with
saturated brine (20 mL.times.3) and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel column chromatography
(silica gel, eluent:hexane/ethyl acetate=80/20.fwdarw.10/90). The
object fraction was concentrated under reduced pressure and dried
to give the title compound (187 mg) as a pale-yellow solid.
[0494] .sup.1H-NMR (CDCl.sub.3) .delta. 1.52 (3H, t, J=7.2 Hz),
4.55 (2H, q, J=7.2 Hz), 6.73 (1H, d, J=3.2 Hz), 7.51 (1H, d, J=3.2
Hz), 8.70 (1H, s).
(ii) Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-ethyl-5H-pyrrolo[3,2-d]pyrim-
idin-4-amine
[0495] To a solution of
4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (85 mg) in
1-methyl-2-pyrrolidone (0.94 mL) was added
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (177 mg). The title
compound (98 mg) was obtained as a pale-purple powder crystals by
the reaction in the same manner as in Example 29.
[0496] .sup.1H-NMR (CDCl.sub.3) .delta. 1.56 (3H, t, J=7.4 Hz),
4.33 (2H, q, J=7.4 Hz), 5.15 (2H, s), 6.51 (1H, br s), 6.58 (1H, d,
J=3.0 Hz), 6.72 (2H, s), 6.95 (1H, d, J=8.7 Hz), 7.02 (1H, m), 7.21
(1H, d, J=8.5 Hz), 7.25 (1H, d, J=3.0 Hz), 7.33-7.40 (2H, m), 7.60
(1H, d, J=2.5 Hz), 8.49 (1H, br s).
Example 34
##STR00082##
[0497] Production of
5-ethyl-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d-
]pyrimidin-4-amine
[0498] To a solution of
4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (85 mg) in
1-methyl-2-pyrrolidone (0.94 mL) was added
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (150 mg). The title
compound (67 mg) was obtained as white powder crystals by the
reaction in the same manner as in Example 29.
[0499] .sup.1H-NMR (CDCl.sub.3) .delta. 1.57 (3H, t, J=7.4 Hz),
2.25 (3H, s), 2.53 (3H, s), 4.35 (2H, q, J=7.4 Hz), 6.58 (1H, d,
J=3.0 Hz), 6.67 (1H, br s), 6.89 (1H, d, J=8.7 Hz), 7.08 (1H, d,
J=8.5 Hz), 7.13 (1H, dd, J=3.0, 8.7 Hz), 7.25 (1H, d, J=3.0 Hz),
7.34 (1H, dd, J=2.6, 8.7 Hz), 7.42 (1H, d, J=2.5 Hz), 8.23 (1H, d,
1H, J=2.5 Hz), 8.50 (1H, s).
Example 35
##STR00083##
[0500] Production of
N-benzyl-N'-[3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenyl]urea
[0501] To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100
mg) in 1-methyl-2-pyrrolidone (1.3 mL), was added
N-(3-aminophenyl)-N'-benzylurea (220 mg), and the mixture was
heated to 140.degree. C. and stirred for 1.5 hrs. The reaction
mixture was allowed to cool to room temperature, diluted with 5%
aqueous sodium hydrogen carbonate solution (20 mL), and extracted
with a mixed solvent (30 mL.times.3) of ethyl
acetate/tetrahydrofuran (1/1). The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography (basic
silica gel, eluent:ethyl acetate/methanol=100/0.fwdarw.85/15). The
object fraction was concentrated under reduced pressure. Ethyl
acetate was added to the residue, and the resultant precipitate was
collected by filtration and dried under reduced pressure to give
the title compound (97 mg) as pale-yellow powder crystals.
[0502] .sup.1H-NMR (DMSO-d.sub.6) .delta. 4.32 (2H, d, J=5.8 Hz),
6.47 (1H, s), 6.63 (1H, t, J=5.8 Hz), 7.02 (1H, d, J=8.4 Hz),
7.16-7.32 (6H, m), 7.62 (2H, d, J=8.4 Hz), 7.98 (1H, s), 8.33 (1H,
s), 8.63 (1H, s), 9.15 (1H, s), 11.22 (1H, s).
Example 36
##STR00084##
[0503] Production of
4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}-N-(2-hydroxyethyl)benzamide
[0504] To a solution of
4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoic acid (126 mg) in N,N-dimethylformamide
(1.2 mL) were added
N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (72
mg) and 1-hydroxypyrrolidine-2,5-dione (43 mg), and the mixture was
stirred at room temperature for 3 hrs. To this reaction mixture was
added dropwise a solution of 2-aminoethanol (23 mg) in a mixed
solvent of N,N-dimethylformamide (1.2 mL) and 10% aqueous sodium
hydrogen carbonate (1.2 mL), and the mixture was stirred at room
temperature for 48 hrs. The reaction mixture was diluted with water
(25 mL) and extracted with ethyl acetate (25 mL.times.3). The
organic layer was washed with saturated brine (25 mL.times.3), and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained residue was subjected to
silica gel column chromatography (basic silica gel, eluent:ethyl
acetate/methanol=10/0.fwdarw.8/2). The object fraction was
concentrated under reduced pressure. Chloroform/diisopropyl ether
(1/4) was added to the residue, and the resultant precipitate was
collected by filtration and dried under reduced pressure to give
the title compound (105 mg) as white powder crystals.
[0505] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.27 (2H, t, J=5.9 Hz),
3.41-3.48 (2H, m), 4.68 (1H, t, J=5.9 Hz), 5.21 (2H, s), 5.84 (2H,
s), 6.56 (1H, d, J=3.0 Hz), 7.06 (2H, d, J=8.1 Hz), 7.08 (2H, t,
J=7.5 Hz), 7.27-7.35 (3H, m), 7.46 (1H, dt, J=5.8, 8.1 Hz), 7.64
(1H, d, J=2.5 Hz), 7.73 (2H, d, J=8.3 Hz), 7.82 (1H, d, J=3.0 Hz),
8.27 (2H, s), 8.33 (1H, t, J=5.4 Hz).
Example 37
##STR00085##
[0506] Production of
N-(3-amino-3-oxopropyl)-4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}am-
ino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzamide
[0507] The title compound (83 mg) was obtained as white powder
crystals by the reaction in the same manner as in Example 27 using
4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoic acid (120 mg) and P-alaninamide
hydrochloride (45 mg).
[0508] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.29 (1H, t, J=7.2 Hz),
3.37-3.42 (4H, m), 5.21 (2H, s), 5.83 (2H, s), 6.56 (1H, d, J=3.3
Hz), 6.80 (1H, br s), 7.06 (2H, d, J=8.3 Hz), 7.18 (2H, t, J=9.0
Hz), 7.29-7.34 (4H, m), 7.46 (1H, dt, J=5.8, 7.9 Hz), 7.63 (1H, d,
J=2.4 Hz), 7.71 (2H, d, J=8.3 Hz), 7.81 (1H, d, J=3.2 Hz), 8.26
(1H, d, J=3.3 Hz), 8.40 (1H, t, J=5.7 Hz).
Example 38
##STR00086##
[0509] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-ethoxyethyl)-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
(i) Production of
4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine
[0510] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500
mg) in N,N-dimethylformamide (4.5 mL) was added cesium carbonate
(1324 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. 1-Bromo-2-ethoxyethane
(1016 mg) was added to the reaction mixture, and the mixture was
stirred at room temperature for 14 hrs. The reaction mixture was
diluted with water (100 mL) and extracted with ethyl acetate (120
mL.times.3). The organic layer was washed with saturated brine (100
mL.times.3) and dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure, and the obtained residue was
subjected to silica gel column chromatography (silica gel,
eluent:hexane/ethyl acetate=85/15.fwdarw.20/80). The object
fraction was concentrated under reduced pressure and dried to give
the title compound (697 mg) as a pale-yellow oil.
[0511] .sup.1H-NMR (CDCl.sub.3) .delta. 1.13 (3H, t, J=6.9 Hz),
3.43 (2H, q, J=6.9 Hz), 3.78 (2H, t, J=5.1 Hz), 4.67 (2H, t, J=5.1
Hz), 6.71 (1H, d, J=3.0 Hz), 7.59 (1H, d, J=3.0 Hz), 8.70 (1H,
s).
(ii) Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-ethoxyethyl)-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
[0512] To a solution of
4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (90 mg) in
1-methyl-2-pyrrolidone (0.7 mL),
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (151 mg) was added, and the
mixture was heated to 140.degree. C. and stirred for 7 hrs. The
reaction mixture was allowed to cool to room temperature. The
reaction mixture was diluted with 5% aqueous sodium hydrogen
carbonate solution (20 mL) and extracted with ethyl acetate (25
mL.times.3). The organic layer was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained residue was subjected to
silica gel column chromatography (basic silica gel, eluent:ethyl
acetate/methanol=10/0.fwdarw.8/2). The object fraction was
concentrated under reduced pressure. The residue was recrystallized
from diisopropyl ether, collected by filtration and dried under
reduced pressure to give the title compound (90 mg) as pale-yellow
needle crystals.
[0513] .sup.1H-NMR (CDCl.sub.3) .delta. 1.22 (3H, t, J=7.0 Hz),
3.63 (2H, q, J=7.0 Hz), 3.90 (2H, t, J=4.4 Hz), 4.50 (2H, t, J=4.4
Hz), 5.13 (2H, s), 6.61 (1H, d, J=3.2 Hz), 6.94 (1H, d, J=8.9 Hz),
7.01 (1H, t, J=8.1 Hz), 7.17-7.25 (3H, m), 7.35 (1H, dt, J=5.6, 7.9
Hz), 7.47 (1H, dd, J=1.3, 8.9 Hz), 7.64 (1H, d, J=2.6 Hz), 8.48
(1H, s), 8.79 (1H, s).
Example 39
##STR00087##
[0514] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-methyl-5H-pyrrolo[3,2-d]pyri-
midin-4-amine
(i) Production of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine
[0515] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (320
mg) in N,N-dimethylformamide (2.0 mL), was added potassium
carbonate (452 mg) under ice-cooling, and the mixture was stirred
while warming to room temperature for 15 min. Iodomethane (444 mg)
was added to the reaction mixture, and the mixture was stirred at
room temperature for 3 hrs. The reaction mixture was diluted with
water (25 mL) and extracted with ethyl acetate (30 mL.times.3). The
organic layer was washed with saturated brine (20 mL.times.3) and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained residue was subjected to
silica gel column chromatography (silica gel, eluent:hexane/ethyl
acetate=80/20.fwdarw.10/90). The object fraction was concentrated
under reduced pressure and dried to give the title compound (325
mg) as a pale-yellow solid.
[0516] .sup.1H-NMR (CDCl.sub.3) .delta. 4.16 (3H, s), 6.70 (1H, d,
J=3.9 Hz), 7.42 (1H, d, J=3.9 Hz), 8.69 (1H, s).
(ii) Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-methyl-5H-pyrrolo[3,2-d]pyri-
midin-4-amine
[0517] To a solution of
4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in
1-methyl-2-pyrrolidone (1.0 mL) was added
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (225 mg), and the mixture
was heated to 140.degree. C. and stirred for 1.5 hrs. The reaction
mixture was allowed to cool to room temperature, diluted with 5%
aqueous sodium hydrogen carbonate solution (25 mL), and extracted
with ethyl acetate (30 mL.times.3). The organic layer was washed
with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography
(eluent:hexane/ethyl acetate=95/5->0/100). The object fraction
was concentrated under reduced pressure. The residue was
recrystallized from a mixed solvent of diisopropyl ether and
chloroform, collected by filtration and dried under reduced
pressure to give the title compound (121 mg) as a pale-purple
powder crystals.
[0518] .sup.1H-NMR (DMSO-d.sub.6) .delta. 4.14 (3H, s), 5.24 (2H,
s), 6.42 (1H, d, J=3.0 Hz), 7.16-7.23 (2H, m), 7.29-7.34 (2H, m),
7.44-7.56 (3H, m), 7.78 (1H, d, J=2.4 Hz), 8.24 (1H, s), 8.36 (1H,
s).
Example 40
##STR00088##
[0519] Production of 5-methyl-N-{3-methyl-4-[(6-methylpyridin-3-yl)
oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0520] To a solution of
4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in
1-methyl-2-pyrrolidone (1.0 mL) was added
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (192 mg).
[0521] The title compound (106 mg) was obtained as white powder
crystals by the reaction in the same manner as in Example 39
(ii).
[0522] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.17 (3H, s), 2.44 (3H,
s), 4.15 (3H, s), 6.43 (1H, dd, J=0.9, 3.0 Hz), 6.94 (1H, d, J=8.4
Hz), 7.18 (1H, dd, J=3.0, 8.4 Hz), 7.24 (1H, d, J=8.7 Hz), 7.51
(1H, d, J=8.7 Hz), 7.56 (1H, d, J=3.0 Hz), 8.17 (1H, d, J=3.0 Hz),
8.25 (1H, d, J=0.9 Hz), 8.40 (1H, s), 8.63 (1H, s).
Example 41
##STR00089##
[0523] Production of
2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-5-yl]ethanol
(i) Production of
5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-chloro-5H-pyrrolo[3,2-d]pyr-
imidine
[0524] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307
mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate
(977 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added tert-butyl(2-iodoethoxy)dimethylsilane (839 mg), and the
mixture was stirred at room temperature for 16 hrs. The reaction
mixture was diluted with water (20 mL) and extracted with ethyl
acetate (30 mL.times.3). The organic layer was washed with
saturated brine (30 mL.times.3) and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel column chromatography
(silica gel, eluent:hexane/ethyl acetate=85/15.fwdarw.10/90). The
object fraction was concentrated under reduced pressure and dried
to give the title compound (591 mg) as a white solid.
[0525] .sup.1H-NMR (DMSO-d.sub.6) .delta. 0.95 (9H, s), 4.10 (2H,
t, J=5.2 Hz), 4.76 (2H, t, J=5.2 Hz), 6.87 (1H, d, J=3.0 Hz), 7.57
(1H, d, J=3.0 Hz), 8.85 (1H, s).
(ii) Production of
2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol
[0526] To a solution of
5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-chloro-5H-pyrrolo[3,2-d]pyr-
imidine (560 mg) in tetrahydrofuran (1.7 mL), was added
tetrabutylammonium fluoride (1M tetrahydrofuran solution) (2.69 mL)
under ice-cooling, and the mixture was stirred for 4 hrs. The
reaction mixture was diluted with water (20 mL) and extracted with
ethyl acetate (30 mL.times.3). The organic layer was washed with
saturated brine (30 mL.times.3) and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel column chromatography
(silica gel, eluent:ethyl acetate/methanol=10/0.fwdarw.9/1). The
object fraction was concentrated under reduced pressure and dried
to give the title compound (391 mg) as a white solid.
[0527] .sup.1H-NMR (CDCl.sub.3) .delta. 2.13 (2H, td, J=6.3, 12.6
Hz), 4.66 (2H, t, J=6.3 Hz), 6.72 (1H, d, J=3.0 Hz), 7.57 (1H, d,
J=3.0 Hz), 8.70 (1H, s).
(iii) Production of
2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-5-yl]ethanol
[0528] To a solution of
2-(4-chloro-5H-pyrrolo[3,2-O]pyrimidin-5-yl)ethanol (130 mg) in
1-methyl-2-pyrrolidone (1.3 mL) was added
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction
mixture was stirred at 120.degree. C. for 2 hrs. The reaction
mixture was allowed to cool to room temperature and ethyl acetate
(20 mL) was added. The resultant precipitate was recrystallized
from a mixed solvent of hexane/methanol (3/7), collected by
filtration and dried under reduced pressure to give the title
compound (206 mg) as pale purple crystals.
[0529] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.86 (2H, t, J=4.3 Hz),
4.54 (2H, m), 5.24 (2H, s), 6.23 (1H, br s), 6.53 (1H, d, J=3.2
Hz), 7.18 (1H, dt, J=2.6, 8.1 Hz), 7.25 (1H, d, J=9.0 Hz),
7.29-7.34 (2H, m), 7.43-7.51 (2H, m), 7.70 (1H, d, J=3.2 Hz), 7.78
(1H, d, J=2.6 Hz), 8.37 (1H, br s), 9.82 (1H, br s).
Example 42
##STR00090##
[0530] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-propyl-5H-pyrrolo[3,2-d]pyri-
midin-4-amine
(i) Production of 4-chloro-5-propyl-5H-pyrrolo[3,2-d]pyrimidine
[0531] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150
mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate
(798 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added 1-bromopropane (301 mg), and the mixture was stirred at room
temperature for 15 hrs. The reaction mixture was diluted with water
(20 mL) and extracted with ethyl acetate (30 mL.times.3). The
organic layer was washed with saturated brine (30 mL.times.3) and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained residue was subjected to
silica gel column chromatography (silica gel, eluent:hexane/ethyl
acetate=90/10.fwdarw.20/80). The object fraction was concentrated
under reduced pressure and dried to give the title compound (161
mg) as a white solid.
[0532] .sup.1H-NMR (CDCl.sub.3) .delta. 0.96 (3H, t, J=7.5 Hz),
1.86-1.98 (2H, m), 4.44 (2H, t, J=7.5 Hz), 6.73 (1H, t, J=3.3 Hz),
7.48 (1H, d, J=3.3 Hz), 8.70 (1H, s).
(ii) Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-propyl-5H-pyrrolo[3,2-d]pyri-
midin-4-amine
[0533] To a solution of
4-chloro-5-propyl-5H-pyrrolo[3,2-d]pyrimidine (80 mg) in
1-methyl-2-pyrrolidone (0.8 mL) was added
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction
mixture was stirred at 120.degree. C. for 2 hrs. The reaction
mixture was allowed to cool to room temperature, diluted with 5%
aqueous sodium hydrogen carbonate solution (25 mL), and extracted
with ethyl acetate (30 mL.times.3). The organic layer was washed
with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography
(eluent:ethyl acetate/methanol=100/0.fwdarw.95/5). The object
fraction was concentrated under reduced pressure. To the residue
was added a mixed solvent of diisopropyl ether and chloroform. The
resultant precipitate was collected by filtration and dried under
reduced pressure to give the title compound (96 mg) as a
pale-purple powder.
[0534] .sup.1H-NMR (DMSO-d.sub.6) .delta. 0.85 (3H, t, J=6.0 Hz),
1.81 (2H, q, J=6.9 Hz), 4.42 (2H, t, J=6.9 Hz), 5.18 (2H, s), 6.47
(1H, dd, J=1.8, 3.0 Hz), 7.02 (1H, d, J=8.7 Hz), 7.06 (1H, d, J=2.4
Hz), 7.21-7.49 (4H, m), 7.71 (1H, d, J=2.4 Hz), 7.77 (1H, br s),
8.07 (1H, br s), 8.34 (1H, d, J=2.1 Hz).
Example 43
##STR00091##
[0535] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-isobutyl-5H-pyrrolo[3,2-d]py-
rimidin-4-amine
(i) Production of
4-chloro-5-isobutyl-5H-pyrrolo[3,2-d]pyrimidine
[0536] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150
mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate
(478 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added 1-bromo-2-methylpropane (336 mg), and the mixture was stirred
at room temperature for 19 hrs. The reaction mixture was diluted
with water (20 mL) and extracted with ethyl acetate (30
mL.times.3). The organic layer was washed with saturated brine (30
mL.times.3) and dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure, and the obtained residue was
subjected to silica gel column chromatography (silica gel,
eluent:hexane/ethyl acetate=90/10.fwdarw.20/80). The object
fraction was concentrated under reduced pressure and dried to give
the title compound (210 mg) as a white solid.
[0537] .sup.1H-NMR (CDCl.sub.3) .delta. 0.94 (6H, d, J=6.6 Hz),
2.14-2.27 (1H, m), 4.26 (2H, d, J=7.5 Hz), 6.72 (1H, d, J=2.4 Hz),
7.46 (1H, d, J=2.4 Hz), 8.70 (1H, s).
(ii) Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-isobutyl-5H-pyrrolo[3,2-d]py-
rimidin-4-amine
[0538] The title compound (89 mg) was obtained as a pale-purple
powder by the reaction in the same manner as in Example 42 (ii)
using a solution of 4-chloro-5-isobutyl-5H-pyrrolo[3,2-d]pyrimidine
(90 mg) in 1-methyl-2-pyrrolidone (0.8 mL).
[0539] .sup.1H-NMR (DMSO-d.sub.6) .delta. 0.83 (6H, d, J=6.3 Hz),
2.08 (1H, m), 4.24 (2H, d, J=7.5 Hz), 5.17 (2H, s), 6.47 (1H, d,
J=2.7 Hz), 7.02 (2H, d, J=8.7 Hz), 7.22-7.29 (2H, m), 7.32 (1H, d,
J=3.0 Hz), 7.40 (1H, dt, J=6.0, 8.1 Hz), 7.46 (1H, dd, J=2.7, 9.0
Hz), 7.73 (1H, d, J=2.7 Hz), 7.79 (1H, s), 8.09 (1H, br s).
Example 44
##STR00092##
[0540] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(tetrahydrofuran-2-ylmethyl)-
-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of
4-chloro-5-(tetrahydrofuran-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidine
[0541] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150
mg) in N,N-dimethylformamide (1.0 mL) was added cesium carbonate
(478 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added 2-(bromomethyl)tetrahydrofuran (242 mg), and the mixture was
stirred at room temperature for 26 hrs. The reaction mixture was
diluted with water (20 mL) and extracted with ethyl acetate (30
mL.times.3). The organic layer was washed with saturated brine (30
mL.times.3) and dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure, and the obtained residue was
subjected to silica gel column chromatography (silica gel,
eluent:hexane/ethyl acetate=90/10.fwdarw.20/80). The object
fraction was concentrated under reduced pressure and dried to give
the title compound (200 mg) as a colorless oil.
[0542] .sup.1H-NMR (CDCl.sub.3) .delta. 1.47-1.64 (1H, m),
1.85-2.17 (3H, m), 3.75-3.90 (2H, m), 4.18-4.31 (1H, m), 4.42-4.53
(1H, m), 4.71 (1H, dd, J=3.4, 14.6 Hz), 6.74 (1H, d, J=3.0 Hz),
7.63 (1H, d, J=3.0 Hz), 8.70 (1H, s).
(ii) Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(tetrahydrofuran-2-ylmethyl)-
-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0543] The title compound (139 mg) was obtained as white powder by
the reaction in the same manner as in Example 42 (ii) using a
solution of
4-chloro-5-(tetrahydrofuran-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidine
(200 mg) in 1-methyl-2-pyrrolidone (1.6 mL).
[0544] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.56-1.65 (2H, m),
1.78-1.80 (1H, m), 1.97-2.07 (1H, m), 3.70 (2H, m), 4.17-4.19 (1H,
m), 4.43 (1H, dd, J=6.0, 15.0 Hz), 4.67 (1H, d, J=13.8 Hz), 5.21
(2H, s), 7.14 (1H, dd, J=8.1 Hz), 7.20 (1H, d, J=8.1 Hz), 7.27-7.48
(4H, m), 7.61 (1H, d, J=2.1 Hz), 7.78 (1H, d, J=1.5 Hz), 8.25 (1H,
d, J=1.2 Hz), 8.60 (1H, d, J=1.2 Hz), 9.03 (1H, s).
Example 45
##STR00093##
[0545] Production of methyl
3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoate
(i) Production of methyl
3-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate
[0546] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300
mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate
(955 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added methyl 3-(bromomethyl)benzoate (671 mg), and the mixture was
stirred at room temperature for 4 hrs. The reaction mixture was
diluted with water (40 mL), and extracted with a mixed solvent (40
mL.times.3) of ethyl acetate/tetrahydrofuran (1/1). The organic
layer was washed with saturated brine (120 mL.times.3) and dried
over anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure, and the obtained residue was subjected to silica
gel column chromatography (silica gel, eluent:hexane/ethyl
acetate=80/20.fwdarw.10/90). The object fraction was concentrated
under reduced pressure. Chloroform/diisopropyl ether (4/1) was
added to the residue, and the resultant precipitate was collected
by filtration, washed and dried under reduced pressure to give the
title compound (319 mg) as a pale-brown powder.
[0547] .sup.1H-NMR (CDCl.sub.3) .delta. 3.90 (3H, s), 5.77 (2H, s),
6.82 (1H, d, J=3.4 Hz), 7.19 (1H, dd, J=1.2, 7.8 Hz), 7.41 (1H, t,
J=7.8 Hz), 7.54 (1H, d, J=3.4 Hz), 7.82 (1H, s), 7.98 (1H, dt,
J=1.2, 7.8 Hz), 8.73 (1H, s).
(ii) Production of methyl
3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoate
[0548] To a solution of methyl
3-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate (670
mg) in 1-methyl-2-pyrrolidone (3.0 mL) was added
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (549 mg), and the reaction
mixture was stirred at 120.degree. C. for 1.5 hrs. The reaction
mixture was allowed to cool to room temperature, diluted with 5%
aqueous sodium hydrogen carbonate solution (50 mL), and extracted
with ethyl acetate (50 mL.times.3). The organic layer was washed
with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography (basic
silica gel, eluent:hexane/ethyl acetate=9/1.fwdarw.0/10). The
object fraction was concentrated under reduced pressure and dried
to give the title compound (1010 mg) as a yellow oil.
[0549] .sup.1H-NMR (CDCl.sub.3) .delta. 3.93 (3H, s), 5.08 (2H, s),
5.60 (2H, s), 6.39 (1H, s), 6.67 (1H, d, J=3.4 Hz), 6.82 (1H, d,
J=9.2 Hz), 7.01 (2H, dd, J=2.6, 8.8 Hz), 7.16-7.40 (3H, m), 7.56
(1H, t, J=7.8 Hz), 7.94 (1H, s), 8.09 (1H, d, J=7.8 Hz), 8.47 (1H,
s).
Example 46
##STR00094##
[0550] Production of
3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoic acid
[0551] To a solution of methyl
3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoate (800 mg) in a mixed solvent of
tetrahydrofuran (4.0 mL) and methanol (4.0 mL) was added 1N aqueous
sodium hydroxide solution (4.0 mL), and the mixture was stirred at
room temperature for 12 hrs. 1N Hydrochloric acid (4.0 mL) and
water (15 mL) were added to the reaction mixture, and the mixture
was stirred at room temperature for 30 min. The resultant
precipitate was collected by filtration, washed with water (10
mL.times.3) and diisopropyl ether (10 mL.times.3) and dried under
reduced pressure (80.degree. C.) to give the title compound (610
mg) as a white powder.
[0552] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.21 (2H, s), 5.86 (2H,
s), 6.57 (1H, dd, J=1.5, 3.3 Hz), 7.14-7.51 (8H, m), 7.58 (1H, dd,
J=1.5, 2.4 Hz), 7.69 (1H, s), 7.78 (1H, d, J=6.3 Hz), 7.84 (1H, d,
J=1.8 Hz), 8.27 (1H, d, J=1.5 Hz), 8.30 (1H, s).
Example 47
##STR00095##
[0553] Production of
5-(2-ethoxyethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyr-
rolo[3, 2-0]pyrimidin-4-amine
[0554] To a solution of
4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in
1-methyl-2-pyrrolidone (1.4 mL) was added
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (228 mg), and the
reaction mixture was stirred at 120.degree. C. for 2 hrs. The
reaction mixture was allowed to cool to room temperature, diluted
with 5% aqueous sodium hydrogen carbonate solution (25 mL), and
extracted with ethyl acetate (40 mL.times.3). The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel column chromatography
(eluent:hexane/ethyl acetate=90/10.fwdarw.0/100). The object
fraction was concentrated under reduced pressure and dried to give
the title compound (191 mg) as a colorless transparent oil.
[0555] .sup.1H-NMR (CDCl.sub.3) .delta. 1.25 (3H, dt, J=2.1, 7.2
Hz), 2.14 (3H, s), 2.52 (3H, s), 3.65 (2H, q, J=7.2 Hz), 3.92 (2H,
t, J=4.5 Hz), 4.54 (2H, t, J=4.5 Hz), 6.62 (1H, d, J=3.0 Hz), 6.91
(1H, d, J=8.4 Hz), 7.11 (1H, dd, J=2.7, 8.4 Hz), 7.20 (1H, d, J=3.0
Hz), 7.40 (1H, dd, J=2.7, 8.4 Hz), 7.51 (1H, d, J=3.0 Hz), 8.26
(1H, dd, J=0.6, 2.7 Hz), 8.50 (1H, s), 8.84 (1H, br s).
Example 48
##STR00096##
[0556] Production of
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-(2-ethoxyethyl)-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
[0557] To a solution of
4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in
1-methyl-2-pyrrolidone (1.4 mL) was added
3-chloro-4-(pyridin-2-ylmethoxy)aniline (250 mg). The title
compound (160 mg) was obtained as pale-yellow needle crystals by
the reaction in the same manner as in Example 42 (ii).
[0558] .sup.1H-NMR (CDCl.sub.3) .delta. 1.23 (3H, t, J=7.2 Hz),
3.64 (2H, q, J=7.2 Hz), 3.91 (2H, t, J=7.2 Hz), 4.51 (2H, t, J=7.2
Hz), 5.27 (2H, s), 6.12 (1H, s), 6.61 (1H, d, J=3.3 Hz), 6.97 (1H,
d, J=8.7 Hz), 7.18 (1H, d, J=3.3 Hz), 7.42 (1H, dd, J=2.7, 8.7 Hz),
7.66 (1H, s), 7.69 (1H, d, J=2.1 Hz), 7.76 (1H, dt, J=1.5, 8.7 Hz),
8.49 (1H, s), 8.60 (1H, d, J=4.5 Hz), 8.81 (1H, s).
Example 49
##STR00097##
[0559] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-fluoroethyl)-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
(i) Production of
4-chloro-5-(2-fluoroethyl)-5H-pyrrolo[3,2-d]pyrimidine
[0560] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100
mg) in N,N-dimethylformamide (0.6 mL) was added cesium carbonate
(281 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added 1-bromo-2-fluoroethane (124 mg), and the mixture was stirred
at room temperature for 5 hrs. The reaction mixture was diluted
with water (20 mL) and extracted with ethyl acetate (20
mL.times.3). The organic layer was washed with saturated brine (20
mL.times.3) and dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure, and the obtained residue was
subjected to silica gel column chromatography (silica gel,
eluent:hexane/ethyl acetate=90/10.fwdarw.0/10). The object fraction
was concentrated under reduced pressure and dried to give the title
compound (110 mg) as a colorless transparent oil.
[0561] .sup.1H-NMR (CDCl.sub.3) .delta. 4.64-4.69 (1H, m),
4.75-4.79 (1H, m), 4.91 (2H, d, J=5.1 Hz), 6.77 (1H, dd, J=1.4, 3.4
Hz), 7.57 (1H, d, J=3.4 Hz), 8.73 (1H, s).
(ii) Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-fluoroethyl)-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
[0562] The title compound (124 mg) was obtained as white powder
crystals by the reaction in the same manner as in Example 39 (ii)
using a solution of
4-chloro-5-(2-fluoroethyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg) in
1-methyl-2-pyrrolidone (1.0 mL).
[0563] .sup.1H-NMR (CDCl.sub.3) .delta. 4.65(2H, dt, J=4.0, 29.0
Hz), 4.90 (2H, dt, J=4.0, 47.2 Hz), 5.14 (2H, s), 6.65 (1H, d,
J=3.0 Hz), 6.93 (1H, d, J=8.8 Hz), 7.04 (1H, d, J=8.8 Hz),
7.21-7.41 (6H, m), 7.55 (1H, s), 8.48 (1H, s).
Example 50
##STR00098##
[0564] Production of
3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}-N-(2-hydroxyethyl)benzamide
[0565] The title compound (93 mg) was obtained as white powder
crystals by the reaction in the same manner as in Example 36 using
3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]py-
rimidin-5-yl]methyl}benzoic acid (126 mg).
[0566] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.26-3.48 (4H, m), 4.71
(1H, t, J=5.6 Hz), 5.21 (2H, s), 5.83 (2H, s), 6.55 (1H, d, J=2.6
Hz), 7.06-7.52 (7H, m), 7.61-7.72 (4H, m), 7.80 (1H, d, J=3.2 Hz),
8.26 (2H, s), 8.39 (1H, m).
Example 51
##STR00099##
[0567] Production of ethyl
[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d-
]pyrimidin-5-yl]acetate
(i) Production of ethyl
(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate
[0568] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200
mg) in N,N-dimethylformamide (1.3 mL) was added cesium carbonate
(615 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added ethyl bromoacetate (326 mg), and the mixture was stirred at
room temperature for 2.5 hrs. The reaction mixture was diluted with
water (20 mL) and extracted with ethyl acetate (20 mL.times.3). The
organic layer was washed with saturated brine (20 mL.times.3) and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained residue was subjected to
silica gel column chromatography (silica gel, eluent:hexane/ethyl
acetate=90/10.fwdarw.0/10). The object fraction was concentrated
under reduced pressure and dried to give the title compound (210
mg) as white powder crystals.
[0569] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.29 (3H, t, J=7.2 Hz),
4.27 (2H, q, J=7.2 Hz), 5.21 (2H, s), 6.80 (1H, d, J=3.3 Hz), 7.45
(1H, d, J=3.3 Hz), 8.74 (1H, s).
(ii) Production of ethyl
[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d-
]pyrimidin-5-yl]acetate
[0570] To a solution of ethyl
(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (140 mg) in
isopropyl alcohol (0.6 mL) was added
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (188 mg), and the
mixture was stirred in an oil bath at a temperature of 110.degree.
C. for 2 hrs. The reaction mixture was allowed to cool to room
temperature, diluted with 5% aqueous sodium hydrogen carbonate
solution (20 mL) and extracted with ethyl acetate (25 mL.times.3).
The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate.
[0571] The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel column chromatography
(basic silica gel, eluent:ethyl acetate/methanol=10/0.fwdarw.9/1).
The object fraction was concentrated under reduced pressure.
Diisopropyl ether was added to the residue, and the resultant
precipitate was collected by filtration and dried under reduced
pressure to give the title compound (210 mg) as white powder
crystals.
[0572] .sup.1H-NMR (CDCl.sub.3) .delta. 1.35 (3H, t, J=7.0 Hz),
2.25 (3H, s), 2.53 (3H, s), 4.35 (2H, q, J=7.0 Hz), 4.96 (2H, s),
6.64 (1H, d, J=3.4 Hz), 6.90 (1H, d, J=8.8 Hz), 7.08 (1H, d, J=1.8
Hz), 7.09 (1H, d, J=2.6 Hz), 7.22 (1H, d, J=3.4 Hz), 7.37 (1H, d,
J=8.8 Hz), 7.44 (1H, d, J=2.6 Hz), 8.17 (1H, br s), 8.26 (1H, d,
J=1.8 Hz), 8.53 (1H, s).
Example 52
##STR00100##
[0573] Production of
[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d-
]pyrimidin-5-yl]acetic acid
[0574] The title compound (101 mg) was obtained as white powder by
the reaction in the same manner as in Example 46 using ethyl
[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d-
]pyrimidin-5-yl]acetate (200 mg).
[0575] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.43 (3H, s), 2.51 (3H,
s), 5.30 (2H, s), 6.49 (1H, s), 6.92 (1H, d, J=8.8 Hz), 7.20-7.25
(2H, m), 7.37-7.44 (2H, m), 7.62 (1H, s), 8.17 (1H, s), 8.31 (1H,
s).
Example 53
##STR00101##
[0576] Production of
3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-5-yl]propan-1-ol
(i) Production of
5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-chloro-5H-pyrrolo[3,2-d]py-
rimidine
[0577] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (400
mg) in N,N-dimethylformamide (2.6 mL) was added cesium carbonate
(957 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added (3-bromopropoxy)(tert-butyl)dimethylsilane (979 mg), and the
mixture was stirred at room temperature for 16 hrs. The reaction
mixture was diluted with water (20 mL) and extracted with ethyl
acetate (30 mL.times.3). The organic layer was washed with
saturated brine (30 mL.times.3) and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel column chromatography
(silica gel, eluent:hexane/ethyl acetate=85/15.fwdarw.10/90). The
object fraction was concentrated under reduced pressure and dried
to give the title compound (630 mg) as a white solid.
[0578] .sup.1H-NMR (CDCl.sub.3) .delta. 0.95 (9H, s), 2.83 (2H, t,
J=5.2 Hz), 4.10 (2H, t, J=5.2 Hz), 4.76 (2H, t, J=5.2 Hz), 6.87
(1H, d, J=2.8 Hz), 7.71 (1H, d, J=2.8 Hz), 8.85 (1H, s).
(ii) Production of
3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-1-ol
[0579] The title compound (320 mg) was obtained as white powder
crystals by the reaction in the same manner as in Example 41 (ii)
using
5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-chloro-5H-pyrrolo[3,2-d]py-
rimidine (600 mg).
[0580] .sup.1H-NMR (CDCl.sub.3) .delta. 2.13 (2H, dt, J=6.3, 12.6
Hz), 3.65 (2H, dd, J=6.3, 10.2 Hz), 4.66 (2H, t, J=6.3 Hz), 6.72
(1H, d, J=3.0 Hz), 7.57 (1H, d, J=3.0 Hz), 8.70 (1H, s).
(iii) Production of
3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-5-yl]propan-1-ol
[0581] The title compound (180 mg) was obtained as pale purple
crystals by the reaction in the same manner as in Example 41 (iii)
using 3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-1-ol (100
mg).
[0582] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.98 (2H, t, J=6.0 Hz),
3.39 (2H, t, J=6.0 Hz), 4.66 (2H, t, J=6.0 Hz), 5.30 (2H, s), 6.66
(1H, d, J=3.2 Hz), 7.19 (1H, dt, J=1.9, 8.3 Hz), 7.29-7.34 (3H, m),
7.44-7.52 (2H, m), 7.72 (1H, d, J=2.6 Hz), 8.00 (1H, d, J=3.2 Hz),
8.66 (1H, s), 9.97 (1H, s).
Example 54
##STR00102##
[0583] Production of
N-(2-hydroxyethyl)-2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}am-
ino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetamide
[0584] The title compound (38 mg) was obtained as white powder by
the reaction in the same manner as in Example 36 using
[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenylamino}-5H-pyrrolo[3,2-d]-
pyrimidin-5-yl)acetic acid (70 mg).
[0585] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.17 (3H, s), 2.43 (3H,
s), 3.24 (2H, dd, J=5.6, 11.3 Hz), 3.47 (2H, dd, J=5.6, 11.3 Hz),
4.86 (1H, t, J=5.3 Hz), 5.04 (2H, s), 6.49 (1H, d, J=3.0 Hz), 6.97
(1H, d, J=8.5 Hz), 7.15 (1H, dd, J=2.8, 8.5 Hz), 7.22 (1H, d, J=8.5
Hz), 7.54-7.57 (3H, m), 8.16 (1H, d, J=2.5 Hz), 8.30 (1H, s), 8.91
(1H, t, J=5.6 Hz), 10.10 (1H, s).
Example 55
##STR00103##
[0586] Production of
N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-(4,4,4-trifluorobutyl)-
-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of
4-chloro-5-(4,4,4-trifluorobutyl)-5H-pyrrolo[3,2-d]pyrimidine
[0587] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (250
mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate
(675 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added 4-bromo-1,1,1-trifluorobutane (466 mg), and the mixture was
stirred at room temperature for 15 hrs. The reaction mixture was
diluted with water (20 mL) and extracted with ethyl acetate (20
mL.times.3). The organic layer was washed with saturated brine (20
mL.times.3) and dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure, and the obtained residue was
subjected to silica gel column chromatography (silica gel,
eluent:hexane/ethyl acetate=9/1.fwdarw.0/10). The object fraction
was concentrated under reduced pressure and dried to give the title
compound (440 mg) as a colorless transparent oil.
[0588] .sup.1H-NMR (CDCl.sub.3) .delta. 2.17 (4H, m), 4.57 (2H, t,
J=6.6 Hz), 6.76 (1H, d, J=3.3 Hz), 7.47 (1H, d, J=3.3 Hz), 8.72
(1H, s).
(ii) Production of
N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-(4,4,4-trifluorobutyl)-
-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0589] The title compound (171 mg) was obtained as colorless oil by
the reaction in the same manner as in Example 38 using
4-chloro-5-(4,4,4-trifluorobutyl)-5H-pyrrolo[3,2-d]pyrimidine (150
mg).
[0590] .sup.1H-NMR (CDCl.sub.3) .delta. 2.00-2.17 (4H, m), 2.25
(3H, s), 2.53 (3H, s), 4.29 (2H, t, J=6.9 Hz), 6.54 (1H, br s),
6.63 (1H, d, J=3.2 Hz), 6.88 (1H, d, J=8.5 Hz), 7.09 (1H, d, J=8.5
Hz), 7.13 (1H, dd, J=2.6, 8.5 Hz), 7.20 (1H, d, J=2.6 Hz), 7.23
(1H, d, J=3.2 Hz), 7.26 (1H, s), 7.32 (1H, d, J=2.6 Hz), 8.23 (1H,
d, J=2.6 Hz), 8.54 (1H, s).
Example 56
##STR00104##
[0591] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[2-(2-ethoxyethoxy)ethyl]-5H-
-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of
4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine
[0592] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300
mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate
(728 mg) under ice-cooling, and the mixture was stirred while
warming to room temperature for 15 min. To the reaction mixture was
added 1-bromo-2-(2-ethoxyethoxy)ethane (496 mg), and the mixture
was stirred at room temperature for 20 hrs. The reaction mixture
was diluted with water (20 mL) and extracted with ethyl acetate (20
mL.times.3). The organic layer was washed with saturated brine (20
mL.times.3) and dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure, and the obtained residue was
subjected to silica gel column chromatography (silica gel,
eluent:hexane/ethyl acetate=9/1.fwdarw.0/10). The object fraction
was concentrated under reduced pressure and dried to give the title
compound (440 mg) as a colorless transparent oil.
[0593] .sup.1H-NMR (CDCl.sub.3) .delta. 1.17 (3H, t, J=7.1 Hz),
3.40-3.58 (6H, m), 3.87 (2H, t, J=5.1 Hz), 4.69 (2H, t, J=5.1 Hz),
6.70 (1H, d, J=3.3 Hz), 7.63 (1H, d, J=3.3 Hz), 8.69 (1H, s).
(ii) Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[2-(2-ethoxyethoxy)ethyl]-5H-
-pyrrolo[3,2-d]pyrimidin-4-amine
[0594] To a solution of
4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine
(150 mg) in 1-methyl-2-pyrrolidone (1.1 mL) was added
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg), and the reaction
mixture was stirred at 120.degree. C. for 1 hr. The reaction
mixture was allowed to cool to room temperature, diluted with 5%
aqueous sodium hydrogen carbonate solution (25 mL), and extracted
with ethyl acetate (30 mL.times.3). The organic layer was washed
with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography (basic
silica gel, eluent:ethyl acetate/methanol=100/0.fwdarw.95/5). The
object fraction was concentrated under reduced pressure and dried
to give the title compound (146 mg) as a colorless oil.
[0595] .sup.1H-NMR (CDCl.sub.3) .delta. 1.09 (3H, t, J=6.9 Hz),
3.36 (2H, q, J=6.9 Hz), 3.51 (2H, t, J=4.2 Hz), 3.71 (2H, t, J=4.5
Hz), 3.98 (2H, t, J=4.5 Hz), 4.51 (2H, t, J=4.2 Hz), 5.24 (2H, s),
6.60 (1H, d, J=3.0 Hz), 6.91 (2H, d, J=8.8 Hz), 7.00 (2H, t, J=7.2
Hz), 7.17-7.37 (2H, m), 7.50 (1H, dd, J=2.7, 8.8 Hz), 7.68 (1H, d,
J=3.0 Hz), 8.47 (1H, s), 8.68 (1H, s).
Example 57
##STR00105##
[0596] Production of
5-[2-(2-ethoxyethoxy)ethyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phen-
yl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0597] The title compound (98 mg) was obtained as colorless oil by
the reaction in the same manner as in Example 47 using
4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine
(150 mg).
[0598] .sup.1H-NMR (DMSO-d.sub.6) .delta. 0.93 (3H, t, J=7.0 Hz),
2.24 (3H, s), 2.74 (3H, s), 3.23 (2H, q, J=7.0 Hz), 3.37-3.40 (2H,
m), 3.56-3.59 (2H, m), 3.86 (2H, t, J=4.5 Hz), 4.89 (2H, t, J=4.5
Hz), 6.72 (1H, d, J=3.0 Hz), 7.22 (1H, d, J=8.7 Hz), 7.58-7.66 (2H,
m), 7.91 (1H, d, J=8.7 Hz), 8.05 (1H, t, J=3.0 Hz), 8.09 (1H, d,
J=3.0 Hz), 8.36 (1H, d, J=2.8 Hz), 8.73 (1H, s), 10.07 (1H, br
s).
Example 58
##STR00106##
[0599] Production of
2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-
-d]pyrimidin-5-yl]ethanol
[0600] The title compound (241 mg) was obtained as white powder
crystals by the reaction in the same manner as in Example 47 using
2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol (250 mg).
[0601] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.17 (3H, s), 2.43 (3H,
s), 3.87 (2H, t, J=4.5 Hz), 4.52 (2H, t, J=4.5 Hz), 6.27 (1H, br
s), 6.48 (1H, dd, J=1.6, 3.0 Hz), 6.97 (1H, d, J=9.6 Hz), 7.16 (1H,
ddd, J=1.6, 3.0, 8.7 Hz), 7.23 (1H, d, J=8.4 Hz), 7.53 (2H, br s),
7.63 (1H, dd, J=1.6, 3.0 Hz), 8.17 (1H, d, J=3.0 Hz), 8.28 (1H, d,
J=1.6 Hz), 9.66 (1H, br s).
Example 59
##STR00107##
[0602] Production of
4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5,6-dihydro-4H-pyrrolo[3-
,2,1-de]pteridine
[0603] To a suspension of
2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-
-d]pyrimidin-5-yl]ethanol (50 mg) and tributylphosphine (54 mg) in
toluene (2.5 mL) was added
1,1'-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine (67 mg), and the
mixture was stirred at room temperature for 3 hrs. The reaction
mixture was diluted with water (15 mL) and extracted with ethyl
acetate (20 mL.times.3). The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography (basic
silica gel, eluent:ethyl acetate/methanol=100/0.fwdarw.90/10). The
object fraction was concentrated under reduced pressure and dried
to give the title compound (36 mg) as a white powder.
[0604] .sup.1H-NMR (CDCl.sub.3) .delta. 2.29 (3H, s), 2.54 (3H, s),
4.21 (2H, t, J=5.1 Hz), 4.41 (2H, t, J=5.1 Hz), 6.59 (1H, d, J=2.7
Hz), 6.92 (1H, d, J=8.4 Hz), 7.11 (1H, d, J=8.4 Hz), 7.18 (1H, dd,
J=2.7, 8.4 Hz), 7.23-7.27 (2H, m), 7.38 (1H, d, J=2.7 Hz), 8.26
(1H, d, J=2.7 Hz), 8.49 (1H, s).
Example 60
##STR00108##
[0605] Production of ethyl 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)
benzoate
[0606] A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (2.78 g),
ethyl 3-aminobenzoate (4.49 g) and 1-methyl-2-pyrrolidone (20 mL)
was stirred at 120.degree. C. for 1.5 hrs. To the reaction mixture
were added ethyl acetate, water and saturated aqueous sodium
hydrogen carbonate solution. The insoluble material was filtered
off, and the ethyl acetate layer was separated. The aqueous layer
was extracted with ethyl acetate, and the mixed ethyl acetate layer
was washed with saturated brine and dried over anhydrous magnesium
sulfate. The filtered insoluble material was suspended in methanol
and ethyl acetate and saturated brine were added. The ethyl acetate
layer was separated. The ethyl acetate layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
mixed ethyl acetate layer was concentrated under reduced pressure
and the obtained residue was purified by silica gel column
chromatography (eluent, ethyl acetate) and crystallized from
methanol-acetone-diisopropyl ether to give the title compound (2.85
g) as a pale-brown powder.
[0607] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (3H, t, J=7.2 Hz),
4.37 (2H, q, J=7.2 Hz), 6.51 (1H, d, J=3.3 Hz), 7.28-7.32 (1H, m),
7.42 (1H, t, J=8.0 Hz), 7.70 (1H, d, J=7.8 Hz), 8.09 (1H, s), 8.29
(1H, d, J=8.1 Hz), 8.49 (1H, m).
Example 61
##STR00109##
[0608] Production of
3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid
[0609] A mixture of ethyl
3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate (3.34 g), 1N
aqueous sodium hydroxide solution (25 mL) and methanol (50 mL) was
stirred overnight at room temperature. To the reaction mixture was
added 1N hydrochloric acid (25 mL), and methanol was evaporated
under reduced pressure. The precipitated crystals were collected by
filtration and washed with water to give the title compound (3.09
g) as a pale-brown powder.
[0610] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 6.50 (1H, m), 7.49 (1H,
t, J=7.8 Hz), 7.60 (1H, d, J=7.8 Hz), 7.69 (1H, t, J=2.7 Hz), 8.25
(1H, d, J=7.8 Hz), 8.39 (1H, s), 8.43 (1H, s), 9.54 (1H, s), 11.24
(1H, s), 13.01 (1H, br).
Example 62
##STR00110##
[0611] Production of
N-[3-(piperidin-1-ylcarbonyl)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0612] A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic
acid (153 mg), piperidine (0.078 mL),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173
mg) and N,N-dimethylformamide (10 mL) was stirred at room
temperature for 2 hrs. Piperidine (0.078 mL) and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173
mg) were added and the mixture was stirred for 1 hr.
1-Hydroxybenzotriazole (138 mg) was added, and the mixture was
stirred for 3 days. Saturated brine was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced
pressure and the obtained residue was purified by silica gel column
chromatography (eluent, methanol:ethyl acetate=0:100.fwdarw.20:80).
Diisopropyl ether was added and the precipitate was collected by
filtration to give the title compound (78 mg) as a pale-brown
powder.
[0613] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.56 (2H, m), 1.73 (4H,
m), 3.42 (2H, m), 3.83 (2H, m), 6.58 (1H, d, J=2.4 Hz), 6.90 (1H,
d, J=7.5 Hz), 7.18-7.22 (1H, m), 7.23 (1H, s), 7.30 (1H, t, J=2.4
Hz), 7.88 (1H, d, J=8.3 Hz), 8.47 (1H, s), 8.70 (1H, s), 10.71 (1H,
s).
Example 63
##STR00111##
[0614] Production of
N-[3-(thiomorpholin-4-ylcarbonyl)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-ami-
ne
[0615] A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic
acid (153 mg), thiomorpholine (0.091 mL),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173
mg) and N,N-dimethylformamide (10 mL) was stirred at room
temperature for 2 hrs. Thiomorpholine (0.030 mL) and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173
mg) were added and the mixture was stirred for 1 hr.
1-Hydroxybenzotriazole (138 mg) was added, and the mixture was
stirred for 3 days. Saturated brine was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced
pressure, and the obtained residue was purified by silica gel
column chromatography (eluent, methanol:ethyl
acetate=0:100.fwdarw.20:80). Diisopropyl ether was added and the
precipitate was collected by filtration. The precipitate was
dissolved in ethyl acetate containing methanol, washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and diisopropyl
ether was added to the obtained residue and the precipitate was
collected by filtration to give the title compound (82 mg) as a
pale-brown powder.
[0616] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.65 (2H, m), 2.77 (2H,
m), 3.78 (2H, m), 4.05 (2H, m), 6.59 (1H, d, J=3.0 Hz), 6.98 (1H,
d, J=6.9 Hz), 7.33 (1H, d, J=7.8 Hz), 7.38 (1H, d, J=3.0 Hz), 7.53
(1H, s), 7.95 (1H, br), 8.48 (1H, s).
Example 64
##STR00112##
[0617] Production of
N-{3-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-
-4-amine
[0618] A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic
acid (153 mg), 4-benzylpiperidine (158 mg),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173
mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10
mL) was stirred at room temperature for 3 hrs. The reaction mixture
was concentrated under reduced pressure, water was added and
extracted with ethyl acetate containing tetrahydrofuran. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced
pressure, and the obtained residue was purified by silica gel
column chromatography (eluent, methanol:ethyl
acetate=0:100.fwdarw.20:80). The obtained product was dissolved in
ethyl acetate containing methanol and tetrahydrofuran, washed with
aqueous sodium hydrogen carbonate solution and saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and diisopropyl ether was added to the
obtained residue. The precipitate was collected by filtration to
give the title compound (201 mg) as a pale-brown powder.
[0619] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-2.00 (6H, m), 2.86
(2H, d, J=6.9 Hz), 2.75-3.05 (2H, m), 3.78-3.91 (1H, m), 4.68-4.82
(1H, m), 6.55 (1H, d, J=3.0 Hz), 6.90 (1H, d, J=7.5 Hz), 7.10-7.33
(7H, m), 7.40 (1H, s), 7.72 (1H, d, J=8.1 Hz), 8.45 (1H, s), 8.77
(1H, s), 10.83 (1H, s).
Example 65
##STR00113##
[0620] Production of
N-benzyl-3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzamide
[0621] A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic
acid (153 mg), benzylamine (96 mg),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173
mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10
mL) was stirred at room temperature for 3 days. The reaction
mixture was concentrated under reduced pressure, water was added
and the mixture was extracted with ethyl acetate containing
tetrahydrofuran. The extract was washed with saturated aqueous
sodium hydrogen carbonate solution and saturated brine and dried
over anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure, and the obtained residue was purified by silica
gel column chromatography (eluent, methanol:ethyl
acetate=0:100.fwdarw.50:50). Ethyl acetate and diethyl ether were
added and the precipitate was collected by filtration to give the
title compound (128 mg) as a colorless powder.
[0622] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.50 (2H, d, J=6.0 Hz),
6.49 (1H, m), 7.21-7.38 (5H, m), 7.46 (1H, t, J=8.0 Hz), 7.55 (1H,
d, J=8.1 Hz), 7.68 (1H, t, J=3.0 Hz), 8.19 (1H, s), 8.26 (1H, d,
J=8.0 Hz), 8.37 (1H, s), 9.06 (1H, t, J=6.0 Hz), 9.41 (1H, s),
11.13 (1H, s).
Example 66
##STR00114##
[0623] Production of
[2-(benzyloxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenyl]methanol
[0624] A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg),
[5-amino-2-(benzyloxy)phenyl]methanol (459 mg) and
N,N-dimethylformamide (10 mL) was stirred at 80.degree. C. for 4
hrs. The reaction mixture was concentrated under reduced pressure,
aqueous sodium hydrogen carbonate solution was added and the
mixture was extracted with ethyl acetate containing
tetrahydrofuran. The extract was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained residue was purified by
silica gel column chromatography (eluent, methanol:ethyl
acetate=0:100.fwdarw.30:70). Ethanol and ethyl acetate were added
and the precipitate was collected by filtration to give the title
compound (279 mg) as a brown powder.
[0625] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.60 (2H, d, J=5.5 Hz),
5.12 (2H, s), 5.17 (1H, t, J=5.5 Hz), 6.45 (1H, m), 7.03 (1H, d,
J=8.8 Hz), 7.29-7.51 (5H, m), 7.62 (1H, t, J=2.9 Hz), 7.65 (1H, d,
J=2.7 Hz), 7.93 (1H, dd, J=8.8, 2.7 Hz), 8.29 (1H, s), 9.08 (1H,
s), 11.05 (1H, s).
Example 67
##STR00115##
[0626] Production of
N-[4-(benzyloxy)-3-methoxyphenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0627] A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg),
4-(benzyloxy)-3-methoxyaniline (298 mg) and 1-methyl-2-pyrrolidone
(5 mL) was stirred at 80.degree. C. for 4 hrs. Methanol and
activated carbon were added to the reaction mixture and the mixture
was stirred. The activated carbon was filtered off, aqueous sodium
hydrogen carbonate solution was added and the mixture was extracted
with ethyl acetate. The extract was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained residue was purified by
silica gel column chromatography (eluent, methanol:ethyl
acetate=10:80.fwdarw.20:80) and recrystallized from methanol-ethyl
acetate to give the title compound (269 mg) as a pale-gray
powder.
[0628] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.82 (3H, s), 5.06 (2H,
s), 6.45 (1H, m), 7.03 (1H, d, J=8.9 Hz), 7.30-7.49 (6H, m), 7.51
(1H, d, J=2.5 Hz), 7.63 (1H, t, J=2.9 Hz), 8.30 (1H, s), 9.07 (1H,
s), 11.06 (1H, s).
Example 68
##STR00116##
[0629] Production of
N-[4-(benzyloxy)-3-chlorophenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0630] A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg),
4-(benzyloxy)-3-chloroaniline (365 mg) and 1-methyl-2-pyrrolidone
(3 mL) was stirred at 80.degree. C. for 4 hrs. Methanol and
activated carbon were added to the reaction mixture and the mixture
was stirred. The activated carbon was filtered off, aqueous sodium
hydrogen carbonate solution was added and the mixture was extracted
with ethyl acetate. The extract was washed with water and saturated
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure, and the obtained residue was
purified by silica gel column chromatography (eluent,
methanol:ethyl acetate=0:100.fwdarw.15:75) and recrystallized from
ethanol-ethyl acetate to give the title compound (226 mg) as a
pale-brown powder.
[0631] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.15 (2H, s), 6.56 (1H,
s), 6.98 (1H, d, J=8.9 Hz), 7.28-7.43 (4H, m), 7.48 (2H, d, J=7.5
Hz), 7.69 (1H, d, J=8.9 Hz), 7.80 (1H, d, J=2.6 Hz), 8.50 (1H, s),
8.63 (1H, s), 10.56 (1H, s).
Example 69
##STR00117##
[0632] Production of ethyl
2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate
[0633] A mixture of ethyl 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (461
mg), 5-amino-2-phenoxybenzoate (926 mg) and 1-methyl-2-pyrrolidone
(5 mL) was stirred at 80.degree. C. for 2 hrs. Ethanol, water and
activated carbon were added to the reaction mixture and the mixture
was stirred. The activated carbon was filtered off, and the solvent
was evaporated under reduced pressure. Aqueous sodium hydrogen
carbonate solution was added to the residue and the mixture was
extracted with ethyl acetate. The extract was washed with water and
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography (eluent,
methanol:ethyl acetate=0:100.fwdarw.20:80) and recrystallized from
ethanol-ethyl acetate to give the title compound (572 mg) as a
colorless powder.
[0634] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (3H, t, J=7.1 Hz),
4.19 (2H, q, J=7.1 Hz), 6.57 (1H, d, J=3.0 Hz), 6.84 (2H, d, J=7.7
Hz), 6.95 (1H, d, J=8.9 Hz), 7.00 (1H, t, J=7.3 Hz), 7.19-7.29 (2H,
m), 7.34 (1H, d, J=3.0 Hz), 7.80 (1H, dd, J=8.9, 2.8 Hz), 8.00 (1H,
d, J=2.8 Hz), 8.67 (1H, s), 8.87 (1H, s), 10.89 (1H, s).
Example 70
##STR00118##
[0635] Production of
2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid
[0636] A mixture of ethyl
2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate (899
mg), 1N aqueous sodium hydroxide solution (5 mL) and methanol (15
mL) was stirred at 60.degree. C. for 1.5 hrs. To the reaction
mixture was added 1N hydrochloric acid (5 mL), and methanol was
evaporated under reduced pressure. The precipitated crystals were
collected by filtration, and washed with water and acetone to give
the title compound (768 mg) as a pale-brown powder.
[0637] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 6.50 (1H, m), 6.89 (2H,
d, J=7.7 Hz), 7.04 (1H, t, J=7.3 Hz), 7.12 (1H, d, J=8.9 Hz), 7.33
(2H, t, J=8.0 Hz), 7.69 (1H, t, J=2.9 Hz), 8.16 (1H, dd, J=8.9, 2.9
Hz), 8.31 (1H, d, J=2.9 Hz), 8.37 (1H, s), 9.46 (1H, s), 11.11 (1H,
s), 12.95 (1H, br).
Example 71
##STR00119##
[0638] Production of
[2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenyl]methanol
[0639] To a solution of
2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (173
mg) in N,N-dimethylformamide (5 mL) was added
1,1'-carbonyldiimidazole (97 mg) and the mixture was stirred at
room temperature for 1 hr. Sodium borohydride (38 mg) was added to
the reaction mixture at room temperature, and methanol (1 mL) was
added dropwise. After stirring overnight at room temperature, water
was added to the reaction mixture and the mixture was extracted
with ethyl acetate. The extract was washed with water and saturated
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure, and the obtained residue was
purified by silica gel column chromatography (eluent,
methanol:ethyl acetate=0:100.fwdarw.20:80) and crystallized from
methanol-ethyl acetate, to give the title compound (44 mg) as a
colorless powder.
[0640] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.50 (2H, d, J=5.1 Hz),
5.28 (1H, t, J=255.1 Hz), 6.48 (1H, m), 6.90 (2H, d, J=7.7 Hz),
6.96 (1H, d, J=8.7 Hz), 7.06 (1H, t, J=7.3 Hz), 7.30-7.40 (2H, m),
7.66 (1H, t, J=2.9 Hz), 7.85 (1H, d, J=2.7 Hz), 8.04 (1H, dd,
J=8.7, 2.7 Hz), 8.34 (1H, s), 9.28 (1H, s), 11.11 (1H, s).
Example 72
##STR00120##
[0641] Production of
6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
(i) Production of 2-cyano-1-(2-furyl)vinyl
4-methylbenzenesulfonate
[0642] To a mixture of 3-(2-furyl)-3-oxopropanenitrile (5.29 g),
p-toluenesulfonyl chloride (9.00 g) and dichloromethane (60 mL) was
added dropwise triethylamine (5.99 g) under ice-cooling. After
stirring under ice-cooling for 1.5 hrs, the mixture was diluted
with dichloromethane (100 mL). The mixture was washed with water
(150 mL), dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (eluent, hexane:methyl
acetate=9:1.fwdarw.3:1) to give the title compound (10.48 g) as a
mixture of (E)-form and (Z)-form (3:1).
[0643] .sup.1H-NMR (CDCl.sub.3) .delta. 2.47 (3/4H, s), 2.49 (9/4H,
s), 5.27 (1/4H, s), 5.63 (3/4H, s), 6.47 (1/4H, m), 6.53 (3/4H, m),
6.86 (1/4H, d, J=3.6 Hz), 6.95 (3/4H, d, J=3.6 Hz), 7.38 (1/2H, d,
J=7.8 Hz), 7.42 (3/2H, d, J=7.8 Hz), 7.51 (3/4H, m), 7.55 (1/4H,
m), 7.83 (1/2H, d, J=7.8 Hz), 7.97 (3/2H, d, J=7.8 Hz).
(ii) Production of ethyl
3-amino-5-(2-furyl)-1H-pyrrole-2-carboxylate
[0644] To a solution of 2-cyano-1-(2-furyl)vinyl
4-methylbenzenesulfonate (10.48 g) and diethyl aminomalonate
hydrochloride (7.67 g) in a mixed solvent of ethanol (120
mL)-tetrahydrofuran (64 mL) was added dropwise a solution (36.9 mL)
of 20% sodium ethoxide in ethanol under ice-cooling. After stirring
at room temperature for 12 hrs, the reaction mixture was poured
into ice water (350 mL) and adjusted to pH 7 with 1N hydrochloric
acid. The organic solvent was evaporated under reduced pressure,
and the residue was extracted with ethyl acetate (150 mL.times.3).
The organic layers were combined, washed with saturated brine (100
mL), and dried over anhydrous magnesium sulfate. After
concentration under reduced pressure, the residue was purified by
silica gel column chromatography (eluent, hexane:methyl
acetate=3:1.fwdarw.1:1) and the obtained solid was recrystallized
from ethyl acetate-hexane to give the title compound (2.66 g).
[0645] .sup.1H-NMR (CDCl.sub.3) .delta. 1.37 (3H, t, J=7.0 Hz),
4.34 (2H, q, J=7.0 Hz), 4.37 (2H, br s), 5.93 (1H, d, J=2.7 Hz),
6.45 (1H, dd, J=3.6, 1.8 Hz), 6.49 (1H, d, J=3.6 Hz), 7.41 (1H, d,
J=1.8 Hz), 8.35 (1H, br s).
(iii) Production of
6-(2-furyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one
[0646] To a solution of ethyl
3-amino-5-(2-furyl)-1H-pyrrole-2-carboxylate (2.58 g) in ethanol
(35 mL) was added formamidine acetate (1.83 g), and the mixture was
heated under reflux for 18 hrs. After cooling to room temperature,
the precipitated solid was collected by filtration, washed with
ethanol, and dried under reduced pressure at 60.degree. C. to give
the title compound (2.26 g).
[0647] .sup.1H-NMR (DMSO-d.sub.6) .delta. 6.58 (1H, d, J=2.1 Hz),
6.61 (1H, dd, J=3.5, 2.1 Hz), 7.08 (1H, m), 7.76 (1H, m), 7.80 (1H,
d, J=3.5 Hz), 11.91 (1H, br s), 12.50 (1H, br s).
(iv) Production of
4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine
[0648] A mixture of
6-(2-furyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (2.20 g)
and phosphoryl chloride (10.7 g) was stirred at 100.degree. C. for
20 min, dioxane (30 mL) was added, and the mixture was stirred at
100.degree. C. for 3 hrs. After concentration under reduced
pressure, saturated aqueous sodium hydrogen carbonate was added to
the residue, and the mixture was extracted with ethyl
acetate-acetone (155 mL.times.4). The organic layers were combined,
washed with saturated brine (100 mL), dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was washed with ethyl acetate-diethyl ether, and dried
under reduced pressure at 60.degree. C. to give the title compound
(2.19 g).
[0649] .sup.1H-NMR (DMSO-d.sub.6) .delta. 6.74 (1H, dd, J=3.6, 2.1
Hz), 6.95 (1H, d, J=1.8 Hz), 7.37 (1H, dd, J=3.6, 0.6 Hz), 7.95
(1H, dd, J=2.1, 0.6 Hz), 8.60 (1H, s), 12.71 (1H, br s).
(v) Production of
6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
[0650] A mixture of
4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg),
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (161 mg) and
1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140.degree. C. for
2 hrs, poured into water (10 mL) and adjusted to pH 8 with
saturated aqueous sodium hydrogen carbonate. The mixture was
extracted with ethyl acetate (25 mLx2) and the organic layers were
combined and dried over anhydrous magnesium sulfate. After
concentration under reduced pressure, the residue was subjected to
silica gel column chromatography (eluent, hexane:ethyl
acetate=1:1.fwdarw.0:1). The object fraction was concentrated under
reduced pressure. Chloroform--diisopropyl ether was added to the
residue, and the solid was collected by filtration and dried under
reduced pressure at 60.degree. C. to give the title compound (114
mg).
[0651] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.21 (3H, s), 2.48 (3H,
s), 6.72 (1H, dd, J=3.3, 1.8 Hz), 6.78 (1H, d, J=1.8 Hz), 6.98 (1H,
d, J=8.4 Hz), 7.02 (1H, d, J=3.6 Hz), 7.17 (1H, dd, J=8.4, 2.7 Hz),
7.22 (1H, d, J=8.4 Hz), 7.74 (1H, dd, J=8.4, 2.7 Hz), 7.80 (1H, d,
J=2.1 Hz), 7.92 (1H, dd, J=1.8, 0.9 Hz), 8.16 (1H, dd, J=2.7, 0.9
Hz), 8.33 (1H, s), 9.17 (1H, br s), 11.67 (1H, br s).
Example 73
##STR00121##
[0652] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(2-furyl)-5H-pyrrolo[3,2-d]p-
yrimidin-4-amine
[0653] A mixture of
4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg),
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg) and
1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140.degree. C. for
2 hrs, poured into water (10 mL) and adjusted to pH 8 with
saturated aqueous sodium hydrogen carbonate. The mixture was
extracted with ethyl acetate (30 mL.times.2). The organic layers
were combined and dried over anhydrous magnesium sulfate. After
concentration under reduced pressure, the residue was subjected to
silica gel column chromatography (eluent, hexane:ethyl
acetate=4:1.fwdarw.1:1). The object fraction was concentrated under
reduced pressure. Chloroform--diisopropyl ether was added to the
residue, and the solid was collected by filtration and dried under
reduced pressure at 60.degree. C. to give the title compound (122
mg).
[0654] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.23 (2H, s), 6.71 (1H,
dd, J=3.3, 2.1 Hz), 6.78 (1H, d, J=2.1 Hz), 7.02 (1H, d, J=3.3 Hz),
7.18 (1H, m), 7.25 (1H, d, J=9.0 Hz), 7.28-7.33 (2H, m), 7.46 (1H,
m), 7.57 (1H, dd, J=9.0, 3.0 Hz), 7.92 (1H, d, J=1.8 Hz), 8.18 (1H,
d, J=2.4 Hz), 8.33 (1H, s), 9.18 (1H, br s), 11.61 (1H, br s).
Example 74
##STR00122##
[0655] Production of
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6-(2-furyl)-5H-pyrrolo[3,2-d]p-
yrimidin-4-amine
[0656] A mixture of
4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (80 mg),
3-chloro-4-(pyridin-2-ylmethoxy)aniline (94 mg) and
1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140.degree. C. for
2 hrs, poured into water (10 mL) and adjusted to pH 8 with
saturated aqueous sodium hydrogen carbonate. The mixture was
extracted with ethyl acetate (30 mL.times.2). The organic layers
were combined and dried over anhydrous magnesium sulfate. After
concentration under reduced pressure, the residue was subjected to
silica gel column chromatography (eluent, hexane:ethyl
acetate=1:1.fwdarw.0:1). The object fraction was concentrated under
reduced pressure. Chloroform--diisopropyl ether was added to the
residue, and the solid was collected by filtration and dried under
reduced pressure at 60.degree. C. to give the title compound (71
mg).
[0657] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.27 (2H, s), 6.72 (1H,
m), 6.78 (1H, d, J=1.2 Hz), 7.02 (1H, d, J=3.3 Hz), 7.26 (1H, d,
J=9.0 Hz), 7.36 (1H, m), 7.53-7.59 (2H, m), 7.81 (1H, d, J=8.1 Hz),
7.91 (1H, s), 8.21 (1H, d, J=2.4 Hz), 8.34 (1H, s), 8.59 (1H, d,
J=5.1 Hz), 9.19 (1H, br s), 11.62 (1H, br s).
Example 75
##STR00123##
[0658] Production of
4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-
-d]pyrimidin-6-yl]benzoic acid hydrochloride
(i) Production of methyl
4-(2-cyano-1-{[(4-methylphenyl)sulfonyl]oxy}vinyl)benzoate
[0659] To a mixture of methyl 4-(cyanoacetyl)benzoate (10.29 g),
p-toluenesulfonyl chloride (11.58 g) and dichloromethane (110 mL)
was added dropwise triethylamine (7.68 g) under ice-cooling. After
stirring under ice-cooling for 2.5 hrs, the mixture was diluted
with dichloromethane (100 mL), washed with water (150 mL), dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (eluent, hexane:methyl acetate=9:1.fwdarw.1:1) to
give the title compound (17.60 g) as a mixture of (E)-form and
(Z)-form (6:5).
[0660] .sup.1H-NMR (CDCl.sub.3) .delta. 2.44 (18/11H, s), 2.47
(15/11H, s), 3.94 (18/11H, s), 3.95 (15/11H, s), 5.66 (6/11H, s),
5.68 (5/11H, s), 7.33 (12/11H, d, J=7.8 Hz), 7.38 (10/11H, d, J=7.8
Hz), 7.62-8.09 (6H, m).
(ii) Production of ethyl
3-amino-5-[4-(ethoxycarbonyl)phenyl]-1H-pyrrole-2-carboxylate
[0661] To a suspension of methyl
4-(2-cyano-1-{[(4-methylphenyl)sulfonyl]oxy}vinyl)benzoate (17.5 g)
and diethyl aminomalonate hydrochloride (10.36 g) in a mixed
solvent of ethanol (165 mL)-tetrahydrofuran (80 mL) was added
dropwise a solution (50 mL) of 20% sodium ethoxide in ethanol under
ice-cooling. After stirring under ice-cooling for 1 hr, the mixture
was stirred at room temperature for 21 hr. the reaction mixture was
poured into ice water (400 mL) and adjusted to pH 7 with 1N
hydrochloric acid. The organic solvent was evaporated under reduced
pressure, and the residue was extracted with ethyl acetate (250
mL.times.3). The organic layers were combined, washed with
saturated brine (150 mL), and dried over anhydrous magnesium
sulfate. After concentration under reduced pressure, the residue
was purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=2:1.fwdarw.1:1) and the obtained solid was
recrystallized from ethyl acetate to give the title compound (4.76
g).
[0662] .sup.1H-NMR (CDCl.sub.3) .delta. 1.36-1.43 (6H, m),
4.31-4.42 (6H, m), 6.11 (1H, d, J=3.0 Hz), 7.55 (2H, d, J=8.4 Hz),
8.04 (2H, d, J=8.4 Hz), 8.40 (1H, br s).
(iii) Production of ethyl
4-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate
[0663] A mixture of ethyl
3-amino-5-[4-(ethoxycarbonyl)phenyl]-1H-pyrrole-2-carboxylate (3.36
g), formamidine acetate (1.74 g) and ethanol (60 mL) was heated
under reflux for 15 hrs. After cooling to room temperature, the
precipitated solid was collected by filtration, washed with
ethanol, and dried under reduced pressure at 60.degree. C. to give
the title compound (2.97 g).
[0664] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.34 (3H, t, J=7.1 Hz),
4.33 (2H, q, J=7.1 Hz), 7.04 (1H, s), 7.84 (1H, d, J=2.7 Hz), 8.00
(2H, d, J=8.1 Hz), 8.11 (2H, d, J=8.1 Hz), 11.97 (1H, br s), 12.64
(1H, br s).
(iv) Production of ethyl
4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate
hydrochloride
[0665] A mixture of ethyl
4-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate (2.97
g) and phosphoryl chloride (16.45 g) was stirred at 110.degree. C.
for 1 hr, dioxane (10 mL) was added and the mixture was heated
under reflux for 4 hrs. After concentration under reduced pressure,
ethanol (30 mL) was added to the residue and, after stirring at
room temperature for 30 min, the precipitated solid was collected
by filtration. The solid was washed with ethanol and dried under
reduced pressure at 60.degree. C. to give the title compound (3.34
g).
[0666] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.36 (3H, d, J=7.1 Hz),
4.36 (2H, q, J=7.1 Hz), 7.40 (1H, s), 8.09 (2H, d, J=8.7 Hz), 8.26
(2H, d, J=8.7 Hz), 8.67 (1H, s), 12.77 (1H, br s).
(v) Production of
4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-
-d]pyrimidin-6-yl]benzoic acid hydrochloride
[0667] A mixture of ethyl
4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate hydrochloride
(1.297 g), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (1.00 g),
diisopropylethylamine (0.834 g) and 1-methyl-2-pyrrolidinone (12.5
mL) was stirred at 140.degree. C. for 3 hrs, poured into water (100
mL)-ethyl acetate (150 mL) and the precipitated solid was collected
by filtration. The solid was washed with ethyl acetate and dried
under reduced pressure at 60.degree. C. The obtained solid was
suspended in methanol (40 mL), and 1N aqueous sodium hydroxide
solution (20 mL) was added. After stirring at room temperature for
12 hrs, the solvent was evaporated under reduced pressure, and the
residue was adjusted to pH 2 with 1N hydrochloric acid. The
precipitated solid was collected by filtration, washed with water
and dried under reduced pressure at 60.degree. C. to give the title
compound (1.08 g).
[0668] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.21 (3H, s), 2.44 (3H,
s), 6.98 (1H, d, J=9.0 Hz), 7.15 (1H, s), 7.17-7.25 (2H, m), 7.76
(1H, d, J=8.7 Hz), 7.85 (1H, s), 8.01-8.17 (5H, m), 8.48 (1H, s),
9.99 (1H, br s), 12.47 (1H, br s).
Example 76
##STR00124##
[0669] Production of
4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-6-yl]benzoic acid hydrochloride
[0670] A mixture of ethyl
4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate hydrochloride
(517 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (462 mg) and
1-methyl-2-pyrrolidinone (8 mL) was stirred at 140.degree. C. for 5
hrs, poured into water (40 mL), and adjusted to pH 8 with saturated
aqueous sodium hydrogen carbonate. The precipitated solid was
collected by filtration, washed with water and suspended in
methanol (15 mL). After stirring at room temperature for 30 min,
the solid was collected by filtration and dried under reduced
pressure at 60.degree. C. The obtained solid was suspended in
ethanol (10 mL) and 1N aqueous sodium hydroxide solution (1.5 mL)
was added. After stirring at room temperature for 6.5 hrs, and at
60.degree. C. for 3.5 hrs, the mixture was cooled to room
temperature. 1N Hydrochloric acid (155 mL) was added, and the
precipitated solid was collected by filtration, washed with water
and dried under reduced pressure at 60.degree. C. to give the title
compound (498 mg).
[0671] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.24 (2H, s), 7.12-7.35
(5H, m), 7.48 (1H, m), 7.70 (1H, d, J=8.7 Hz), 8.01-8.12 (4H, m),
8.27 (1H, s), 8.37 (1H, s), 9.65 (1H, br s), 12.15 (1H, br s).
Example 77
##STR00125##
[0672] Production of
6-(2-furyl)-5-methyl-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H--
pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of
4-chloro-6-(2-furyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine
[0673] To a solution of
4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220 mg) in
N,N-dimethylformamide (2.5 mL) were added potassium carbonate (139
mg) and methyl iodide (0.25 mL) and the mixture was stirred at room
temperature for 8 hrs. The mixture was poured into water (30 mL)
and extracted with ethyl acetate (30 mL.times.3). The organic
layers were combined and dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the residue was
subjected to silica gel column chromatography (eluent, hexane:ethyl
acetate=4:1.fwdarw.0:1) to give the title compound (94 mg).
[0674] .sup.1H-NMR (CDCl.sub.3) .delta. 4.29 (3H, s), 6.62 (1H, dd,
J=3.6, 1.8 Hz), 6.86 (1H, d, J=3.6 Hz), 6.94 (1H, s), 7.67 (1H, d,
J=1.8 Hz), 8.68 (1H, s).
(ii) Production of
6-(2-furyl)-5-methyl-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H--
pyrrolo[3,2-d]pyrimidin-4-amine
[0675] A mixture of
4-chloro-6-(2-furyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (92 mg),
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (102 mg) and
1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140.degree. C. for
3.5 hrs, poured into water (10 mL) and adjusted to pH 8 with
saturated aqueous sodium hydrogen carbonate. The mixture was
extracted with ethyl acetate (25 mL.times.2), and the organic
layers were combined and dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the residue was
subjected to silica gel column chromatography (eluent, hexane:ethyl
acetate=1:1.fwdarw.0:1). The object fraction was concentrated under
reduced pressure. Diethyl ether was added to the residue, and the
solid was collected by filtration and dried under reduced pressure
at 60.degree. C. to give the title compound (105 mg).
[0676] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.17 (3H, s), 2.43 (3H,
s), 4.12 (3H, s), 6.74 (1H, dd, J=3.6, 1.2 Hz), 6.76 (1H, s), 6.93
(1H, d, J=8.7 Hz), 7.05 (1H, d, J=3.6 Hz), 7.17 (1H, dd, J=8.7, 2.4
Hz), 7.23 (1H, d, J=8.7 Hz), 7.46 (1H, dd, J=8.7, 3.0 Hz), 7.52
(1H, d, J=2.4 Hz), 7.94 (1H, d, J=1.2 Hz), 8.16 (1H, d, J=3.0 Hz),
8.27 (1H, s), 8.71 (1H, br s).
Example 78
##STR00126##
[0677] Production of
5-(2-ethoxyethyl)-6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]ph-
enyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of
4-chloro-5-(2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine
[0678] To a solution of
4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220 mg) in
N,N-dimethylformamide (1.2 mL) was added cesium carbonate (489 mg)
under ice-cooling, and the mixture was stirred under ice-cooling
for 15 min. 2-Bromoethyl ethyl ether (0.169 mL) was added and the
mixture was stirred at room temperature for 2 days. Cesium
carbonate (326 mg) and 2-bromoethyl ethyl ether (0.113 mL) were
added and the mixture was stirred at room temperature for 1 day.
The reaction mixture was poured into water (30 mL) and extracted
with ethyl acetate (60 mL). The organic layer was dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was subjected to silica gel column
chromatography (eluent, hexane:ethyl acetate=4:1.fwdarw.1:4) to
give the title compound (76 mg).
[0679] .sup.1H-NMR (CDCl.sub.3) .delta. 1.09 (3H, t, J=6.9 Hz),
3.42 (2H, q, J=6.9 Hz), 3.82 (2H, t, J=6.3 Hz), 4.92 (2H, t, J=6.3
Hz), 6.60 (1H, dd, J=3.6, 2.1 Hz), 6.94 (1H, s), 6.98 (1H, d, J=3.6
Hz), 7.64 (1H, d, J=2.1 Hz), 8.68 (1H, s).
(ii) Production of
5-(2-ethoxyethyl)-6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]ph-
enyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0680] A mixture of
4-chloro-5-(2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine
(76 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (67 mg) and
1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 140.degree. C. for
2 hrs, poured into water (8 mL) and adjusted to pH 8 with saturated
aqueous sodium hydrogen carbonate. The mixture was extracted with
ethyl acetate (20 mL.times.2) and the organic layers were combined
and dried over anhydrous magnesium sulfate. After concentration
under reduced pressure, the residue was subjected to silica gel
column chromatography (eluent, hexane:ethyl
acetate=1:1.fwdarw.0:1). The object fraction was concentrated under
reduced pressure. Diisopropyl ether-hexane was added to the
residue, and the solid was collected by filtration and dried under
reduced pressure at 60.degree. C. to give the title compound (78
mg).
[0681] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.08 (3H, t, J=6.9 Hz),
2.18 (3H, s), 2.43 (3H, s), 3.52 (2H, q, J=6.9 Hz), 3.95 (2H, t,
J=4.4 Hz), 4.68 (2H, brt, J=4.4 Hz), 6.73 (1H, dd, J=3.6, 1.8 Hz),
6.84 (1H, s), 6.96 (1H, d, J=8.1 Hz), 7.01 (1H, d, J=3.6 Hz), 7.16
(1H, dd, J=8.4, 2.7 Hz), 7.22 (1H, d, J=8.4 Hz), 7.50-7.55 (2H, m),
7.93 (1H, d, J=1.8,Hz), 8.15 (1H, d, J=2.7 Hz), 8.31 (1H, s), 9.15
(1H, br s).
Example 79
##STR00127##
[0682] Production of
{4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-6-yl]phenyl}methanol
[0683] To a suspension of
4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-
-d]pyrimidin-6-yl]benzoic acid (122 mg) in tetrahydrofuran (10 mL)
was added triethylamine (30.5 mg) and, after stirring at room
temperature for 10 min, 1,1'-carbonyldiimidazole (49 mg) was added,
and the mixture was stirred at room temperature for 13 hrs. Under
ice-cooling, sodium borohydride (28 mg) was added, and methanol
(2.5 mL) was further added. After stirring under ice-cooling for 2
hrs, water (1.5 mL) was added, and tetrahydrofuran and methanol
were evaporated under reduced pressure. Water (20 mL) was added,
and the mixture was extracted with ethyl acetate (30
mL)-tetrahydrofuran (15 mL). The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate (15
mL)-tetrahydrofuran (5 mL). The organic layers were combined and
dried over anhydrous magnesium sulfate. After concentration under
reduced pressure, the residue was subjected to silica gel column
chromatography (eluent, ethyl acetate:methanol=99:1.fwdarw.9:1).
The object fraction was concentrated under reduced pressure. The
residue was recrystallized from methanol-ethyl acetate to give the
title compound (65 mg).
[0684] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.21 (3H, s), 2.43 (3H,
s), 4.57 (2H, d, J=4.8 Hz), 5.32 (1H, brt, J=4.8 Hz), 6.96 (1H, s),
6.99 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=8.7, 2.7 Hz), 7.23 (1H, d,
J=8.7 Hz), 7.50 (2H, d, J=7.8 Hz), 7.74 (1H, dd, J=8.4, 2.7 Hz),
7.81-7.85 (3H, m), 8.16 (1H, d, J=2.7 Hz), 8.34 (1H, s), 9.09 (1H,
br s), 11.56 (1H, br s).
Example 80
##STR00128##
[0685] Production of
N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-6-[4-({[2-(methylsulfony-
l)ethyl]amino}methyl)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[0686] A mixture of
{4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-6-yl]phenyl}methanol (96 mg), manganese dioxide (1.0
g) and N,N-dimethylformamide (5 mL) was stirred at room temperature
for 12 hrs. After celite filtration, the filtrate was concentrated
under reduced pressure. The residue was subjected to silica gel
column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.9:1). A mixture of the obtained
solid, methylsulfonylethylamine hydrochloride (27.5 mg),
N,N-dimethylformamide (2 mL) and acetic acid (0.02 mL) was stirred
at room temperature for 1 hr, and sodium triacetoxyborohydride
(36.6 mg) was added. After stirring at room temperature for 4.5
hrs, saturated aqueous sodium hydrogen carbonate (10 mL) was added,
and the mixture was extracted with ethyl acetate (25 mL.times.2).
The organic layers were combined, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (ethyl
acetate:methanol=10:0.fwdarw.9:1). The object fraction was
concentrated under reduced pressure. Chloroform--diisopropyl ether
was added to the residue, and the solid was collected by filtration
and dried under reduced pressure at 60.degree. C. to give the title
compound (28 mg).
[0687] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.21 (3H, s), 2.44 (3H,
s), 2.94 (2H, t, J=6.6 Hz), 3.00 (3H, s), 3.29 (2H, t, J=6.6 Hz),
3.78 (2H, s), 6.97 (1H, s), 7.00 (1H, d, J=8.7 Hz), 7.19 (1H, dd,
J=8.4, 2.7 Hz), 7.24 (1H, d, J=8.4 Hz), 7.51 (2H, d, J=8.4 Hz),
7.77 (1H, dd, J=8.7, 2.4 Hz), 7.83-7.87 (3H, m), 8.18 (1H, d, J=2.4
Hz), 8.34 (1H, s), 9.23 (1H, br s), 11.73 (1H, br s).
Example 81
##STR00129##
[0688] Production of
6-(aminomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-
-d]pyrimidin-4-amine dihydrochloride
(i) Production of
N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine
[0689] A solution of 5-amino-4,6-diiodopyrimidine (3.83 g) and
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (2.78 g) in
1-methyl-2-pyrrolidone (30 mL) was stirred at 70.degree. C. for 14
hrs. Water was added to the reaction system and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine and dried over magnesium sulfate. After
concentration under reduced pressure, the residue was separated and
purified by column chromatography (eluent, ethyl
acetate:hexane=1:4.fwdarw.2:3.fwdarw.1:1) to give the title
compound (4.21 g) as brown powder crystals.
[0690] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.47 (2H, br s), 5.13 (2H,
s), 6.73 (1H, br s), 6.92 (1H, d, J=9.0 Hz), 6.96-7.04 (1H, m),
7.15-7.25 (2H, m), 7.31-7.38 (2H, m), 7.64 (1H, d, J=2.7 Hz), 8.04
(1H, s).
(ii) Production of tert-butyl
3-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-y-
l]prop-2-ynylcarbamate
[0691] To a solution of
N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine
(0.84 g) and tert-butyl prop-2-ynylcarbamae (0.36 g) in
acetonitrile-triethylamine (20 mL-15 mL) were added
bis(triphenylphosphine)palladium(II) dichloride (62.5 mg) and
copper(I) iodide (20.3 mg) at room temperature, and the mixture was
stirred at room temperature under an argon atmosphere for 6 hrs.
After concentration under reduced pressure, the residue was
separated and purified by column chromatography (eluent, ethyl
acetate:hexane=1:1.fwdarw.ethyl acetate) to give the title compound
(766.5 mg) as a brown solid.
[0692] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42 (9H, s), 4.06 (2H,
d, J=5.4 Hz), 5.22 (2H, s), 5.45 (2H, br s), 7.13-7.23 (2H, m),
7.26-7.34 (2H, m), 7.42-7.51 (2H, m), 7.54-7.60 (1H, m), 7.95 (2H,
s), 8.54 (1H, s).
(iii) Production of tert-butyl
[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrim-
idin-6-yl]methylcarbamate
[0693] A mixture of tert-butyl
(3-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4--
yl]prop-2-ynylcarbamate (720 mg) and copper(I) iodide (55.2 mg) in
N,N-dimethylformamide (7.0 mL) was stirred at 80.degree. C. for 12
hrs. After concentration under reduced pressure, the residue was
separated and purified by column chromatography (basic silica gel,
eluent, ethyl acetate.fwdarw.methanol:ethyl acetate=1:9) to give
the title compound (604 mg) as pale-yellow powder crystals.
[0694] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42 (9H, s), 4.33 (2H,
d, J=5.7 Hz), 5.22 (2H, s), 6.29 (1H, s), 7.14-7.35 (4H, m),
7.41-7.60 (3H, m), 8.16 (1H, d, J=2.7 Hz), 8.30 (1H, s), 9.29 (1H,
s), 10.96 (1H, br s).
(iv) Production of
6-(aminomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-
-d]pyrimidin-4-amine dihydrochloride
[0695] To a solution of tert-butyl
[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrim-
idin-6-yl]methylcarbamate (500 mg) in tetrahydrofuran (12 mL) was
added 2N hydrochloric acid (6.0 mL) at room temperature. The
mixture was stirred at 60.degree. C. for 2 hrs, ethanol was added
to the reaction system and the mixture was concentrated under
reduced pressure. The resultant crystals were collected by
filtration and washed with diisopropyl ether to give the title
compound (481.4 mg) as pale-yellow powder crystals.
[0696] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.28-4.39 (2H, m), 5.28
(2H, s), 6.89 (1H, s), 7.15-7.25 (1H, m), 7.29-7.40 (3H, m),
7.45-7.54 (1H, m), 7.73-7.80 (1H, m), 8.15 (1H, s), 8.48-8.65 (3H,
m), 8.82 (1H, s).
Example 82
##STR00130##
[0697] Production of
(2E)-N-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-
-d]pyrimidin-6-yl]methyl}-4-(dimethylamino)but-2-enamide
[0698] A solution of
6-(aminomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-
-d]pyrimidin-4-amine dihydrochloride (150 mg),
(2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (105 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (244
mg), 1-hydroxybenzotriazole monohydrate (196 mg) and triethylamine
(0.30 mL) in N,N-dimethylformamide (5 mL) was stirred at room
temperature for 2 days. Water was added to the reaction system and
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure, and the residue was separated
and purified by column chromatography (basic silica gel, eluent,
methanol:ethyl acetate=1:9.fwdarw.1:4) to give the title compound
(104.2 mg) as pale-brown powder crystals.
[0699] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.14 (6H, s), 3.00 (2H,
d, J=6.1 Hz), 4.54 (2H, d, J=5.7 Hz), 5.21 (2H, s), 6.11 (1H, d,
J=15.3 Hz), 6.35 (1H, s), 6.66 (1H, dt, J=15.3, 6.1 Hz), 7.12-7.34
(4H, m), 7.41-7.49 (1H, m), 7.53-7.60 (1H, m), 8.14 (1H, d, J=2.4
Hz), 8.29 (1H, s), 8.69 (1H, t, J=5.7 Hz), 9.34 (1H, br s), 10.99
(1H, br s).
Example 83
##STR00131##
[0700] Production of
6-(3-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
(i) Production of
6-[(3-aminophenyl)ethynyl]-N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}pyr-
imidine-4,5-diamine
[0701] The title compound (1.35 g) was obtained as brown powder
crystals by the reaction in the same manner as in Example 81 (ii)
using
N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine
(1.90 g), 3-aminophenylacetylene (0.41 mL),
bis(triphenylphosphine)palladium(II) dichloride (102 mg), copper(I)
iodide (27 mg), acetonitrile (24 mL) and triethylamine (18 mL).
[0702] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.65-3.78 (4H, m), 5.15
(2H, s), 6.59 (1H, s), 6.73 (1H, d, J=8.1 Hz), 6.90-7.06 (4H, m),
7.14-7.41 (5H, m), 7.68 (1H, d, J=2.7 Hz), 8.35 (1H, s).
(ii) Production of
6-(3-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
[0703] The title compound (673 mg) was obtained as brown powder
crystals by the reaction in the same manner as in Example 81 (iii)
using
6-[(3-aminophenyl)ethynyl]-N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}pyr-
imidine-4,5-diamine (1.30 g), copper(I) iodide (54 mg) and
N,N-dimethylformamide (7.0 mL).
[0704] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 5.23 (2H, s), 5.31 (2H,
s), 6.58-6.65 (1H, m), 6.75 (1H, s), 6.94-7.01 (2H, m), 7.13-7.34
(5H, m), 7.43-7.50 (1H, m), 7.57 (1H, dd, J=8.9, 2.6 Hz), 8.19 (1H,
d, J=2.1 Hz), 8.32 (1H, s), 9.13 (1H, s), 11.40 (1H, s).
Example 84
##STR00132##
[0705] Production of
N-{3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]-
pyrimidin-6-yl]phenyl}-2-methoxyacetamide
[0706] The title compound (42.9 mg) was obtained as pale-brown
powder crystals by the reaction in the same manner as in Example 82
using
6-(3-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine (80 mg), methoxyacetic acid (31 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67
mg), 1-hydroxybenzotriazole monohydrate (54 mg), triethylamine (0.1
mL) and N,N-dimethylformamide (5 mL).
[0707] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.42 (3H, s), 4.06 (2H,
s), 5.24 (2H, s) 6.87 (1H, s), 7.13-7.36 (4H, m), 7.44-7.69 (5H,
m), 8.19-8.26 (2H, m), 8.35 (1H, s), 9.25 (1H, s), 9.95 (1H, s),
11.56 (1H, s).
Example 85
##STR00133##
[0708] Production of
6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
(i) Production of
6-[(4-aminophenyl)ethynyl]-N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}pyr-
imidine-4,5-diamine
[0709] The title compound (1.12 g) was obtained as a yellow solid
by the reaction in the same manner as in Example 81 (ii) using
N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine
(1.50 g), 4-aminophenylacetylene (411 mg),
bis(triphenylphosphine)palladium(II) dichloride (112 mg), copper(I)
iodide (36.5 mg), acetonitrile (24 mL) and triethylamine (18
mL).
[0710] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.68 (2H, br s), 3.94 (2H,
br s), 5.14 (2H, s), 6.58 (1H, br s), 6.65 (2H, d, J=7.8 Hz), 6.95
(1H, d, J=9.0 Hz), 6.96-7.06 (1H, m), 7.19-7.43 (6H, m), 7.68 (1H,
d, J=2.7 Hz), 8.34 (1H, s).
(ii) Production of
6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine
[0711] The title compound (768.6 mg) was obtained as yellow powder
crystals by the reaction in the same manner as in Example 81 (iii)
using
6-[(4-aminophenyl)ethynyl]-N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}pyr-
imidine-4,5-diamine (1.11 g), copper(I) iodide (46 mg) and
N,N-dimethylformamide (6.0 mL).
[0712] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 5.22 (2H, s), 5.53 (2H,
s), 6.65-6.70 (3H, m), 7.12-7.35 (4H, m), 7.42-7.61 (4H, m), 8.17
(1H, d, J=2.7 Hz), 8.28 (1H, s), 8.99 (1H, s), 11.21 (1H, br
s).
Example 86
##STR00134##
[0713] Production of
N-{4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]-
pyrimidin-6-yl]phenyl}-2-methoxyacetamide
[0714] A solution of
6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3-
,2-d]pyrimidin-4-amine (100 mg), methoxyacetic acid (29.4 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94
mg), 1-hydroxybenzotriazole monohydrate (75 mg) and triethylamine
(0.23 mL) in N,N-dimethylformamide (5 mL) was stirred at room
temperature for 20 hrs. Methoxyacetic acid (29.4 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg)
and 1-hydroxybenzotriazole monohydrate (75 mg) were added to the
reaction system, and the mixture was further stirred for 24 hrs.
Water was added to the reaction system and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure, and the residue was separated and purified
by column chromatography (basic silica gel, eluent, ethyl
acetate.fwdarw.methanol:ethyl acetate=14:85) to give the title
compound (63.5 mg) as pale-brown powder crystals.
[0715] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.40 (3H, s), 4.04 (2H,
s), 5.23 (2H, s), 6.90 (1H, s), 7.12-7.21 (1H, m), 7.23-7.35 (3H,
s), 7.43-7.49 (1H, m), 7.52-7.60 (1H, m), 7.78-7.87 (4H, m), 8.19
(1H, d, J=1.8 Hz), 8.33 (1H, s), 9.07 (1H, s), 9.97 (1H, s), 11.45
(1H, s).
Example 87
##STR00135##
[0716] Production of
(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2--
d]pyrimidin-6-yl]prop-2-en-1-ol
(i) Production of
(2E)-5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidi-
n-4-yl]pent-2-en-4-yn-1-ol
[0717] The title compound (188.2 mg) was obtained as a brown solid
by the reaction in the same manner as in Example 81 (ii) using
N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine
(300 mg), 2-penten-4-yn-1-ol (58 mg),
bis(triphenylphosphine)palladium(II) dichloride (22.5 mg),
copper(I) iodide (7.3 mg), acetonitrile (6.0 mL) and triethylamine
(4.5 mL).
[0718] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.06-4.15 (2H, m), 5.06
(1H, t, J=5.4 Hz), 5.21 (2H, s), 5.45 (2H, br s), 5.98-6.07 (1H,
m), 6.46-6.57 (1H, m), 7.12-7.34 (4H, m), 7.39-7.59 (2H, m),
7.92-7.99 (2H, m), 8.55 (1H, br s).
(ii) Production of
(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2--
d]pyrimidin-6-yl]prop-2-en-1-ol
[0719] The title compound (98 mg) was obtained as pale-yellow
powder crystals by the reaction in the same manner as in Example 81
(iii) using
(2E)-5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidi-
n-4-yl]pent-2-en-4-yn-1-ol (170 mg), copper(I) iodide (7.6 mg) and
N,N-dimethylformamide (1.5 mL).
[0720] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.16-4.24 (2H, m),
5.02-5.09 (1H, m), 5.22 (2H, s), 6.40-6.52 (2H, m), 6.66 (1H, d,
J=15.9 Hz), 7.13-7.34 (4H, m), 7.41-7.50 (1H, m), 7.52-7.60 (1H,
m), 8.17 (1H, d, J=2.7 Hz), 8.29 (1H, s), 9.13 (1H, br s), 11.38
(1H, br s).
Example 88
##STR00136##
[0721] Production of
3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-6-yl]propan-1-ol
(i) Production of
5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-y-
l]pent-4-yn-1-ol
[0722] To a solution of
N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine
(300 mg) and 4-pentyn-1-ol (65 mg) in acetonitrile-triethylamine
(6.0 mL-4.5 mL) were added bis(triphenylphosphine)palladium(II)
dichloride (22.5 mg) and copper(I) iodide (7.3 mg) at room
temperature, and the mixture was stirred at room temperature under
an argon atmosphere for 24 hrs. 4-Pentyn-1-ol (65 mg),
bis(triphenylphosphine)palladium(II) dichloride (22.5 mg) and
copper(I) iodide (7.3 mg) were added to the reaction system and the
mixture was stirred at 60.degree. C. for 2 hrs. After concentration
under reduced pressure, the residue was separated and purified by
column chromatography (basic silica gel, eluent, ethyl
acetate.fwdarw.methanol:ethyl acetate=1:19) to give the title
compound (157.2 mg) as a yellow solid.
[0723] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.66-1.79 (2H, m),
2.43-2.58 (2H, m), 3.53 (2H, q, J=5.4 Hz), 4.61 (1H, t, J=5.1 Hz),
5.20 (2H, s), 5.31 (2H, s), 7.11-7.21 (2H, m), 7.25-7.33 (2H, m),
7.39-7.50
[0724] (1H, m), 7.55 (1H, dd, J=9.0, 2.1 Hz), 7.92-7.94 (2H, m),
8.50 (1H, s).
(ii) Production of
3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-6-yl]propan-1-ol
[0725] A mixture of
5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-y-
l]pent-4-yn-1-ol (140 mg) and copper(I) iodide (19 mg) in
N,N-dimethylformamide (2.0 mL) was stirred at 80.degree. C. for 5
hrs. After concentration under reduced pressure, and the residue
was separated and purified by column chromatography (basic silica
gel, eluent, ethyl acetate.fwdarw.methanol:ethyl acetate=15:85) to
give the title compound (95.2 mg) as pale-brown powder
crystals.
[0726] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.79-1.91 (2H, m), 2.84
(2H, t, J=7.8 Hz), 3.44-3.52 (2H, m), 4.62-4.68 (1H, m), 5.22 (2H,
s), 6.24 (1H, s), 7.13-7.35 (4H, m), 7.43-7.59 (2H, m), 8.17 (1H,
d, J=2.7 Hz), 8.29 (1H, s), 9.01 (1H, br s), 10.94-11.05 (1H,
m).
Example 89
##STR00137##
[0727] Production of
4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-6-yl]butan-1-ol
(i) Production of
6-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-y-
l]hex-5-yn-1-ol
[0728] The title compound (242 mg) was obtained as a brown solid by
the reaction in the same manner as in Example 81 (ii) using
N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine
(300 mg), 5-hexyn-1-ol (94.2 mg),
bis(triphenylphosphine)palladium(II) dichloride (22.5 mg),
copper(I) iodide (7.3 mg), acetonitrile (6.0 mL) and triethylamine
(4.5 mL).
[0729] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.51-1.69 (4H, m),
2.39-2.58 (2H, m), 3.41-3.47 (2H, m), 4.46 (1H, t, J=4.8 Hz), 5.20
(2H, s), 5.28 (2H, br s), 7.12-7.22 (2H, m), 7.25-7.33 (2H, m),
7.41-7.49 (1H, m), 7.55 (1H, dd, J=8.6, 2.9 Hz), 7.89-7.96 (2H, m),
8.50 (1H, s).
(ii) Production of
4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-6-yl]butan-1-ol
[0730] The title compound (109 mg) was obtained as pale-brown
powder crystals by the reaction in the same manner as in Example 81
(iii) using
6-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-y-
l]hex-5-yn-1-ol (220 mg), copper(I) iodide (9.5 mg) and
N,N-dimethylformamide (4.0 mL).
[0731] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.44-1.56 (2H, m),
1.67-1.81 (2H, m), 2.80 (2H, t, J=7.8 Hz), 3.45 (2H, t, J=6.0 Hz),
4.40-4.50 (1H, m), 5.21 (2H, s), 6.22 (1H, s), 7.12-7.32 (4H, m),
7.42-7.55 (2H, m), 8.15 (1H, d, J=2.7 Hz), 8.27 (1H, s), 8.98 (1H,
s), 10.93 (1H, br s).
Example 90
##STR00138##
[0732] Production of
6-[(1E)-3-aminoprop-1-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-
-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of tert-butyl
(2E)-5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidi-
n-4-yl]pent-2-en-4-ynylcarbamate
[0733] The title compound (373.8 mg) was obtained as a yellow solid
by the reaction in the same manner as in Example 81 (ii) using
N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine
(600 mg), tert-butyl pent-2-en-4-ynylcarbamate (0.26 g),
bis(triphenylphosphine)palladium(II) dichloride (44.6 mg),
copper(I) iodide (14.5 mg), acetonitrile (12 mL) and triethylamine
(9 mL).
[0734] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40 (9H, s), 3.66-3.75
(2H, m), 5.21 (2H, s), 5.49 (2H, br s), 5.91 (1H, d, J=10.2 Hz),
6.30-6.42 (1H, m), 7.12-7.25 (3H, m), 7.27-7.36 (2H, m), 7.42-7.51
(1H, m), 7.54-7.62 (1H, m), 7.93-7.99 (2H, m), 8.58 (1H, s).
(ii) Production of tert-butyl
(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2--
d]pyrimidin-6-yl]prop-2-enylcarbamate
[0735] The title compound (189 mg) was obtained as pale-brown
powder crystals by the reaction in the same manner as in Example 81
(iii) using tert-butyl
(2E)-5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidi-
n-4-yl]pent-2-en-4-ynylcarbamate (350 mg), copper(I) iodide (12.7
mg) and N,N-dimethylformamide (2.0 mL).
[0736] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41 (9H, s), 3.73-3.85
(2H, m), 5.23 (2H, s), 6.22-6.36 (1H, m), 6.48-6.62 (2H, m),
7.14-7.38 (5H, m), 7.42-7.50 (1H, m), 7.52-7.62 (1H, m), 8.18 (1H,
s), 8.30 (1H, s), 9.06 (1H, br s), 11.29 (1H, br s).
(iii) Production of
6-[(1E)-3-aminoprop-1-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-
-pyrrolo[3,2-d]pyrimidin-4-amine
[0737] To a solution of tert-butyl
(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2--
d]pyrimidin-6-yl]prop-2-enylcarbamate (150 mg) in tetrahydrofuran
(6.0 mL) was added 2N hydrochloric acid (3.0 mL) at room
temperature and the mixture was stirred at 60.degree. C. for 2 hrs.
1N Aqueous sodium hydroxide solution was added to alkalize the
reaction system. After extraction with chloroform, the organic
layer was dried over sodium sulfate and concentrated under reduced
pressure. The resultant crystals were collected by filtration. The
crystals were washed with diisopropyl ether to give the title
compound (104 mg) as pale-brown powder crystals.
[0738] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.42 (2H, d, J=4.2 Hz),
5.22 (2H, s), 6.41-6.50 (2H, m), 6.62 (1H, d, J=15.9 Hz), 7.12-7.35
(4H, m), 7.42-7.50 (1H, m), 7.57-7.60 (1H, m), 8.18 (1H, d, J=2.1
Hz), 8.28 (1H, s), 9.20 (1H, br s), 11.39 (1H, br s).
Example 91
##STR00139##
[0739] Production of
N-{(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-6-yl]prop-2-enyl}-2-methoxyacetamide
[0740] The title compound (23.2 mg) was obtained as pale-brown
powder crystals by the reaction in the same manner as in Example 82
using
6-[(1E)-3-aminoprop-1-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-
-pyrrolo[3,2-d]pyrimidin-4-amine (30 mg), methoxyacetic acid (14
mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(55 mg), 1-hydroxybenzotriazole monohydrate (44 mg), triethylamine
(0.1 mL) and N,N-dimethylformamide (5 mL).
[0741] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.34 (3H, s), 3.87 (2H,
s), 3.95 (2H, t, J=5.4 Hz), 5.21 (2H, s), 6.35 (1H, dt, J=16.2, 5.7
Hz), 6.47 (1H, s), 6.56 (1H, d, J=16.2 Hz), 7.12-7.32 (4H, m),
7.41-7.50 (1H, m), 7.62 (1H, dd, J=9.0. 2.7 Hz), 8.16-8.25 (2H, m),
8.28 (1H, s), 9.37-9.52 (1H, m), 11.67-11.84 (1H, m).
Example 92
##STR00140##
[0742] Production of
(2E)-N-{(2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-6-yl]prop-2-enyl}-4-(dimethylamino)but-2-enamide
[0743] The title compound (25.6 mg) was obtained as pale-yellow
powder crystals by the reaction in the same manner as in Example 82
using
6-[(1E)-3-aminoprop-1-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-
-pyrrolo[3,2-d]pyrimidin-4-amine (40 mg),
(2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (31 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (72
mg), 1-hydroxybenzotriazole monohydrate (58 mg), triethylamine
(0.13 mL) and N,N-dimethylformamide (5 mL).
[0744] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.15 (6H, s), 3.00 (2H,
d, J=6.3 Hz), 3.97-4.06 (2H, m), 5.23 (2H, s), 6.10 (1H, d, J=15.3
Hz), 6.27-6.40 (1H, m), 6.51 (1H, s), 6.55-6.68 (2H, m), 7.14-7.36
(4H, m), 7.43-7.60 (2H, m), 8.17 (1H, d, J=2.7 Hz), 8.31 (1H, s),
8.41-8.45 (1H, m), 9.01 (1H, s), 11.22 (1H, s).
Example 93
##STR00141##
[0745] Production of
2-{[2-chloro-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]methyl}benzo-
nitrile
[0746] The title compound (272 mg) was obtained by the reaction in
the same manner as in Example 2 (ii) using
4-chloro-5H-pyrrolo[3,2-d.]pyrimidine (200 mg) and
2-[(4-amino-2-chlorophenoxy)methyl]benzonitrile (337 mg).
[0747] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.33 (2H, s), 6.49 (1H,
s), 7.32 (1H, d, J=9.0 Hz), 7.57-7.68 (3H, m), 7.78-7.80 (2H, m),
7.94 (1H, d, J=8.1 Hz), 8.20 (1H, m), 8.36 (1H, s), 9.32 (1H, br
s), 11.1 (1H, br s).
Example 94
##STR00142##
[0748] Production of
3-[2-methyl-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]benzonitrile
[0749] The title compound (338 mg) was obtained by the reaction in
the same manner as in Example 2 (ii) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) and
3-(4-amino-2-methylphenoxy)benzonitrile (292 mg).
[0750] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.16 (3H, s), 6.49 (1H,
s), 7.06 (1H, d, J=9.3 Hz), 7.21 (1H, m), 7.35 (1H, s), 7.51-7.59
(2H, m), 7.69 (1H, m), 7.80-7.83 (2H, m), 8.35 (1H, s), 9.26 (1H,
s), 11.1 (1H, br s).
Example 95
##STR00143##
[0751] Production of
3-[2-chloro-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]benzonitrile
[0752] The title compound (230 mg) was obtained by the reaction in
the same manner as in Example 2 (ii) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) and
3-(4-amino-2-chlorophenoxy)benzonitrile (219 mg).
[0753] .sup.1H-NMR (DMSO-d.sub.6) .delta. 6.53 (1H, s), 7.26 (1H,
m), 7.32 (1H, d, J=8.7 Hz), 7.45 (1H, s), 7.58 (2H, d, J=5.7 Hz),
7.70-7.73 (2H, m), 8.41 (2H, s), 9.50 (1H, s), 11.1 (1H, br s).
Example 96
##STR00144##
[0754] Production of
2-{[2-methyl-4-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenoxy]methyl}benzo-
nitrile
[0755] The title compound (250 mg) was obtained by the reaction in
the same manner as in Example 2 (ii) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) and
2-[(4-amino-2-methylphenoxy)methyl]benzonitrile (310 mg).
[0756] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.24 (3H, s), 5.26 (2H,
s), 6.46 (1H, t, J=1.5 Hz), 7.08 (1H, d, J=9.0 Hz), 7.58-7.68 (4H,
m), 7.78 (2H, d, J=4.2 Hz), 7.94 (1H, d, J=7.5 Hz), 8.29 (1H, s),
9.02 (1H, br s), 11.1 (1H, br s).
Example 97
##STR00145##
[0757] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[4,3-d]pyrimidin-7--
amine
[0758] A mixture of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine
(known compound from literature: J. Am. Chem. Soc., 1956, 78, 2418)
(150 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (227 mg) and
pyridine hydrochloride (156 mg) in 1-methyl-2-pyrrolidone (3 mL)
was stirred at 120.degree. C. for 10 hrs. After the completion of
the reaction, the mixture was diluted with ethyl acetate and washed
with saturated aqueous sodium hydrogen carbonate and saturated
brine. The organic layer was concentrated under reduced pressure,
and the residue was subjected to silica gel column chromatography
(hexane/ethyl acetate=1/3.fwdarw.1/10) to give the title compound
(220 mg, yield 61%) as a pale-yellow solid.
[0759] .sup.1H-NMR (CDCl.sub.3) .delta. 5.15 (2H, s), 6.96 (1H, d,
J=8.7 Hz), 7.03 (1H, m), 7.20-7.26 (2H, m), 7.36 (1H, dt, J=5.7,
8.4 Hz), 7.71 (1H, dd, J=2.7, 9.0 Hz), 7.81 (1H, d, J=2.7 Hz), 8.14
(1H, s), 8.57 (1H, s).
Example 98
##STR00146##
[0760] Production of
N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[4,3-d]pyrimi-
din-7-amine
[0761] The title compound (195 mg) was obtained as a brown solid by
the reaction in the same manner as in Example 97 using
7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (150 mg),
3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (193 mg) and pyridine
hydrochloride (156 mg).
[0762] .sup.1H-NMR (CDCl.sub.3) .delta. 2.13 (3H, s), 6.89 (1H, d,
J=8.4 Hz), 7.11 (1H, d, J=8.1 Hz), 7.15 (1H, dd, J=2.7, 8.4 Hz),
7.50 (1H, dd, J=2.7, 9.0 Hz), 7.68 (1H, d, J=2.7 Hz), 8.14 (1H, s),
8.25 (1H, d, J=2.7 Hz), 8.58 (1H, s).
Example 99
##STR00147##
[0763] Production of methyl
4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]p-
yrimidin-1-yl]methyl}benzoate
[0764] The title compound (45 mg) was obtained as a brown solid by
the reaction in the same manner as in Example 97 using methyl
4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate
(120 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (87 mg) and
pyridine hydrochloride (60 mg).
[0765] .sup.1H-NMR (CDCl.sub.3) .delta. 3.94 (3H, s), 5.11 (2H, s),
5.90 (2H, s), 6.34 (1H, br s), 6.85 (1H, d, J=8.7 Hz), 6.94 (1H,
dd, J=2.7, 8.7 Hz), 7.01 (1H, m), 7.16-7.22 (2H, m), 7.32 (2H, d,
J=8.7 Hz), 7.35 (1H, m), 8.14 (2H, d, J=8.7 Hz), 8.18 (1H, s), 8.51
(1H, s).
Example 100
##STR00148##
[0766] Production of methyl
4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]p-
yrimidin-2-yl]methyl}benzoate
[0767] The title compound (140 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 97 using
methyl
4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate
(150 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (109 mg) and
pyridine hydrochloride (75 mg).
[0768] .sup.1H-NMR (CDCl.sub.3) .delta. 3.92 (3H, s), 5.16 (2H, s),
5.62 (2H, s), 6.97 (1H, d, J=8.8 Hz), 7.02 (1H, m), 7.18-7.42 (4H,
m), 7.55-7.68 (2H, m), 8.00-8.08 (4H, m), 8.50 (1H, s).
Example 101
##STR00149##
[0769] Production of
4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]p-
yrimidin-1-yl]methyl}benzoic acid
[0770] To a solution of methyl
4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]p-
yrimidin-1-yl]methyl}benzoate (25 mg) in a mixed solvent of
tetrahydrofuran/methanol (1:1, 1 mL) was added 1N aqueous sodium
hydroxide solution (0.5 mL), and the mixture was stirred at room
temperature for 1 hr. After the completion of the reaction, 1N
aqueous hydrochloric acid solution (0.5 mL) and water (1 mL) were
added under ice-cooling, and the mixture was stirred at room
temperature for 1 hr. The resultant solid was collected by
filtration, and washed with diisopropyl ether and dried to give the
title compound (16 mg) as pale-yellow crystals.
[0771] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.24 (2H, s), 6.10 (2H,
s), 7.13-7.31 (5H, m), 7.42-7.47 (2H, m), 7.70 (1H, m), 7.83-7.91
(2H, m), 8.27 (1H, s), 8.35 (1H, s), 8.81 (1H, s), 12.9 (1H, br
s).
Example 102
##STR00150##
[0772] Production of
4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]p-
yrimidin-2-yl]methyl}benzoic acid
[0773] The title compound (130 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 101 using
methyl
4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]p-
yrimidin-2-yl]methyl}benzoate (150 mg) and 1N aqueous sodium
hydroxide solution (6 mL).
[0774] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.26 (2H, s), 5.85 (2H,
s), 7.15-7.32 (4H, m), 7.41 (2H, d, J=8.1 Hz), 7.45 (1H, m), 7.72
(1H, dd, J=2.4, 8.7 Hz), 7.94 (2H, d, J=8.1 Hz), 8.06 (1H, d, J=2.1
Hz), 8.65 (1H, s), 8.85 (1H, s), 11.4 (1H, br s).
Example 103
##STR00151##
[0775] Production of 4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)
oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoic
acid
[0776] Methyl 4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)
oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate
was obtained as a mixture with 1-methyl-2-pyrrolidone by the
reaction in the same manner as in Example 97 using methyl
4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate
(120 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (87 mg) and
pyridine hydrochloride (60 mg).
[0777] The title compound (20 mg) was obtained as yellow crystals
by the reaction in the same manner as in Example 101 using the
above-mentioned mixture and 1N aqueous sodium hydroxide solution (1
mL).
[0778] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.17 (3H, s), 2.43 (3H,
s), 6.12 (2H, s), 6.91 (2H, d, J=8.7 Hz), 7.12-7.24 (4H, m),
7.38-7.47 (2H, m), 7.85 (2H, d, J=8.1 Hz), 8.16 (1H, d, J=2.4 Hz),
8.28 (1H, s), 8.35 (1H, s), 8.81 (1H, s).
Example 104
##STR00152##
[0779] Production of methyl
4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4-
,3-d]pyrimidin-2-yl]methyl}benzoate
[0780] The title compound (160 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 97 using
methyl
4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate
(150 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (93 mg) and
pyridine hydrochloride (75 mg).
[0781] .sup.1H-NMR (CDCl.sub.3) .delta. 2.27 (3H, s), 2.52 (3H, s),
3.91 (3H, s), 5.60 (2H, s), 6.90 (1H, d, J=8.7 Hz), 7.08-7.09 (2H,
m), 7.31 (1H, s), 7.66 (1H, dd, J=3.0, 9.0 Hz), 7.76 (1H, d, J=2.4
Hz), 7.86 (1H, m), 8.02 (2H, s), 8.04 (1H, s), 8.25 (1H, m), 8.51
(1H, s).
Example 105
##STR00153##
[0782] Production of
4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4-
,3-d]pyrimidin-2-yl]methyl}benzoic acid
[0783] The title compound (120 mg) was obtained as white crystals
by the reaction in the same manner as in Example 101 using methyl
4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4-
,3-d]pyrimidin-2-yl]methyl}benzoate (150 mg) and 1N aqueous sodium
hydroxide solution (3 mL).
[0784] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.17 (3H, s), 2.43 (3H,
s), 5.80 (2H, s), 6.93 (1H, d, J=8.7 Hz), 7.13-7.23 (2H, m), 7.37
(2H, d, J=7.8 Hz), 7.84 (1H, dd, J=2.1, 9.0 Hz), 7.92-7.97 (2H, m),
8.15 (1H, d, J=2.1 Hz), 8.32 (1H, s), 8.67 (1H, s), 10.09 (1H, s),
13.0 (1H, br s).
Example 106
##STR00154##
[0785] Production of
4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]p-
yrimidin-2-yl]methyl}-N-(2-methoxyethyl)benzamide
[0786] A solution of
4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]p-
yrimidin-2-yl]methyl}benzoic acid (45 mg), 2-methoxyethylamine (9
mg), 1-hydroxybenzotriazole (18 mg),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (26
mg) and triethylamine (0.08 mL) in N,N-dimethylformamide (2 mL) was
stirred at room temperature for 30 hrs. After the completion of the
reaction, the reaction solution was concentrated under reduced
pressure, and the residue was subjected to silica gel column
chromatography (basic silica gel; ethyl acetate) to give the title
compound (115 mg) as a pale-yellow solid.
[0787] .sup.1H-NMR (CDCl.sub.3) .delta. 3.38 (3H, s), 3.54-3.57
(2H, m), 3.63-3.68 (2H, m), 5.12 (2H, s), 5.60 (2H, s), 6.53 (1H,
br s), 6.97 (1H, d, J=8.7 Hz), 7.02 (1H, m), 7.20-7.40 (3H, m),
7.31 (1H, d, J=8.4 Hz), 7.64 (1H, d, J=8.7 Hz), 7.65 (1H, d, J=8.4
Hz), 7.79 (1H, d, J=8.4 Hz), 8.00-8.01 (2H, m), 8.50 (1H, s).
Example 107
##STR00155##
[0788] Production of
N-(2-methoxyethyl)-4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}a-
mino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzamide
[0789] The title compound (30 mg) was obtained as white crystals by
the reaction in the same manner as in Example 106 using
4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4-
,3-d]pyrimidin-2-yl]methyl}benzoic acid (45 mg),
2-methoxyethylamine (10 mg), 1-hydroxybenzotriazole (20 mg),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (28
mg) and triethylamine (0.08 mL).
[0790] .sup.1H-NMR (CDCl.sub.3) .delta. 2.29 (3H, s), 2.53 (3H, s),
3.38 (3H, s), 3.54-3.57 (2H, m), 3.63-3.68 (2H, m), 5.62 (2H, s),
6.51 (1H, br s), 6.93 (1H, d, J=8.7 Hz), 7.09-7.10 (2H, m), 7.34
(2H, d, J=8.1 Hz), 7.62-7.69 (2H, m), 7.76 (1H, m), 7.80 (1H, d,
J=8.1 Hz), 8.02 (1H, s), 8.26 (1H, m), 8.51 (1H, s).
Example 108
##STR00156##
[0791] Production of N-{3-methyl-4-[(6-methylpyridin-3-yl)
oxy]phenyl}-2-(4-nitrophenyl)-2H-pyrazolo[4,
3-0]pyrimidin-7-amine
(i) Production of
7-(methylthio)-2-(4-nitrophenyl)-2H-pyrazolo[4,3-d]pyrimidine
[0792] To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine
(500 mg) in N,N-dimethylformamide (10 mL) was added potassium
tert-butoxide (405 mg) under ice-cooling, and the mixture was
stirred at room temperature for 10 min. Subsequently,
1-fluoro-4-nitrobenzene (465 mg) was added, and the mixture was
stirred at 70.degree. C. for 30 min. After the completion of the
reaction, water was added to the reaction mixture and the mixture
was stirred at room temperature for 30 min. The resultant solid was
collected by filtration, washed with diisopropyl ether and dried to
give the title compound (860 mg) as brown crystals.
[0793] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.72 (3H, s), 8.39 (2H,
d, J=8.7 Hz), 8.46 (2H, d, J=8.7 Hz), 8.76 (1H, s), 9.64 (1H,
s).
(ii) Production of
N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H-pyr-
azolo[4,3-d]pyrimidin-7-amine
[0794] The title compound (667 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 97 using
7-(methylthio)-2-(4-nitrophenyl)-2H-pyrazolo[4,3-d]pyrimidine (430
mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (321 mg) and
pyridine hydrochloride (259 mg).
[0795] .sup.1H-NMR (CDCl.sub.3) .delta. 2.32 (3H, s), 2.54 (3H, s),
6.95 (1H, d, J=9.0 Hz), 7.07-7.15 (2H, m), 7.71 (1H, dd, J=2.7, 8.4
Hz), 7.80-7.81 (2H, m), 8.12 (2H, d, J=9.3 Hz), 8.25 (1H, dd,
J=0.6, 2.7 Hz), 8.45 (2H, d, J=9.3 Hz), 8.55 (1H, s), 8.57 (1H,
s).
Example 109
##STR00157##
[0796] Production of
2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyr-
azolo[4,3-d]pyrimidin-7-amine
[0797] To a solution of
N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H-pyr-
azolo[4, 3-0]pyrimidin-7-amine (200 mg) in a mixed solvent of
ethanol/water (9:1, 6 mL) was added calcium chloride (90%, 28 mg)
and the mixture was stirred at 100.degree. C. for 10 min. Reduced
iron (90%, 164 mg) was added at room temperature, and the mixture
was stirred at 100.degree. C. for 5 hrs. After the completion of
the reaction, the reaction mixture was filtered (celite), and the
filtrate was concentrated under reduced pressure. Water was added
to the residue and the mixture was diluted with ethyl acetate and
washed with water and saturated brine. The organic layer was dried
over anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/methylene chloride=10/1) to give the
title compound (140 mg) as a white solid.
[0798] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.20 (3H, s), 2.44 (3H,
s), 5.55 (2H, s), 6.71-6.74 (2H, m), 6.95-6.98 (1H, m), 7.18-7.23
(2H, m), 7.73-7.76 (2H, m), 7.901 (1H, m), 8.03 (1H, br s), 8.18
(1H, br s), 8.34 (1H, br s), 8.94 (1H, br s), 10.05 (1H, br s).
Example 110
##STR00158##
[0799] Production of
2-methoxy-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2-
H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}acetamide
[0800] The title compound (64 mg) was obtained as white crystals by
the reaction in the same manner as in Example 106 using
2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyr-
azolo[4,3-d]pyrimidin-7-amine (100 mg), methoxyacetic acid (30 mg),
1-hydroxybenzotriazole (48 mg),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (68
mg) and triethylamine (0.20 mL).
[0801] .sup.1H-NMR (CDCl.sub.3) .delta. 2.26 (3H, s), 2.53 (3H, s),
3.55 (3H, s), 4.07 (2H, s), 6.92 (1H, d, J=8.7 Hz), 7.12-7.25 (2H,
m), 7.35-7.45 (3H, m), 7.70-7.83 (4H, m), 8.19 (1H, d, J=2.4 Hz),
8.44 (2H, s), 8.50 (1H, s).
Example 111
##STR00159##
[0802] Production of
2-(N,N-dimethylamino)-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phe-
nyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}acetamide
[0803] The title compound (60 mg) was obtained as white crystals by
the reaction in the same manner as in Example 106 using
2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyr-
azolo[4,3-d]pyrimidin-7-amine (100 mg), N,N-dimethylglycine
hydrochloride (46 mg), 1-hydroxybenzotriazole (48 mg),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (68
mg) and triethylamine (0.20 mL).
[0804] .sup.1H-NMR (CDCl.sub.3) .delta. 2.31 (3H, s), 2.43 (6H, s),
2.53 (3H, s), 3.14 (2H, s), 6.95 (1H, d, J=9.0 Hz), 7.09-7.11 (2H,
m), 7.70-7.76 (2H, m), 7.81-7.85 (5H, m), 8.27 (1H, m), 8.43 (1H,
s), 8.55 (1H, s), 9.35 (1H, br s).
Example 112
##STR00160##
[0805] Production of methyl
4-({4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazol-
o[4,3-d]pyrimidin-2-yl]phenyl}amino)-4-oxobutanoate
[0806] The title compound (175 mg) was obtained as white crystals
by the reaction in the same manner as in Example 106 using
2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyr-
azolo[4,3-d]pyrimidin-7-amine (150 mg), succinic acid monomethyl
ester (66 mg), 1-hydroxybenzotriazole (72 mg),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (102
mg) and triethylamine (0.30 mL).
[0807] .sup.1H-NMR (CDCl.sub.3) .delta. 2.30 (3H, s), 2.53 (3H, s),
2.73-2.75 (2H, m), 2.79-2.81 (2H, m), 3.75 (3H, s), 6.94 (1H, d,
J=8.7 Hz), 7.10-7.12 (2H, m), 7.69-7.74 (3H, m), 7.79-7.82 (4H, m),
8.08 (1H, br s), 8.27 (1H, dd, J=0.6, 2.4 Hz), 8.42 (1H, s), 8.53
(1H, s).
Example 113
##STR00161##
[0808] Production of
4-({4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazol-
o[4,3-d]pyrimidin-2-yl]phenyl)amino)-4-oxobutanoic}acid
[0809] The title compound (98 mg) was obtained as white crystals by
the reaction in the same manner as in Example 101 using methyl
4-({4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazol-
o[4,3-d]pyrimidin-2-yl]phenyl}amino)-4-oxobutanoate (175 mg) and 1N
aqueous sodium hydroxide solution (0.5 mL).
[0810] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.21 (3H, s), 2.44 (3H,
s), 2.50-2.61 (4H, m), 6.97 (1H, d, J=8.4 Hz), 7.20-7.22 (2H, m),
7.81-7.93 (4H, m), 8.03-8.09 (3H, m), 8.18 (1H, m), 8.36 (1H, s),
9.13 (1H, s), 10.2 (1H, br s), 10.3 (1H, s).
Example 114
##STR00162##
[0811] Production of
2-(2-methoxyethoxy)-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]pheny-
l}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}acetamide
[0812] The title compound (88 mg) was obtained as white crystals by
the reaction in the same manner as in Example 106 using
2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H-pyr-
azolo[4,3-d]pyrimidin-7-amine (130 mg), (2-methoxyethoxy)acetic
acid (58 mg), 1-hydroxybenzotriazole (62 mg),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (88
mg) and triethylamine (0.26 mL).
[0813] .sup.1H-NMR (CDCl.sub.3) .delta. 2.30 (3H, s), 2.53 (3H, s),
3.52 (3H, s), 3.63-3.66 (2H, m), 3.80-3.82 (2H, m), 4.16 (2H, s),
6.94 (1H, d, J=8.7 Hz), 7.07-7.10 (2H, m), 7.71 (1H, d, J=8.7 Hz),
7.80 (1H, m), 7.83 (4H, s), 8.27 (1H, s), 8.43 (1H, s), 8.54 (1H,
s), 9.16 (1H, s).
Example 115
##STR00163##
[0814] Production of methyl
4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,-
3-d]pyrimidin-2-yl]benzoate
(i) Production of methyl
4-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoate
[0815] To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine
(100 mg) and methyl 4-fluorobenzoate (102 mg) in
1-methyl-2-pyrrolidone (2 mL) was added potassium carbonate (125
mg), and the mixture was stirred at 120.degree. C. for 3 hrs. After
the completion of the reaction, water was added to the reaction
mixture and the mixture was stirred at room temperature for 30 min.
The resultant solid was collected by filtration, washed with
diisopropyl ether and dried to give the title compound (90 mg) as
yellow crystals.
[0816] .sup.1H-NMR (CDCl.sub.3) .delta. 2.76 (3H, s), 3.98 (3H, s),
8.04 (2H, d, J=8.4 Hz), 8.24 (2H, d, J=8.4 Hz), 8.63 (1H, s), 8.77
(1H, s).
(ii) Production of methyl
4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,-
3-d]pyrimidin-2-yl]benzoate
[0817] The title compound (135 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 97 using
methyl 4-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoate
(115 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (82 mg) and
pyridine hydrochloride (66 mg).
[0818] .sup.1H-NMR (CDCl.sub.3) .delta. 2.32 (3H, s), 2.54 (3H, s),
3.99 (3H, s), 6.95 (1H, d, J=8.7 Hz), 7.10-7.12 (2H, m), 7.73 (1H,
dd, J=2.7, 8.7 Hz), 7.81-7.82 (2H, m), 8.00 (2H, d, J=8.4 Hz), 8.26
(2H, d, J=8.4 Hz), 8.27 (1H, s), 8.55 (1H, s), 8.56 (1H, s).
Example 116
##STR00164##
[0819] Production of
4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,-
3-d]pyrimidin-2-yl]benzoic acid
[0820] The title compound (91 mg) was obtained as white crystals by
the reaction in the same manner as in Example 101 using methyl
4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,-
3-d]pyrimidin-2-yl]benzoate (110 mg) and 1N aqueous sodium
hydroxide solution (0.4 mL).
[0821] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.21 (3H, s), 2.44 (3H,
s), 6.98 (1H, d, J=9.0 Hz), 7.21-7.26 (2H, m), 7.90 (1H, dd, J=2.7,
8.7 Hz), 8.03 (1H, m), 8.12-8.22 (6H, m), 8.38 (1H, s), 9.30 (1H,
s), 10.3 (1H, br s).
Example 117
##STR00165##
[0822] Production of
N-(2-methoxyethyl)-4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}am-
ino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzamide
[0823] The title compound (63 mg) was obtained as white crystals by
the reaction in the same manner as in Example 106 using
4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,-
3-d]pyrimidin-2-yl]benzoic acid (75 mg), 2-methoxyethylamine (17
mg), 1-hydroxybenzotriazole (34 mg),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (48
mg) and triethylamine (0.14 mL).
[0824] .sup.1H-NMR (CDCl.sub.3) .delta. 2.31 (3H, s), 2.54 (3H, s),
3.43 (3H, s), 3.60-3.63 (2H, m), 3.69-3.74 (2H, m), 6.61 (1H, br
s), 6.96 (1H, d, J=8.7 Hz), 7.10-7.12 (2H, m), 7.72 (1H, dd, J=2.4,
8.4 Hz), 7.81 (1H, t, J=3.3 Hz), 8.00 (4H, s), 8.27 (1H, m), 8.53
(1H, s), 8.55 (1H, s).
Example 118
##STR00166##
[0825] Production of
{4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]p-
yrimidin-2-yl]phenyl}methanol
(i) Production of
4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]benzaldehyde
[0826] The title compound (60 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 115 (i)
using
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[4,3-d]pyrimidin-7--
amine (100 mg) and 4-fluorobenzaldehyde (37 mg).
[0827] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.26 (2H, s), 7.16-7.35
(4H, m), 7.46 (1H, m), 7.93 (1H, dd, J=2.6, 8.8 Hz), 8.18 (2H, d,
J=8.4 Hz), 8.30 (1H, d, J=2.2 Hz), 8.38-8.43 (3H, m), 9.40 (1H, s),
10.1 (1H, s), 10.3 (1H, s).
(ii) Production of
{4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]p-
yrimidin-2-yl]phenyl}methanol
[0828] To a solution of
4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]benzaldehyde (50 mg) in methanol (2 mL) was added
sodium borohydride (2 mg) under ice-cooling, and the mixture was
stirred for 30 min. After the completion of the reaction, the
reaction solution was concentrated under reduced pressure, and the
residue was subjected to silica gel column chromatography
(tetrahydrofuran/ethyl acetate=1/1) to give the title compound (20
mg) as a white solid.
[0829] .sup.1H-NMR (DMSO-d.sub.6) .delta. 4.60 (2H, d, J=5.8 Hz),
5.25 (2H, s), 5.38 (1H, t, J=5.8 Hz), 7.16-7.35 (3H, m), 7.49 (1H,
m), 7.56 (2H, d, J=8.8 Hz), 7.93 (1H, m), 8.09 (2H, d, J=8.8 Hz),
8.30 (1H, d, J=2.4 Hz), 8.38 (1H, s), 9.22 (1H, s), 10.2 (1H,
s).
Example 119
##STR00167##
[0830] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-[4-({[2-(methylsulfonyl)ethy-
l]amino}methyl)phenyl]-2H-pyrazolo[4,3-d]pyrimidin-7-amine
[0831] To a solution of
4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]benzaldehyde (80 mg) and 2-(methylsulfonyl)ethylamine
hydrochloride (40 mg) in N,N-dimethylformamide (2 mL) was added
acetic acid (0.02 mL), and the mixture was stirred at room
temperature for 1 hr. Subsequently, sodium triacetoxyborohydride
(54 mg) was added, and the mixture was stirred at the same
temperature for 2 hrs. After the completion of the reaction,
saturated aqueous sodium hydrogen carbonate was added, and the
mixture was concentrated under reduced pressure. The residue was
extracted with ethyl acetate, and the organic layer was washed with
water and saturated brine and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography
(ethyl acetate/methanol=5/1) to give the title compound (70 mg) as
a white solid.
[0832] .sup.1H-NMR (CDCl.sub.3) .delta. 3.02 (3H, s), 3.22 (4H, s),
3.92 (2H, s), 5.17 (2H, s), 6.98-7.04 (2H, m), 7.21-7.26 (3H, m),
7.36 (1H, m), 7.52 (2H, d, J=8.1 Hz), 7.68-7.71 (2H, m), 7.84 (2H,
d, J=8.1 Hz), 8.05 (1H, d, J=2.4 Hz), 8.45 (1H, s), 8.54 (1H,
s).
Example 120
##STR00168##
[0833] Production of
2-({4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3--
d]pyrimidin-2-yl]benzyl}amino)ethanol
[0834] The title compound (83 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 119 using
4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]benzaldehyde (120 mg), ethanolamine (23 mg) and sodium
triacetoxyborohydride (134 mg).
[0835] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.59 (2H, t, J=6.0 Hz),
3.48 (2H, m), 3.80 (2H, s), 4.51 (1H, br s), 5.25 (2H, s),
7.16-7.34 (5H, m), 7.46 (1H, m), 7.57 (2H, d, J=7.8 Hz), 7.91 (1H,
dd, J=1.8, 9.0 Hz), 8.07 (2H, d, J=7.8 Hz), 8.30 (1H, d, J=1.8 Hz),
8.38 (1H, s), 9.21 (1H, s), 10.2 (1H, s).
Example 121
##STR00169##
[0836] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-(4-{[(2-morpholin-4-ylethyl)-
amino]methyl}phenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine
[0837] The title compound (68 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 119 using
4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]benzaldehyde (80 mg), N-(2-aminoethyl)morpholine (33
mg) and sodium triacetoxyborohydride (54 mg).
[0838] .sup.1H-NMR (CDCl.sub.3) .delta. 2.44 (4H, t, J=4.5 Hz),
2.53 (2H, t, J=6.0 Hz), 2.74 (2H, t, J=6.0 Hz), 3.70 (4H, t, J=4.5
Hz), 3.91 (2H, s), 5.16 (2H, s), 6.98 (1H, d, J=8.7 Hz), 7.02 (1H,
m), 7.19-7.25 (3H, m), 7.35 (1H, m), 7.52 (2H, d, J=8.7 Hz),
7.67-7.71 (2H, m), 7.82 (2H, d, J=8.7 Hz), 8.04 (1H, d, J=2.4 Hz),
8.43 (1H, s), 8.52 (1H, s).
Example 122
##STR00170##
[0839] Production of
2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]py-
rimidin-1-yl]ethanol
[0840]
2-[7-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,-
3-d]pyrimidin-1-yl]ethyl benzoate was obtained as a mixture with
1-methyl-2-pyrrolidone by the reaction in the same manner as in
Example 97 using
2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate
(130 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (104 mg) and
pyridine hydrochloride (72 mg).
[0841] The title compound (60 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 101 using
the above-mentioned mixture and 1N aqueous sodium hydroxide
solution (0.2 mL).
[0842] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.87-3.93 (2H, m), 4.75
(2H, t, J=5.7 Hz), 5.24 (2H, s), 6.27 (1H, t, J=3.9 Hz), 7.13-7.32
(4H, m), 7.48 (1H, m), 7.55 (1H, dd, J=2.4, 9.3 Hz), 7.86 (1H, d,
J=1.8 Hz), 8.17 (1H, s), 8.36 (1H, s), 9.85 (1H, s).
Example 123
##STR00171##
[0843] Production of
2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]ethanol
[0844]
2-[7-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,-
3-d]pyrimidin-2-yl]ethyl benzoate was obtained as a mixture with
1-methyl-2-pyrrolidone by the reaction in the same manner as in
Example 97 using
2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate
(120 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (96 mg) and
pyridine hydrochloride (66 mg).
[0845] The title compound (86 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 101 using
the above-mentioned mixture and 1N aqueous sodium hydroxide
solution (0.2 mL).
[0846] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.88-3.93 (2H, m), 4.50
(2H, t, J=5.4 Hz), 5.04 (1H, t, J=5.7 Hz), 5.23 (2H, s), 7.14-7.32
(4H, m), 7.46 (1H, m), 7.88 (1H, dd, J=2.7, 9.0 Hz), 8.28 (1H, d,
J=1.8 Hz), 8.31 (1H, s), 8.45 (1H, s), 10.12 (1H, s).
Example 124
##STR00172##
[0847] Production of
2-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[4,-
3-d]pyrimidin-1-yl]ethanol
[0848] 2-[7-({3-Methyl-4-[(6-methylpyridin-3-yl)
oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate
was obtained as a mixture with 1-methyl-2-pyrrolidone by the
reaction in the same manner as in Example 101 using
2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate
(190 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (129 mg)
and pyridine hydrochloride (105 mg).
[0849] The title compound (88 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 101 using
the above-mentioned mixture and 1N aqueous sodium hydroxide
solution (0.3 mL).
[0850] .sup.1H-NMR (CDCl.sub.3) .delta. 2.22 (3H, s), 2.48 (3H, s),
4.25 (2H, br s), 4.76 (2H, br s), 6.01 (1H, br s), 6.86 (1H, d,
J=8.7 Hz), 7.08 (1H, d, J=8.7 Hz), 7.16 (1H, dd, J=3.0, 8.7 Hz),
7.45 (1H, dd, J=2.7, 8.7 Hz), 7.56 (1H, d, J=2.7 Hz), 8.05 (1H, d,
J=3.0 Hz), 8.37 (1H, s), 9.88 (1H, s).
Example 125
##STR00173##
[0851] Production of
2-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,-
3-d]pyrimidin-2-yl]ethanol
[0852]
2-[7-({3-Methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyraz-
olo[4,3-d]pyrimidin-2-yl]ethyl benzoate was obtained as a mixture
with 1-methyl-2-pyrrolidone by the reaction in the same manner as
in Example 97 using
2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate
(115 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (78 mg) and
pyridine hydrochloride (63 mg).
[0853] The title compound (95 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 101 using
the above-mentioned mixture and 1N aqueous sodium hydroxide
solution (0.3 mL).
[0854] .sup.1H-NMR (CDCl.sub.3) .delta. 2.24 (3H, s), 2.52 (3H, s),
4.16 (2H, t, J=4.5 Hz), 4.26 (1H, br s), 4.50-4.53 (2H, m), 6.86
(1H, d, J=8.7 Hz), 7.05-7.12 (2H, m), 7.57-7.61 (2H, m), 7.69 (1H,
d, J=2.7 Hz), 7.97 (1H, s), 8.23 (1H, m), 8.34 (1H, s).
Example 126
##STR00174##
[0855] Production of
3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]py-
rimidin-1-yl]propanol
[0856] The title compound (240 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 122 using
3-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]propyl benzoate
(623 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (477 mg) and
pyridine hydrochloride (329 mg) and 1N aqueous sodium hydroxide
solution (0.5 mL).
[0857] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.97-2.04 (2H, m),
3.25-3.28 (2H, m), 4.71 (2H, t, J=6.6 Hz), 5.27 (2H, s), 5.44 (1H,
t, J=4.8 Hz), 7.16-7.34 (4H, m), 7.48 (1H, m), 7.57 (1H, dd, J=2.7,
9.0 Hz), 7.82 (1H, d, J=2.4 Hz), 8.19 (1H, s), 8.35 (1H, s), 9.22
(1H, s).
Example 127
##STR00175##
[0858] Production of
3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]propanol
[0859] The title compound (512 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 123 using
3-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl benzoate
(556 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (426 mg),
pyridine hydrochloride (293 mg) and 1N aqueous sodium hydroxide
solution (10 mL).
[0860] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.06-2.13 (2H, m),
3.41-3.46 (2H, m), 4.53 (2H, t, J=6.9 Hz), 4.70 (1H, t, J=5.4 Hz),
5.24 (2H, s), 7.16-7.33 (4H, m), 7.46 (1H, m), 7.89 (1H, dd, J=2.4,
9.0 Hz), 8.28 (1H, d, J=2.4 Hz), 8.32 (1H, s), 8.51 (1H, s), 10.12
(1H, s).
Example 128
##STR00176##
[0861] Production of
4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5,6-dihydro-4H-pyrazolo[4,5,1--
de]pteridine
[0862] A solution of
2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]py-
rimidin-1-yl]ethanol (40 mg), 1,1'-(azodicarbonyl)dipiperidine (48
mg) and tributylphosphine (40 mg) in tetrahydrofuran (2 mL) was
stirred at room temperature for 15 hrs. After the completion of the
reaction, water was added to the reaction mixture and the mixture
was diluted with ethyl acetate and washed with saturated brine. The
organic layer was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/ethyl
acetate=4/1.fwdarw.1/4) to give the title compound (31 mg) as a
white solid.
[0863] .sup.1H-NMR (CDCl.sub.3) .delta. 4.32 (2H, dd, J=5.0, 6.6
Hz), 4.62 (2H, dd, J=5.0, 6.6 Hz), 5.19 (2H, s), 7.04 (1H, d, J=9.2
Hz), 7.05 (1H, m), 7.18-7.26 (2H, m), 7.32-7.43 (2H, m), 7.55 (1H,
d, J=2.6 Hz), 8.09 (1H, s), 8.51 (1H, s).
Example 129
##STR00177##
[0864] Production of 4-{3-methyl-4-[(6-methylpyridin-3-yl)
oxy]phenyl}-5,6-dihydro-4H-pyrazolo[4,5,1-de]pteridine
[0865] The title compound (21 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 128 using
2-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[4,-
3-d]pyrimidin-1-yl]ethanol (30 mg),
1,1'-(azodicarbonyl)dipiperidine (40 mg) and tributylphosphine (32
mg).
[0866] .sup.1H-NMR (CDCl.sub.3) .delta. 2.34 (3H, s), 2.55 (3H, s),
4.36 (2H, t, J=5.7 Hz), 4.64 (2H, t, J=5.7 Hz), 6.92 (1H, d, J=8.4
Hz), 7.13 (1H, d, J=8.4 Hz), 7.20 (1H, dd, J=2.7, 8.4 Hz), 7.27
(1H, dd, J=2.4, 8.4 Hz), 7.41 (1H, d, J=2.4 Hz), 8.09 (1H, s), 8.30
(1H, d, J=2.7 Hz), 8.53 (1H, s).
Example 130
##STR00178##
[0867] Production of
6-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6,7,8,9-tetrahydro-1,3,5,6,9a--
pentaazabenzo[cd]-azulene
[0868] The title compound (29 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 128 using
3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]py-
rimidin-1-yl]propanol (60 mg), 1,1'-(azodicarbonyl)dipiperidine (70
mg) and tributylphosphine (57 mg).
[0869] .sup.1H-NMR (CDCl.sub.3) .delta. 2.49-2.56 (2H, m), 4.03
(2H, m), 4.62 (2H, t, J=5.7 Hz), 5.19 (2H, s), 7.02 (1H, d, J=8.7
Hz), 7.05 (1H, m), 7.15 (1H, dd, J=2.7, 9.0 Hz), 7.21-7.26 (2H, m),
7.35-7.42 (2H, m), 8.12 (1H, s), 8.37 (1H, s).
Example 131
##STR00179##
[0870] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-(3-{[2-(methylsulfonyl)ethyl-
]amino}propyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine
[0871] A solution of
3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]propanol (50 mg),
N-[2-(methylsulfonyl)ethyl]-2-nitrobenzenesulfonamide (47 mg),
1,1'-(azodicarbonyl)dipiperidine (59 mg) and tributylphosphine (47
mg) in tetrahydrofuran (2 mL) was stirred at room temperature for 4
hrs. After the completion of the reaction, water was added to the
reaction mixture and the mixture was diluted with ethyl acetate and
washed with saturated brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/methanol=4/1.fwdarw.1/4) to give
N-{3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d-
]pyrimidin-2-yl]propyl}-N-[2-(methylsulfonyl)ethyl]-2-nitrobenzenesulfonam-
ide. To a solution of this compound in tetrahydrofuran (2 mL) were
added 2-mercaptoethanol (12 mg) and
1,8-diazabicyclo[5.4.0]undec-7-ene (23 mg), and the mixture was
stirred at room temperature for 3 hrs. After the completion of the
reaction, the reaction mixture was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate/methanol=10/1) to give the title
compound (34 mg) as a white solid.
[0872] .sup.1H-NMR (CDCl.sub.3) .delta. 2.05-2.14 (2H, m), 2.57
(2H, t, J=6.3 Hz), 3.08 (3H, s), 3.14-3.16 (2H, m), 3.22-3.26 (2H,
m), 4.54 (2H, t, J=6.3 Hz), 5.16 (2H, s), 6.97 (1H, d, J=8.7 Hz),
7.02 (1H, m), 7.20-7.26 (3H, m), 7.36 (1H, dt, J=6.3, 7.8 Hz), 7.71
(1H, dd, J=2.7, 9.0 Hz), 7.99 (2H, s), 8.09 (1H, d, J=2.7 Hz), 8.49
(1H, s).
Example 132
##STR00180##
[0873] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-{3-[(2-morpholin-4-ylethyl)a-
mino]propyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine
[0874] The title compound (32 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 131 using
3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]propanol (60 mg),
N-(2-morpholin-4-ylethyl)-2-nitrobenzenesulfonamide (53 mg),
1,1'-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57
mg), 2-mercaptoethanol (12 mg) and
1,8-diazabicyclo[5.4.0]undec-7-ene (23 mg).
[0875] .sup.1H-NMR (CDCl.sub.3) .delta. 2.42-2.51 (8H, m),
2.59-2.72 (4H, m), 3.70 (4H, t, J=4.8 Hz), 4.51 (2H, t, J=6.8 Hz),
5.15 (2H, s), 6.97 (1H, d, J=8.8 Hz), 7.02 (1H, m), 7.19-7.26 (2H,
m), 7.31-7.42 (2H, m), 7.66 (2H, m), 7.98 (1H, s), 8.01 (1H, d,
J=2.8 Hz), 8.49 (1H, s).
Example 133
##STR00181##
[0876] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-{3-[(2-methoxyethyl)amino]pr-
opyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine
[0877] The title compound (26 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 131 using
3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]py-
rimidin-2-yl]propanol (60 mg),
N-(2-methoxyethyl)-2-nitrobenzenesulfonamide (44 mg),
1,1'-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57
mg), 2-mercaptoethanol (12 mg) and
1,8-diazabicyclo[5.4.0]undec-7-ene (23 mg).
[0878] .sup.1H-NMR (CDCl.sub.3) .delta. 2.14-2.18 (2H, m), 2.61
(2H, t, J=6.6 Hz), 2.76 (2H, t, J=5.1 Hz), 3.37 (3H, s), 3.50 (2H,
t, J=5.1 Hz), 4.52 (2H, t, J=6.6 Hz), 5.15 (2H, s), 6.97 (1H, d,
J=9.0 Hz), 7.01 (1H, m), 7.18-7.26 (4H, m), 7.35 (1H, m), 7.58 (1H,
br s), 7.65 (1H, dd, J=2.4, 8.7 Hz), 7.99-8.00 (2H, m), 8.48 (1H,
s).
Example 134
##STR00182##
[0879] Production of
2-[[2-chloro-4-(1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)phenoxy]methyl]benz-
onitrile
[0880] The title compound (96 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 97 using
7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (80 mg),
2-[(4-amino-2-chlorophenoxy)methyl]benzonitrile (125 mg) and
pyridine hydrochloride (83 mg).
[0881] .sup.1H-NMR (DMSO-d.sub.6) .delta.2.23 (3H, s), 5.26 (2H,
s), 7.09 (1H, d, J=8.7 Hz), 7.54-7.77 (5H, m), 7.92 (1H, d, J=8.7
Hz), 8.20 (1H, br s), 8.34 (1H, br s), 9.45 (1H, br s), 12.8 (1H,
br s).
Example 135
##STR00183##
[0882] Production of
2-{[2-methyl-4-(1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)phenoxy]methyl}benz-
onitrile
[0883] The title compound (110 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 97 using
7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (80 mg),
2-[(4-amino-2-methylphenoxy)methyl]benzonitrile (115 mg) and
pyridine hydrochloride (83 mg).
[0884] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.23 (3H, s), 5.26 (2H,
s), 7.09 (1H, d, J=8.7 Hz), 7.54-7.77 (5H, m), 7.92 (1H, d, J=8.7
Hz), 8.20 (1H, br s), 8.34 (1H, br s), 9.45 (1H, br s), 12.8 (1H,
br s).
Example 136
##STR00184##
[0885] Production of
3-[2-chloro-4-(1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)phenoxy]benzonitrile
[0886] The title compound (89 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 97 using
7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (80 mg),
3-(4-amino-2-chlorophenoxy)benzonitrile (117 mg) and pyridine
hydrochloride (83 mg).
[0887] .sup.1H-NMR (DMSO-d.sub.6) .delta. 7.26-7.35 (2H, m), 7.46
(1H, m), 7.55-7.59 (2H, m), 7.89 (1H, m), 8.39 (1H, br s), 8.46
(2H, s), 10.16 (1H, br s), 12.6 (1H, br s).
Example 137
##STR00185##
[0888] Production of
3-[2-methyl-4-(1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)phenoxy]benzonitrile
[0889] The title compound (98 mg) was obtained as a pale-yellow
solid by the reaction in the same manner as in Example 97 using
7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (80 mg),
3-(4-amino-2-methylphenoxy)benzonitrile (108 mg) and pyridine
hydrochloride (83 mg).
[0890] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.18 (3H, s), 7.09 (1H,
d, J=8.7 Hz), 7.24 (1H, m), 7.37 (1H, m), 7.53-7.59 (2H, m), 7.86
(1H, d, J=8.7 Hz), 7.93 (1H, br s), 8.32 (1H, br s), 8.42 (1H, br
s), 9.85 (1H, br s), 12.2 (1H, br s).
Example 138
##STR00186##
[0891] Production of
2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]-
pyrimidin-5-yl]ethoxy}ethanol
(i) Production of
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate
[0892] To a solution of 2,2'-oxydiethanol (2.12 g) in pyridine (20
mL) was added benzoic anhydride (4.52 g) by small portions under
ice-cooling, and the reaction mixture was stirred while warming to
room temperature for 18 hrs. Pyridine was evaporated under reduced
pressure and the obtained residue was diluted with diethyl ether
(20 mL). 5% Aqueous sodium hydrogen carbonate solution (100 mL) was
added, and the mixture was extracted with diethyl ether (100
mL.times.3). The solvent was evaporated under reduced pressure, and
the obtained residue was subjected to silica gel chromatography
(eluent:hexane/ethyl acetate=95/5.fwdarw.40/60). The object
fraction was concentrated under reduced pressure and dried to give
2-(2-hydroxyethoxy)ethyl benzoate (2.21 g). To a solution of the
obtained 2-(2-hydroxyethoxy)ethyl benzoate (2.10 g) in
dichloromethane (10 mL) were added 1-iodopyrrolidine-2,5-dione
(2.70 g) and triphenylphosphine (3.14 g) by small portions under
ice-cooling, and the mixture was stirred for 14 hrs. The reaction
mixture was poured into 5% aqueous sodium hydrogen carbonate
solution (100 mL), and extracted with ethyl acetate (120
mL.times.3). The organic layer was washed successively with water
and saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel chromatography
(eluent:hexane/ethyl acetate=100/0.fwdarw.60/40). The object
fraction was concentrated under reduced pressure and dried to give
2-(2-iodoethoxy)ethyl benzoate (2.05 g) as a colorless transparent
oil.
[0893] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine
(0.659 g) in N,N-dimethylformamide (5.0 mL) was added cesium
carbonate (3.13 g) under ice-cooling, and the reaction mixture was
stirred while warming to room temperature for 15 min. To the
reaction mixture was added 2-(2-iodoethoxy)ethyl benzoate (1.45 g)
prepared above, and the mixture was stirred at room temperature for
15 hrs. The reaction mixture was poured into 5% aqueous sodium
hydrogen carbonate solution (100 mL), and extracted with ethyl
acetate (150 mL.times.3). The organic layer was washed successively
with water and saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel chromatography
(eluent:hexane/ethyl acetate=95/5->60/40). The object fraction
was concentrated under reduced pressure and dried to give the title
compound (0.822 g) as a colorless transparent oil.
[0894] .sup.1H-NMR (CDCl.sub.3) .delta. 3.718 (2H, dt, J=3.0, 6.6
Hz), 3.887 (2H, t, J=5.1 Hz), 4.412 (2H, dt, J=3.0, 6.6 Hz), 4.680
(2H, t, J=5.1 Hz), 6.566 (1H, d, J=3.3 Hz), 7.404-7.462 (2H, m),
7.542-7.600 (2H, m), 7.944-7.982 (2H, m), 8.665 (1H, s).
(ii) Production of
2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]-
pyrimidin-5-yl]ethoxy}ethyl benzoate
[0895] To a solution of
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (802 mg) in 1-methyl-2-pyrrolidone (8.0 mL) was added
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (745 mg), and the mixture
was stirred in an oil bath at a temperature of 100.degree. C. for 2
hrs. The reaction mixture was allowed to cool to room temperature,
diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL),
and extracted with a mixed solvent (50 mL.times.3) of ethyl
acetate/tetrahydrofuran (3/1). The solvent was evaporated under
reduced pressure, and the obtained residue was subjected to basic
silica gel chromatography (eluent:hexane/ethyl
acetate=95/5.fwdarw.0/100). The object fraction was concentrated
under reduced pressure and dried to give the title compound (1141
mg) as a yellow amorphous solid.
[0896] .sup.1H-NMR (CDCl.sub.3) .delta. 3.901-3.931 (2H, m), 4.036
(2H, t, J=4.2 Hz), 4.452-4.483 (2H, m), 4.540 (2H, t, J=4.2 Hz),
5.033 (2H, s), 6.590 (1H, d, J=3.0 Hz), 6.704 (1H, d, J=9.0 Hz),
7.005 (1H, td, J=1.8, 7.5 Hz), 7.164-7.372 (7H, m), 7.511 (1H, tt,
J=1.8, 7.5 Hz), 7.679 (1H, d, J=3.0 Hz), 7.769 (1H, t, J=1.8 Hz),
7.788 (1H, t, J=0.6 Hz), 8.431 (1H, s), 8.511 (1H, s).
(iii) Production of
2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]-
pyrimidin-5-yl]ethoxy}ethanol
[0897] To a solution of
2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]-
pyrimidin-5-yl]ethoxy}ethyl benzoate (760 mg) in tetrahydrofuran
(7.0 mL) was added 1N aqueous sodium hydroxide solution (7.0 mL),
and the mixture was stirred at room temperature for 14 hrs. 1N
Hydrochloric acid (7.0 mL) was added to the reaction mixture, and
the mixture was stirred at room temperature for 10 min. and
extracted with a mixed solvent (100 mL.times.3) of ethyl
acetate/tetrahydrofuran (1/1). The organic layer was washed
successively with 5% aqueous sodium hydrogen carbonate and
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to basic silica gel column chromatography
(eluent:ethyl acetate/methanol=100/0.fwdarw.90/10). The object
fraction was concentrated under reduced pressure. A mixed solvent
of ethanol/isopropyl ether (1/4) was added to the residue, and the
mixture was heated to 80.degree. C. and then allowed to cool to
room temperature. The resultant precipitate was collected by
filtration and dried under reduced pressure to give the title
compound (431 mg) as white powder crystals.
[0898] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.471-3.478 (4H, m),
3.817 (2H, t, J=4.6 Hz), 4.616 (2H, t, J=4.6 Hz), 4.681-4.712 (1H,
m), 5.234 (2H, s), 6.480 (1H, d, J=3.2 Hz), 7.173-7.212 (2H, m),
7.289-7.339 (2H, m), 7.433-7.523 (2H, m), 7.641 (1H, d, J=3.2 Hz),
7.829 (1H, d, J=3.2 Hz), 8.271 (1H, s), 8.698 (1H, s).
[0899] melting point: 168-169.degree. C.
Example 139
##STR00187##
[0900] Production of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]butan-1-ol
(i) Production of 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl
acetate
[0901] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine
(0.768 g) in N,N-dimethylformamide (10 mL) was added cesium
carbonate (2.01 g) under ice-cooling, and the reaction mixture was
stirred while warming to room temperature for 15 min. 4-Bromobutyl
acetate (1.26 g) was added dropwise to the reaction mixture, and
the mixture was stirred at room temperature for 30 hrs. The
reaction mixture was poured into 5% aqueous sodium hydrogen
carbonate solution (80 mL), and extracted with ethyl acetate (100
mL.times.3) The organic layer was washed successively with water
and saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel chromatography
(eluent:hexane/ethyl acetate=95/5.fwdarw.0/100). The object
fraction was concentrated under reduced pressure and dried to give
the title compound (1.084 g) as a colorless transparent oil.
[0902] .sup.1H-NMR (CDCl.sub.3) .delta. 1.636-1.730 (2H, m),
1.874-1.971 (2H, m) 2.047 (3H, s), 4.098 (2H, t, J=6.3 Hz), 4.512
(2H, t, J=6.3 Hz), 6.718 (1H, d, J=3.3 Hz), 7.482 (1H, d, J=3.3
Hz), 8.690 (1H, s).
(ii) Production of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]butyl acetate
[0903] To a solution of
4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl acetate (302 mg)
in isopropyl alcohol (2.24 mL) was added
3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421 mg), and the
mixture was stirred in an oil bath at a temperature of 100.degree.
C. for 3.5 hrs. The reaction mixture was allowed to cool to room
temperature, 5% aqueous sodium hydrogen carbonate solution (35 mL)
was added, and the mixture was extracted with ethyl acetate (50
mL.times.3). The organic layer was washed successively with water
and saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to basic silica gel chromatography
(eluent:hexane/ethyl acetate=95/5.fwdarw.20/80). The object
fraction was concentrated under reduced pressure and dried to give
the title compound (293 mg) as a white powder.
[0904] .sup.1H-NMR (CDCl.sub.3) .delta. 1.624-1.714 (2H, m),
1.924-2.005 (2H, m), 2.005 (3H, s), 4.108 (2H, t, J=6.0 Hz), 4.342
(2H, t, J=6.0 Hz), 6.573 (1H, d, J=3.3 Hz), 7.054 (1H, s),
7.083-7.471 (7H, m), 7.793 (1H, d, J=3.3 Hz), 8.526 (1H, s).
(iii) Production of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]butan-1-ol
[0905] To a solution of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]butyl acetate (281 mg) in tetrahydrofuran (4.0
mL) was added 1N aqueous sodium hydroxide solution (2.8 mL), and
the mixture was stirred at room temperature for 4.5 hrs. 1N Aqueous
hydrochloric acid solution (2.8 mL) was added, and the mixture was
stirred for 15 min. The reaction mixture was poured into water (50
mL), and the mixture was extracted with ethyl acetate (50
mL.times.3). The organic layer was washed successively with 5%
aqueous sodium hydrogen carbonate solution, water and saturated
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure, and the obtained residue was
subjected to basic silica gel chromatography (eluent:hexane/ethyl
acetate=95/5.fwdarw.0/100). The object fraction was concentrated
under reduced pressure and dried. Ethanol/diisopropyl ether (5/95)
was added to the residue, and the mixture was stirred with heating
to 80.degree. C., allowed to cool to room temperature, and stood
still.
[0906] The resultant precipitate was collected by filtration. The
obtained precipitate was washed with diisopropyl ether and dried
under reduced pressure to give the title compound (214 mg) as white
powder crystals.
[0907] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.240-1.331 (2H, m),
1.690-1.782 (2H, m), 3.324-3.361 (2H, m), 4.473 (1H, br s), 4.540
(2H, t, J=6.0 Hz), 6.492 (1H, d, J=3.0 Hz), 7.200-7.254 (2H, m),
7.303 (1H, d, J=9.0 Hz), 7.472 (1H, d, J=9.0 Hz), 7.621 (1H, t,
J=9.0 Hz), 7.653-7.713 (2H, m), 7.970 (1H, s), 8.351 (1H, s), 8.632
(1H, s).
Example 140
##STR00188##
[0908] Production of
3-(2-chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}-
phenoxy)benzonitrile
(i) Production of
2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidi-
n-5-yl)ethyl benzoate
[0909] To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (141
mg) in N,N-dimethylformamide (2.5 mL) was added cesium carbonate
(358 mg) under ice-cooling, and the reaction mixture was stirred
while warming to room temperature for 15 min. To the reaction
mixture was added 2-iodoethyl benzoate (298 mg), and the mixture
was stirred at room temperature for 15 hrs. The reaction mixture
was poured into 5% aqueous sodium hydrogen carbonate solution (50
mL), and extracted with ethyl acetate (50 mL.times.3). The organic
layer was washed successively with water and saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained residue was subjected to
silica gel chromatography (eluent:hexane/ethyl
acetate=95/5.fwdarw.60/40). The object fraction was concentrated
under reduced pressure and dried to give
2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (205 mg)
as a colorless transparent oil.
[0910] The title compound (311 mg) was obtained as a yellow solid
by the reaction in the same manner as in Example 42 (ii) using
3-(4-amino-2-chlorophenoxy)benzonitrile (211 mg) and a solution of
2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (205 mg)
in 1-methyl-2-pyrrolidone (1.3 mL).
[0911] .sup.1H-NMR (CDCl.sub.3) .delta. 4.693 (4H, s), 6.688 (1H,
d, J=3.0 Hz), 7.086-7.497 (8H, m), 7.609-7.727 (2H, m), 7.962 (2H,
d, J=6.9 Hz), 8.024 (2H, d, J=6.9 Hz), 8.569 (1H, s).
(ii) Production of
3-(2-chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}-
phenoxy)benzonitrile
[0912] The title compound (187 mg) was obtained as a pale-yellow
powder by the reaction in the same manner as in Example 138 (iii)
using
2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidi-
n-5-yl)ethyl benzoate (310 mg).
[0913] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.977-3.990 (2H, m),
4.542 (2H, br s), 6.470 (1H, d, J=3.0 Hz), 7.162-7.24 (3H, m),
7.421-7.625 (3H, m), 7.645 (1H, d, J=7.2 Hz), 7.989 (1H, d, J=3.0
Hz), 8.078 (1H, d, J=3.0 Hz), 8.368 (1H, s), 10.10 (1H, br s).
Example 141
##STR00189##
[0914] Production of
3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]benzonitrile
(i) Production of
2-[2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrim-
idin-5-yl)ethoxy]ethyl benzoate
[0915] The title compound (117 mg) was obtained as a pale brown
solid by the reaction in the same manner as in Example 138 (ii)
using 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (130 mg) and 3-(4-amino-2-chlorophenoxy)benzonitrile (112
mg).
[0916] .sup.1H-NMR (CDCl.sub.3) .delta. 4.051-4.077 (2H, m), 4.206
(2H, t, J=4.2 Hz), 4.582-4.599 (2H, m), 4.610 (2H, t, J=4.2 Hz),
6.781 (1H, d, J=3.0 Hz), 6.904 (1H, d, J=9.0 Hz), 7.195 (1H, td,
J=1.8, 7.5 Hz), 7.360-7.568 (7H, m), 7.709 (1H, tt, J=1.8, 7.5 Hz),
7.872 (1H, d, J=3.0 Hz), 7.975 (1H, t, J=1.8 Hz), 7.968 (1H, t,
J=0.6 Hz), 8.531 (1H, s), 8.671 (1H, s).
(ii) Production of
3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl} amino)phenoxy]benzonitrile
[0917] The title compound (52 mg) was obtained as a pale-yellow
powder by the reaction in the same manner as in Example 138 (iii)
using
2-[2-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrim-
idin-5-yl)ethoxy]ethyl benzoate (92 mg).
[0918] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.578-3.693 (4H, m),
3.617 (2H, t, J=4.8 Hz), 4.515 (2H, t, J=4.8 Hz), 4.589-4.699 (1H,
m), 6.378 (1H, d, J=3.0 Hz), 7.153-7.181 (3H, m), 7.411-7.461 (1H,
m), 7.553-7.663 (2H, m), 7.840 (1H, d, J=3.2 Hz), 8.049 (1H, d,
J=3.2 Hz), 8.377 (1H, s), 8.879 (1H, s).
Example 142
##STR00190##
[0919] Production of
2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-5-yl]-N-(2-hydroxyethyl)acetamide
(i) Production of ethyl
[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrim-
idin-5-yl]acetate
[0920] To a solution of ethyl
(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (530 mg) in
isopropyl alcohol (4.0 mL) was added
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (695 mg), and the mixture
was stirred in an oil bath at a temperature of 100.degree. C. for
2.5 hrs. The reaction mixture was allowed to cool to room
temperature, diluted with 5% aqueous sodium hydrogen carbonate
solution (25 mL), and extracted with ethyl acetate (30 mL.times.3).
The organic layer was washed successively with water and saturated
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure, and the obtained residue was
subjected to basic silica gel chromatography (eluent:hexane/ethyl
acetate=95/5.fwdarw.20/80). The object fraction was concentrated
under reduced pressure and dried to give the title compound (743
mg) as a white solid.
[0921] .sup.1H-NMR (CDCl.sub.3) .delta. 1.298-1.344 (3H, m), 4.338
(2H, q, J=7.2 Hz), 4.938 (2H, s), 5.132 (2H, s), 6.616 (1H, d,
J=3.4 Hz), 6.935 (1H, d, J=8.8 Hz), 6.979-7.056 (1H, m),
7.190-7.263 (3H, m), 7.301-7.426 (2H, m), 7.638 (1H, t, J=2.4 Hz),
8.200 (1H, s), 8.499 (1H, br s).
(ii) Production of
[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrim-
idin-5-yl]acetic acid
[0922] The title compound (504 mg) was obtained as a pale-purple
powder by the reaction in the same manner as in Example 46 using
ethyl
[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrim-
idin-5-yl]acetate (730 mg).
[0923] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.223 (2H, s), 5.282 (2H,
s), 6.480 (1H, d, J=3.0 Hz), 7.137-7.525 (7H, m), 7.603 (1H, d,
J=3.0 Hz), 7.666 (1H, d, J=3.0 Hz), 8.299 (1H, s).
(iii) Production of
2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyr-
imidin-5-yl]-N-(2-hydroxyethyl)acetamide
[0924] The title compound (39 mg) was obtained as a pale-yellow
powder by the reaction in the same manner as in Example 36 using
[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrim-
idin-5-yl]acetic acid (103 mg).
[0925] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.23 (2H, m), 3.46 (2H,
m), 4.89 (1H, t, J=4.5 Hz), 5.04 (2H, s), 5.22 (2H, s), 6.48 (1H,
d, J=3.0 Hz), 7.14-7.24 (2H, m), 7.29-7.33 (2H, m), 7.43-7.53 (2H,
m), 7.56 (1H, d, J=3.0 Hz), 7.85 (1H, d, J=3.0 Hz), 8.29 (1H, s),
8.97 (1H, br s), 10.08 (1H, br s).
Example 143
##STR00191##
[0926] Production of
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]propan-1-ol
[0927] To a solution of
3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-1-ol (201 mg)
synthesized in Example 53 (ii) in isopropyl alcohol (2.5 mL) was
added 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (381 mg), and
the mixture was stirred in an oil bath at a temperature of
100.degree. C. for 2.0 hrs. The reaction mixture was allowed to
cool to room temperature, diluted with 5% aqueous sodium hydrogen
carbonate solution (25 mL), and extracted with ethyl acetate (30
mL.times.3). The organic layer was washed successively with water
and saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the obtained
residue was subjected to basic silica gel chromatography
(eluent:hexane/ethyl acetate=95/5.fwdarw.20/80). The object
fraction was concentrated under reduced pressure and dried.
[0928] Ethanol/diisopropyl ether (1/9) was added to the residue,
and the mixture was stirred with heating to 80.degree. C., allowed
to cool to room temperature, and stood still. The resultant
precipitate was collected by filtration. The obtained precipitate
was washed with diisopropyl ether and dried under reduced pressure
to give the title compound (375 mg) as white powder crystals.
[0929] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.953 (2H, t, J=5.7 Hz),
3.380 (2H, t, J=5.7 Hz), 4.545 (2H, t, J=6.6 Hz), 5.372 (1H, br s),
6.527 (1H, d, J=3.0 Hz), 7.198-7.327 (3H, m), 7.470 (1H, d, J=7.5
Hz), 7.592-7.707 (3H, m), 7.981 (1H, d, J=3.0 Hz), 8.354 (1H, s),
9.038 (1H, br s).
Example 144
##STR00192##
[0930] Production of
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethoxy}ethyl carbamate hydrochloride
[0931] To a solution of
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethoxy}ethanol (84 mg) in a mixed solvent
(1.0 mL) of toluene/dichloromethane (1/1) was added trichloroacetyl
isocyanate (22 .mu.L) under ice-cooling, and the mixture was
stirred for 3 hrs. To the reaction mixture were added methanol (0.2
mL) and potassium carbonate (71 mg), and the mixture was stirred at
room temperature for 12 hrs. The reaction mixture was poured into
5% aqueous sodium hydrogen carbonate solution (25 mL), and
extracted with ethyl acetate (30 mL.times.3). The organic layer was
washed successively with water and saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure, and the obtained residue was subjected to basic
silica gel chromatography (eluent:ethyl
acetate/methanol=100/0.fwdarw.95/5). The object fraction was
concentrated under reduced pressure and dried to give
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethoxy}ethyl carbamate (83 mg) as a colorless
transparent oil. 4N Hydrochloric acid/ethyl acetate solution was
added to the obtained colorless transparent oil. After stirring at
room temperature for 3 hrs, the resultant precipitate was collected
by filtration, washed with diisopropyl ether, ethyl acetate and ice
water, and dried under reduced pressure at 60.degree. C. to give
the title compound (57 mg) as a pale-yellow powder.
[0932] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.57 (2H, t, J=3.0 Hz),
3.79 (2H, t, J=3.0 Hz), 3.96 (2H, t, J=6.0 Hz), 4.64 (2H, t, J=6.0
Hz), 6.48 (2H, br s), 6.56 (1H, s), 7.15-7.23 (2H, m), 7.30-7.34
(2H, m), 7.41 (1H, dd, J=3.0, 9.0 Hz), 7.47 (1H, dt, J=6.0, 9.0
Hz), 7.63 (1H, d, J=3.0 Hz), 7.82 (1H, s), 8.28 (1H, s), 8.56 (1H,
s).
Example 145
##STR00193##
[0933] Production of
2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]ethanol
[0934] A mixture of
2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (302
mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (288 mg) and
1-methyl-2-pyrrolidone (3 mL) was stirred at 120.degree. C. for 2
hrs. Water and saturated aqueous sodium hydrogen carbonate solution
were added to the reaction mixture and the mixture was extracted
with ethyl acetate. The ethyl acetate layer was washed successively
with water and saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel column chromatography
(eluent, ethyl acetate:hexane=20:80.fwdarw.100:0). The object
fraction was concentrated under reduced pressure. Diethyl ether was
added to the residue to allow crystallization, and diisopropyl
ether was added, which was followed by filtration to give a white
powder (286 mg). To a solution of this white powder (221 mg) in
methanol (5 mL) was added 1N aqueous sodium hydroxide solution (0.8
mL), and the mixture was stirred at room temperature for 2 hrs.
Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The ethyl acetate layer was washed
with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and ethyl
acetate and diisopropyl ether were added to the obtained residue,
which was followed by filtration to give the title compound (160
mg) as a white powder.
[0935] .sup.1H-NMR (CDCl.sub.3) .delta. 4.16 (2H, t, J=4.4 Hz),
4.38 (2H, t, J=4.4 Hz), 6.12 (1H, d, J=3.2 Hz), 6.97 (1H, d, J=3.2
Hz), 7.09 (1H, d, J=8.8 Hz), 7.10-7.17 (1H, m), 7.21 (1H, s), 7.32
(1H, d, J=7.7 Hz), 7.43 (1H, t, J=8.0 Hz), 7.52 (1H, dd, J=8.8, 2.6
Hz), 7.84 (1H, d, J=2.6 Hz), 8.24 (1H, s), 9.59 (1H, br s).
Example 146
##STR00194##
[0937] Production of
2-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyri-
midin-5-yl)ethoxy]ethanol
[0938] A mixture of
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (346 mg), 3-chloro-4-(3-chlorophenoxy)aniline (280 mg) and
1-methyl-2-pyrrolidone (3 mL) was stirred at 120.degree. C. for 2
hrs. Water and saturated aqueous sodium hydrogen carbonate solution
were added to the reaction mixture and the mixture was extracted
with ethyl acetate. The ethyl acetate layer was washed successively
with water and saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel column chromatography
(eluent, ethyl acetate:hexane=30:70.fwdarw.100:0). The object
fraction was concentrated under reduced pressure.
[0939] To a solution of the residue (431 mg) in methanol (10 mL)
was added 1N aqueous sodium hydroxide solution (1 mL), and the
mixture was stirred at room temperature for 4 hrs. Water was added
to the reaction mixture and the mixture was extracted with ethyl
acetate. The ethyl acetate layer was washed with saturated brine
and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure, and the obtained residue was
crystallized from ethyl acetate-diethyl ether to give the title
compound (312 mg) as a white powder.
[0940] .sup.1H-NMR (CDCl.sub.3) .delta. 2.05 (1H, br s), 3.71-3.84
(4H, m), 4.03 (2H, t, J=4.5 Hz), 4.57 (2H, t, J=4.5 Hz), 6.61 (1H,
d, J=3.0 Hz), 6.83-6.88 (1H, m), 6.92 (1H, t, J=2.2 Hz), 7.01-7.06
(1H, m), 7.06 (1H, d, J=8.9 Hz), 7.19-7.27 (2H, m), 7.61 (1H, dd,
J=8.9, 2.6 Hz), 7.89 (1H, d, J=2.6 Hz), 8.52 (1H, s), 8.82 (1H, br
s).
Example 147
##STR00195##
[0941] Production of
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[0942] A mixture of
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (1.037 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline
(863 mg) and 1-methyl-2-pyrrolidone (10 mL) was stirred at
120.degree. C. for 1.5 hrs. Water and saturated aqueous sodium
hydrogen carbonate solution were added to the reaction mixture and
the mixture was extracted with ethyl acetate. The ethyl acetate
layer was washed successively with water and saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained residue was subjected to
silica gel column chromatography (eluent, ethyl
acetate:hexane=50:50.fwdarw.100:0). The object fraction was
concentrated under reduced pressure. To a solution of the residue
(1.420 g) in methanol (30 mL) was added 1N aqueous sodium hydroxide
solution (3 mL), and the mixture was stirred at room temperature
for 1 hr. The reaction mixture was concentrated under reduced
pressure, water was added to the reaction mixture and the mixture
was extracted with ethyl acetate. The ethyl acetate layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was subjected to silica gel column chromatography
(eluent, methanol:ethyl acetate=0:100.fwdarw.5:95). The object
fraction was concentrated under reduced pressure. The precipitated
crystals were collected by filtration, and washed with diethyl
ether. The crude crystals were recrystallized from ethyl
acetate-diisopropyl ether to give the title compound (933 mg) as a
white powder.
[0943] .sup.1H-NMR (CDCl.sub.3) .delta. 1.94 (1H, br s), 3.71-3.85
(4H, m), 4.03 (2H, t, J=4.4 Hz), 4.57 (2H, t, J=4.4 Hz), 6.63 (1H,
d, J=3.2 Hz), 7.07 (1H, d, J=8.9 Hz), 7.08-7.14 (1H, m), 7.19 (1H,
s), 7.22 (1H, d, J=3.2 Hz), 7.31 (1H, d, J=7.7 Hz), 7.42 (1H, t,
J=8.0 Hz), 7.63 (1H, dd, J=8.9, 2.6 Hz), 7.91 (1H, d, J=2.6 Hz),
8.52 (1H, s), 8.83 (1H, br s)
[0944] melting point: 130-132.degree. C.
Example 148
##STR00196##
[0945] Production of
2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[0946] The title compound (293 mg) was obtained as a white powder
by the reaction in the same manner as in Example 146 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (346 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline
(334 mg) and 1-methyl-2-pyrrolidone (3 mL).
[0947] .sup.1H-NMR (CDCl.sub.3) .delta. 1.95 (1H, br s), 3.71-3.84
(4H, m), 4.03 (2H, t, J=4.5 Hz), 4.57 (2H, t, J=4.5 Hz), 6.62 (1H,
d, J=3.2 Hz), 6.80-6.95 (3H, m), 7.08 (1H, d, J=8.8 Hz), 7.21 (1H,
d, J=3.2 Hz), 7.30 (1H, t, J=8.2 Hz), 7.62 (1H, dd, J=8.8, 2.6 Hz),
7.90 (1H, d, J=2.6 Hz), 8.52 (1H, s), 8.82 (1H, br s).
Example 149
##STR00197##
[0948] Production of
1-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidi-
n-4-yl}amino)phenoxy]phenyl}ethanone
[0949] The title compound (493 mg) was obtained as a white powder
by the reaction in the same manner as in Example 146 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (692 mg), 1-[3-(4-amino-2-chlorophenoxy)phenyl]ethanone
(576 mg) and 1-methyl-2-pyrrolidone (5 mL).
[0950] .sup.1H-NMR (CDCl.sub.3) .delta. 1.97 (1H, br s), 2.58 (3H,
s), 3.71-3.84 (4H, m), 4.03 (2H, t, J=4.4 Hz), 4.58 (2H, t, J=4.4
Hz), 6.63 (1H, d, J=3.2 Hz), 7.06 (1H, d, J=8.9 Hz), 7.15-7.20 (1H,
m), 7.22 (1H, d, J=3.2 Hz), 7.41 (1H, t, J=7.9 Hz), 7.48-7.51 (1H,
m), 7.61 (1H, dd, J=8.9, 2.6 Hz), 7.62-7.67 (1H, m), 7.90 (1H, d,
J=2.6 Hz), 8.52 (1H, s), 8.80 (1H, br s).
Example 150
##STR00198##
[0951] Production of
1-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidi-
n-4-yl}amino)phenoxy]phenyl}ethanol
[0952] To a solution of
1-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidi-
n-4-yl}amino)phenoxy]pheny}ethanone (233 mg) in methanol (5 mL) was
added sodium borohydride (38 mg), and the mixture was stirred at
room temperature for 2 hrs. Water was added to the reaction mixture
and the mixture was extracted with ethyl acetate. The ethyl acetate
layer was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced
pressure, and the obtained residue was crystallized from ethyl
acetate-diethyl ether to give the title compound (225 mg) as a
white powder.
[0953] .sup.1H-NMR (CDCl.sub.3) .delta. 2.47 (3H, d, J=6.4 Hz),
3.67-3.77 (4H, m), 4.00 (2H, t, J=4.4 Hz), 4.58 (2H, t, J=4.4 Hz),
4.84 (1H, q, J=6.4 Hz), 6.62 (1H, d, J=3.3 Hz), 6.85-6.90 (1H, m),
6.96-7.00 (1H, m), 7.01-7.09 (2H, m), 7.24-7.32 (2H, m), 7.52 (1H,
dd, J=8.9, 2.6 Hz), 7.86 (1H, d, J=2.6 Hz), 8.45 (1H, s).
Example 151
##STR00199##
[0954] Production of
2-[2-(4-{[3-chloro-4-(pyrimidin-5-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)ethoxy]ethanol
[0955] The title compound (63 mg) was obtained as a white powder by
the reaction in the same manner as in Example 146 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (346 mg), 3-chloro-4-(pyrimidin-5-yloxy)aniline (360 mg)
and 1-methyl-2-pyrrolidone (3 mL).
[0956] .sup.1H-NMR (CDCl.sub.3) .delta. 2.08 (1H, br s), 3.72-3.84
(4H, m), 4.03 (2H, t, J=4.4 Hz), 4.58 (2H, t, J=4.4 Hz), 6.63 (1H,
d, J=3.1 Hz), 7.12 (1H, d, J=8.7 Hz), 7.23 (1H, d, J=3.1 Hz), 7.67
(1H, dd, J=8.7, 2.6 Hz), 7.95 (1H, d, J=2.6 Hz), 8.43 (2H, s), 8.52
(1H, s), 8.89 (1H, br s), 8.94 (1H, s).
Example 152
##STR00200##
[0957] Production of
2-(2-{4-[(3-chloro-4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)amino]-5H-pyr-
rolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol
[0958] The title compound (276 mg) was obtained as a white powder
by the reaction in the same manner as in Example 146 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (277 mg),
3-chloro-4-{[2-(trifluoromethyl)benzyl]oxy}aniline (241 mg) and
1-methyl-2-pyrrolidone (3 mL).
[0959] .sup.1H-NMR (CDCl.sub.3) .delta. 2.02 (1H, br s), 3.68-3.81
(4H, m), 4.00 (2H, t, J=4.4 Hz), 4.53 (2H, t, J=4.4 Hz), 5.34 (2H,
s), 6.58 (1H, d, J=3.2 Hz), 6.93 (1H, d, J=8.8 Hz), 7.17 (1H, d,
J=3.2 Hz), 7.42 (1H, t, J=7.7 Hz), 7.49 (1H, dd, J=8.8, 2.6 Hz),
7.60 (1H, t, J=7.7 Hz), 7.69 (1H, d, J=7.7 Hz), 7.76 (1H, d, J=2.6
Hz), 7.89 (1H, d, J=7.7 Hz), 8.46 (1H, s), 8.57 (1H, br s).
Example 153
##STR00201##
[0960] Production of
2-(2-{4-[(3-chloro-4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)amino]-5H-pyr-
rolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol
[0961] The title compound (393 mg) was obtained as a white powder
by the reaction in the same manner as in Example 146 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (346 mg),
3-chloro-4-{[3-(trifluoromethyl)benzyl]oxy}aniline (302 mg) and
1-methyl-2-pyrrolidone (3 mL).
[0962] .sup.1H-NMR (CDCl.sub.3) .delta. 2.03 (1H, br s), 3.68-3.80
(4H, m), 4.00 (2H, t, J=4.4 Hz), 4.54 (2H, t, J=4.4 Hz), 5.17 (2H,
s), 6.59 (1H, d, J=3.1 Hz), 6.95 (1H, d, J=8.8 Hz), 7.17 (1H, d,
J=3.1 Hz), 7.48-7.62 (3H, m), 7.66-7.76 (3H, m), 8.46 (1H, s), 8.58
(1H, br s).
Example 154
##STR00202##
[0963] Production of
5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]pentan-1-ol
(i) Production of
5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl acetate
[0964] A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g),
5-bromopentyl acetate (0.71 mL), cesium carbonate (1.59 g) and
N,N-dimethylformamide (5.0 mL) was stirred at 40.degree. C. for 4
days. Water was added to the reaction system and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine and dried over magnesium sulfate. After
concentration under reduced pressure, the residue was separated and
purified by silica gel column chromatography (eluent, ethyl
acetate:hexane=1:3.fwdarw.6:4) to give the title compound (637 mg)
as a white solid.
[0965] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33-1.46 (2H, m),
1.61-1.72 (2H, m), 1.84-1.97 (2H, m), 2.04 (3H, s), 4.05 (2H, t,
J=6.6 Hz), 4.48 (2H, t, J=7.5 Hz), 6.71 (1H, d, J=3.3 Hz), 7.46
(1H, d, J=3.3 Hz), 8.69 (1H, s).
(ii) Production of
5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]pentan-1-ol
[0966] A solution of
5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl acetate (200 mg)
and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (265 mg) in
isopropyl alcohol (3.5 mL) was stirred at 80.degree. C. for 14 hrs.
1N Aqueous sodium hydroxide solution (2.1 mL) was added at
0.degree. C., and the mixture was stirred at room temperature for 1
hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction system,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with aqueous sodium hydrogen carbonate and saturated
brine and dried over magnesium sulfate. After concentration under
reduced pressure, the residue was separated and purified by silica
gel column chromatography (eluent, ethyl acetate.fwdarw.ethyl
acetate:methanol=1:19) to give a colorless solid. Recrystallization
from ethyl acetate-hexane gave the title compound (275 mg) as
colorless crystals.
[0967] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35 (1H, t, J=4.7 Hz),
1.50-1.69 (4H, m), 1.92-2.05 (2H, m), 3.63-3.71 (2H, m), 4.32 (2H,
t, J=7.4 Hz), 6.59 (1H, d, J=3.3 Hz), 6.70 (1H, s), 7.08 (1H, d,
J=8.7 Hz), 7.09-7.12 (1H, m), 7.15-7.27 (2H, m), 7.30-7.35 (1H, m),
7.40-7.43 (1H, m), 7.47 (1H, dd, J=8.7, 2.7 Hz), 7.82 (1H, d, J=2.7
Hz), 8.53 (1H, s).
Example 155
##STR00203##
[0968] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-hydroxyacetamide
(i) Production of tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate
[0969] The title compound (687 mg) was obtained as a colorless
solid by the reaction in the same manner as in Example 154 (i)
using 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g), tert-butyl
2-bromoethylcarbamate (0.95 g), cesium carbonate (1.59 g) and
N,N-dimethylformamide (10 ml).
[0970] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31-1.46 (9H, m), 3.55
(2H, dt, J=6.0, 6.0 Hz), 4.51-4.68 (3H, m), 6.74 (1H, d, J=3.2 Hz),
7.47 (1H, d, J=3.2 Hz), 8.71 (1H, s).
(ii) Production of tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}carbamate
[0971] A solution of tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (712
mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (830 mg) in
isopropyl alcohol (7.1 mL) was stirred at 80.degree. C. for 12 hrs.
Aqueous sodium hydrogen carbonate was added to the reaction system
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was
separated and purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=1:1-+ethyl acetate) to give the title compound
(1.12 g) as colorless crystals.
[0972] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.49 (9H, s), 3.43-3.54
(2H, m), 4.43-4.51 (2H, m), 5.10 (1H, t, J=5.6 Hz), 6.60 (1H, d,
J=3.3 Hz), 7.07 (1H, m), 7.09-7.14 (1H, m), 7.16-7.22 (2H, m),
7.25-7.30 (1H, m), 7.37-7.45 (1H, m), 7.89 (1H, dd, J=8.7, 2.4 Hz),
8.02 (1H, d, J=2.4 Hz), 8.50 (1H, s), 8.64 (1H, br s).
(iii) Production of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride
[0973] A mixture of tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}carbamate (1.12 g), 2N hydrochloric acid
(15 mL) and tetrahydrofuran (30 mL) was stirred at 60.degree. C.
for 20 hrs. The solvent was evaporated under reduced pressure,
ethanol was added, and the mixture was further concentrated. The
precipitated crystals were collected by filtration and the crystals
were washed with ethyl acetate to give the title compound (1.07 g)
as pale-yellow crystals.
[0974] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.21-3.35 (2H, m),
4.92-5.02 (2H, m), 6.71-6.76 (1H, m), 7.24-7.32 (2H, m), 7.37 (1H,
d, J=9.0 Hz), 7.50-7.56 (1H, m), 7.64-7.71 (2H, m), 7.91-7.97 (1H,
m), 7.98-8.06 (1H, m), 8.13-8.26 (3H, m), 8.71 (1H, br s),
9.88-9.99 (1H, m).
(iv) Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-hydroxyacetamide
[0975] A mixture of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (105 mg), glycolic
acid (44 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (167 mg), 1-hydroxybenzotriazole monohydrate (133
mg), triethylamine (0.40 mL) and N,N-dimethylformamide (5.0 mL) was
stirred at room temperature for 3 days. Water was added to the
reaction system and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine and
dried over magnesium sulfate. After concentration under reduced
pressure, the residue was separated and purified by basic silica
gel column chromatography (eluent, ethyl
acetate.fwdarw.methanol:ethyl acetate=1:9) to give the title
compound (108 mg) as colorless crystals.
[0976] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.93-3.09 (1H, m),
3.59-3.73 (2H, m), 4.24 (2H, s), 4.43-4.53 (2H, m), 6.59 (1H, d,
J=3.3 Hz), 7.07 (1H, d, J=8.7 Hz), 7.09-7.46 (6H, m), 7.72 (1H, dd,
J=8.7, 2.4 Hz), 8.06 (1H, d, J=2.4 Hz), 8.49 (1H, s), 8.57 (1H,
s).
Example 156
##STR00204##
[0977] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}carbamate
[0978] A solution of tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (100
mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (153 mg) in
isopropyl alcohol (1.5 mL) was stirred at 80.degree. C. for 12 hrs.
Aqueous sodium hydrogen carbonate was added to the reaction system
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was
separated and purifed by silica gel column chromatography (eluent,
hexane:ethyl acetate=1:1.fwdarw.ethyl acetate) to give the title
compound (173 mg) as colorless crystals.
[0979] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (9H, s), 3.45-3.54
(2H, m), 4.43-4.52 (2H, m), 5.01-5.08 (1H, m), 6.61 (1H, d, J=3.0
Hz), 6.80-6.95 (3H, m), 7.09 (1H, d, J=8.7 Hz), 7.19 (1H, d, J=3.0
Hz), 7.29-7.34 (1H, m), 7.90 (1H, dd, J=8.7, 2.7 Hz), 8.03 (1H, d,
J=2.7 Hz), 8.52 (1H, s), 8.62 (1H, br s).
(ii) Production of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-py-
rrolo[3,2-d]pyrimidin-4-amine dihydrochloride
[0980] A mixture of tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}carbamate (173 mg), 2N hydrochloric acid
(2.5 mL) and tetrahydrofuran (5.0 mL) was stirred at 60.degree. C.
for 6 hrs. Ethanol was added to the reaction system. The solvent
was evaporated under reduced pressure. Ethanol was added to the
concentrate, and the mixture was further concentrated under reduced
pressure. The residual crystals were collected by filtration and
the crystals were washed with ethyl acetate to give the title
compound (155 mg) as pale-yellow crystals.
[0981] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.21-3.34 (2H, m),
4.89-5.00 (2H, m), 6.74 (1H, d, J=2.4 Hz), 6.94-7.01 (2H, m), 7.16
(1H, d, J=8.7 Hz), 7.36 (1H, d, J=9.0 Hz), 7.51-7.57 (1H, m),
7.62-7.69 (1H, m), 7.90-7.95 (1H, m), 7.99-8.05 (1H, m), 8.12-8.27
(3H, m), 8.71 (1H, s), 9.92 (1H, br s).
(iii) Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
[0982] A mixture of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-py-
rrolo[3,2-d]pyrimidin-4-amine dihydrochloride (160 mg),
2-(methylsulfonyl)acetic acid (82.3 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171
mg), 1-hydroxybenzotriazole monohydrate (137 mg), triethylamine
(0.42 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room
temperature for 20 hrs. Water was added to the reaction system and
the mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine and dried over magnesium
sulfate. After concentration under reduced pressure, the residue
was separated and purified by basic silica gel column
chromatography (eluent, ethyl acetate.fwdarw.ethyl acetate:
methanol=4:1) and crystallization from ethanol-ethyl
acetate-diisopropyl ether to give the title compound (112 mg) as
pale-yellow crystals.
[0983] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.12 (3H, s), 3.64-3.76
(2H, m), 3.99 (2H, s), 4.34-4.52 (2H, m), 6.62 (1H, d, J=3.0 Hz),
6.81-6.84 (1H, m), 6.86-6.95 (2H, m), 7.08 (1H, d, J=8.7 Hz),
7.17-7.24 (2H, m), 7.29-7.34 (1H, m), 7.76 (1H, dd, J=8.7, 2.7 Hz),
7.95 (1H, d, J=2.7 Hz), 8.18 (1H, s), 8.51 (1H, s).
[0984] melting point: 133-135.degree. C.
Example 157
##STR00205##
[0985] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-methoxyacetamide
[0986] The title compound (120 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
methoxyacetic acid (52 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166
mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine
(0.40 mL) and N,N-dimethylformamide (5.0 mL).
[0987] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.44 (3H, s), 3.60-3.71
(2H, m), 4.00 (2H, s), 4.44-4.53 (2H, m), 6.62 (1H, d, J=3.0 Hz),
7.02-7.15 (3H, m), 7.19 (1H, d, J=3.0 Hz), 7.22-7.35 (2H, m),
7.38-7.45 (1H, m), 7.74 (1H, dd, J=8.7, 2.4 Hz), 8.07 (1H, d, J=2.4
Hz), 8.52 (1H, s), 8.55 (1H, s).
Example 158
##STR00206##
[0988] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide
[0989] A mixture of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
3-hydroxy-3-methylbutyric acid (68 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166
mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine
(0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room
temperature for 5 days. Water was added to the reaction system and
the mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine and dried over magnesium
sulfate. After concentration under reduced pressure, the residue
was separated and purified by basic silica gel column
chromatography (eluent, ethyl acetate.fwdarw.ethyl
acetate:methanol=9:1). Crystallization from ethyl
acetate-diisopropyl ether gave the title compound (122 mg) as
colorless crystals.
[0990] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (6H, s), 2.49 (2H,
s), 2.65-2.77 (1H, m), 3.57-3.68 (2H, m), 4.44-4.53 (2H, m), 6.61
(1H, d, J=3.0 Hz), 6.93-7.01 (1H, m), 7.07 (1H, d, J=9.0 Hz),
7.09-7.15 (1H, m), 7.19 (1H, d, J=3.0 Hz), 7.23-7.35 (2H, m),
7.40-7.45 (1H, m), 7.77 (1H, dd, J=9.0, 2.7 Hz), 8.08 (1H, d, J=2.7
Hz), 8.52 (1H, s), 8.66 (1H, s).
[0991] melting point: 167-169.degree. C.
Example 159
##STR00207##
[0992] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-hydroxy-2-methylpropanamide
[0993] To a suspension of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg) and
triethylamine (0.40 mL) in tetrahydrofuran (5.0 mL) was added
1-chlorocarbonyl-1-methylethyl acetate (0.12 mL) at room
temperature. After stirring at room temperature for 3 days, aqueous
sodium hydrogen carbonate was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine, dried over magnesium sulfate and concentrated under reduced
pressure. To a solution of the residue in ethanol (3.0 mL) was
added 1N aqueous sodium hydroxide solution (1.5 mL) at room
temperature. After stirring at room temperature for 24 hrs, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure, and the residue was separated
and purified by basic silica gel column chromatography (eluent,
ethyl acetate.fwdarw.ethyl acetate:methanol=9:1) to give the title
compound (133 mg) as colorless crystals.
[0994] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.49 (6H, s), 2.12-2.27
(1H, m), 3.56-3.67 (2H, m), 4.42-4.52 (2H, m), 6.61 (1H, d, J=3.3
Hz), 7.06 (1H, d, J=9.0 Hz), 7.08-7.14 (1H, m), 7.15-7.43 (5H, m),
7.86 (1H, dd, J=9.0, 2.7 Hz), 8.10 (1H, d, J=2.7 Hz), 8.51 (1H, s),
8.72 (1H, s).
Example 160
##STR00208##
[0995] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
[0996] A mixture of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
2-(methylsulfonyl)acetic acid (79.6 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166
mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine
(0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room
temperature for 20 hrs. Water was added to the reaction system and
the mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine and dried over magnesium
sulfate. After concentration under reduced pressure, the residue
was separated and purified by basic silica gel column
chromatography (eluent, ethyl acetate.fwdarw.ethyl
acetate:methanol=4:1). Crystallization from ethyl
acetate-diisopropyl ether gave the title compound (128 mg) as
colorless powder crystals.
[0997] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.12 (3H, s), 3.64-3.75
(2H, m), 3.98 (2H, s), 4.43-4.53 (2H, m), 6.62 (1H, d, J=3.0 Hz),
7.07 (1H, d, J=9.0 Hz), 7.09-7.15 (1H, m), 7.18-7.33 (4H, m),
7.40-7.45 (1H, m), 7.77 (1H, dd, J=9.0, 2.7 Hz), 7.96 (1H, d, J=2.7
Hz), 8.19 (1H, s), 8.51 (1H, s).
[0998] melting point: 177-178.degree. C.
Example 161
##STR00209##
[0999] Production of
5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]-3-methylpentane-1,3-diol
(i) Production of 3,5-dihydroxy-3-methylpentyl benzoate
[1000] A solution of 3-methyl-1,3,5-pentanetriol (21.9 g), benzoic
anhydride (7.39 g), pyridine (4.0 mL) and
4-(N,N-dimethylamino)pyridine (0.39 g) in acetonitrile (200 mL) was
stirred at room temperature for 2 days. After concentration under
reduced pressure, water was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine, dried over magnesium sulfate and concentrated under reduced
pressure, and the residue was separated and purified by silica gel
column chromatography (eluent, hexane:ethyl acetate=1:1->ethyl
acetate) to give the title compound (4.27 g) as a colorless
oil.
[1001] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36 (3H, s), 1.72-1.81
(1H, m), 1.86-2.13 (3H, m), 2.47 (1H, t, J=4.7 Hz), 2.89 (1H, s),
3.85-4.02 (2H, m), 4.52 (2H, t, J=6.8 Hz), 7.42-7.48 (2H, m),
7.54-7.60 (1H, m), 8.00-8.04 (2H, m).
(ii) Production of 5-bromo-3-hydroxy-3-methylpentyl benzoate
[1002] To a solution of 3,5-dihydroxy-3-methylpentyl benzoate (1.0
g) and carbon tetrabromide (2.78 g) in tetrahydrofuran (30 mL) was
added dropwise a solution of triphenylphosphine (2.20 g) in
tetrahydrofuran (10 mL) under ice-cooling. After stirring at room
temperature for 3 days, water was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure, and the residue was separated and purified
by silica gel column chromatography (eluent, hexane:ethyl
acetate=9:1.fwdarw.6:4) to give the title compound (979 mg) as a
colorless oil.
[1003] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (3H, s), 1.78 (1H,
s), 1.97-2.02 (2H, m), 2.11-2.23 (2H, m), 3.53 (2H, t, J=8.1 Hz),
4.51 (2H, t, J=6.5 Hz), 7.42-7.48 (2H, m), 7.55-7.60 (1H, m),
8.00-8.04 (2H, m).
(iii) Production of
5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3-hydroxy-3-methylpentyl
benzoate
[1004] The title compound (773 mg) was obtained as a colorless oil
by the reaction in the same manner as in Example 154 (i) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (400 mg),
5-bromo-3-hydroxy-3-methylpentyl benzoate (979 mg), cesium
carbonate (0.94 g) and N,N-dimethylformamide (10 mL).
[1005] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.41 (3H, s), 1.91 (1H,
s), 2.01-2.13 (4H, m), 4.54 (2H, t, J=6.6 Hz), 4.59-4.76 (2H, m),
6.71 (1H, d, J=3.0 Hz), 7.40-7.46 (2H, m), 7.51 (1H, d, J=3.0 Hz),
7.54-7.60 (1H, m), 7.98-8.01 (2H, m), 8.69 (1H, s).
(iv) Production of
5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]-3-methylpentane-1,3-diol
[1006] The title compound (223 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 154 (ii)
using
5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3-hydroxy-3-methylpentyl
benzoate (250 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline
(230 mg), isopropyl alcohol (1.5 mL) and 1N aqueous sodium
hydroxide solution (2.0 mL).
[1007] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35 (3H, s), 1.62-1.71
(1H, m), 1.89-2.22 (4H, m), 3.93-4.18 (2H, m), 4.54-4.65 (3H, m),
6.56 (1H, d, J=3.0 Hz), 7.04 (1H, d, J=8.7 Hz), 7.08-7.14 (1H, m),
7.19-7.25 (2H, m), 7.29-7.35 (1H, m), 7.39-7.44 (1H, m), 7.61 (1H,
dd, J=8.7, 2.7 Hz), 7.93 (1H, d, J=2.7 Hz), 8.49 (1H, s), 8.52 (1H,
br s).
Example 162
##STR00210##
[1008] Production of
2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol
(i) Production of 2-[(2-hydroxyethyl)thio]ethyl benzoate
[1009] A solution of 2-mercaptoethanol (1.52 mL), 2-iodoethyl
benzoate (6.00 g) and ethyldiisopropylamine (4.53 mL) in
N,N-dimethylformamide (60 mL) was stirred at 40.degree. C. for 3
days. Water was added to the reaction system and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was separated and purified by
silica gel column chromatography (eluent, hexane:ethyl
acetate=4:1.fwdarw.3:7) to give the title compound (3.77 g) as an
orange oil.
[1010] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.15 (1H, t, J=6.0 Hz),
2.83 (2H, t, J=5.9 Hz), 2.92 (2H, t, J=6.8 Hz), 3.79 (2H, dt,
J=6.0, 6.0 Hz), 4.50 (2H, t, J=6.8 Hz), 7.43-7.48 (2H, m),
7.55-7.61 (1H, m), 8.03-8.08 (2H, m).
(ii) Production of 2-[(2-bromoethyl)thio]ethyl benzoate
[1011] The title compound (966 mg) was obtained as a colorless oil
by the reaction in the same manner as in Example 161 (ii) using
2-[(2-hydroxyethyl)thio]ethyl benzoate (1.0 g), carbon tetrabromide
(2.20 g), triphenylphosphine (1.74 g) and dichloromethane (50
mL).
[1012] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.95 (2H, t, J=6.8 Hz),
3.02-3.08 (2H, m), 3.50-3.56 (2H, m), 4.49 (2H, t, J=6.8 Hz),
7.43-7.48 (2H, m), 7.55-7.61 (1H, m), 8.03-8.06 (2H, m).
(iii) Production of
2-{[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]thio}ethyl
benzoate
[1013] The title compound (790 mg) was obtained as a colorless oil
by the reaction in the same manner as in Example 154 (i) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (420 mg),
2-[(2-bromoethyl)thio]ethyl benzoate (966 mg), cesium carbonate
(1.34 g) and N,N-dimethylformamide (4.2 mL).
[1014] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.81 (2H, t, J=6.8 Hz),
3.08 (2H, t, J=6.9 Hz), 4.45 (2H, t, J=6.8 Hz), 4.69 (2H, t, J=6.9
Hz), 6.73 (1H, d, J=3.3 Hz), 7.39-7.46 (2H, m), 7.53-7.62 (2H, m),
7.96-8.06 (2H, m), 8.71 (1H, s).
(iv) Production of
2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol
[1015] The title compound (420 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 154 (ii)
using
2-{[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]thio}ethyl
benzoate (505 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline
(480 mg), isopropyl alcohol (10 mL) and 1N aqueous sodium hydroxide
solution (3.0 mL).
[1016] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.92-2.00 (1H, m), 2.52
(2H, t, J=5.6 Hz), 3.13 (2H, t, J=6.5 Hz), 3.65-3.75 (2H, m), 4.61
(2H, t, J=6.5 Hz), 6.67 (1H, d, J=3.3 Hz), 7.08 (1H, d, J=8.7 Hz),
7.09-7.13 (1H, m), 7.18-7.23 (1H, m), 7.29 (1H, d, J=3.3 Hz),
7.32-7.35 (1H, m), 7.41-7.46 (1H, m), 7.51 (1H, dd, J=8.7, 2.7 Hz),
7.77 (1H, d, J=2.7 Hz), 7.80 (1H, s), 8.55 (1H, s).
Example 163
##STR00211##
[1017] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N-methyl-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]methylcarbamate
[1018] To a solution of 2-(methylamino)ethanol (1.00 g) in
tetrahydrofuran (10 mL) was added di-tert-butyl dicarbonate (3.60
mL) at room temperature. After stirring at room temperature for 2
hrs, the mixture was concentrated under reduced pressure. To a
solution of the residue and triethylamine (3.71 mL) in
tetrahydrofuran (50 mL) was added dropwise methanesulfonyl chloride
(1.55 mL) at 0.degree. C., and the mixture was stirred at 0.degree.
C. for 1 hr. Aqueous sodium hydrogen carbonate was added to the
reaction system and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over
magnesium sulfate and concentrated under reduced pressure to give a
colorless oil.
[1019] The title compound (902 mg) was obtained as a pale-yellow
oil by the reaction in the same manner as in Example 154 (i) using
the obtained oil, 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.34 g),
cesium carbonate (5.69 g) and N,N-dimethylformamide (20 mL).
[1020] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (4.5H, s), 1.43
(4.5H, m), 2.55 (1.5H, s), 2.81 (1.5H, s), 3.58-3.60 (2H, m),
4.54-4.69 (2H, m), 6.73 (1H, d, J=3.0 Hz), 7.29-7.35 (0.5H, m),
7.38-7.46 (0.5H, m), 8.71 (1H, s).
(ii) Production of tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}methylcarbamate
[1021] The title compound (622 mg) was obtained as a colorless
amorphous solid by the reaction in the same manner as in Example
155 (ii) using tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]methylcarbamate
(450 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (500 mg)
and isopropyl alcohol (4.5 mL).
[1022] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.51 (9H, s), 3.01 (3H,
s), 3.51-3.59 (2H, m), 4.41-4.51 (2H, m), 6.60 (1H, d, J=3.0 Hz),
7.06 (1H, d, J=8.7 Hz), 7.08-7.13 (1H, m), 7.15-7.24 (2H, m), 7.30
(1H, d, J=8.4 Hz), 7.38-7.44 (1H, m), 7.85-7.93 (1H, m), 7.99-8.04
(1H, m), 8.50 (1H, s), 8.82 (1H, s).
(iii) Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(methylamino)ethyl-
]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride
[1023] The title compound (538 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 155 (iii)
using tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}methylcarbamate (622 mg), 2N hydrochloric
acid (10 mL) and tetrahydrofuran (20 mL).
[1024] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.54 (3H, t, J=5.3 Hz),
3.32-3.44 (2H, m), 5.01-5.15 (2H, m), 6.74 (1H, d, J=3.3 Hz),
7.22-7.27 (2H, m), 7.36 (1H, d, J=8.7 Hz), 7.51 (1H, d, J=8.4 Hz),
7.60-7.69 (2H, m), 7.91-7.96 (1H, m), 8.01-8.07 (1H, m), 8.72 (1H,
s), 9.00-9.18 (2H, m), 10.06 (1H br s).
(iv) Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N-methyl-2-(methylsulfonyl)acetamide
[1025] The title compound (131 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(methylamino)ethyl-
]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (170 mg),
2-(methylsulfonyl)acetic acid (88 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (183
mg), 1-hydroxybenzotriazole monohydrate (146 mg), triethylamine
(0.44 mL) and N,N-dimethylformamide (5.0 mL).
[1026] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.17 (3H, s), 3.34 (3H,
s), 3.75-3.84 (2H, m), 4.18 (2H, s), 4.43-4.52 (2H, m), 6.64 (1H,
d, J=3.0 Hz), 7.08 (1H, d, J=8.7 Hz), 7.10-7.16 (1H, m), 7.17-7.25
(2H, m), 7.32-7.37 (1H, m), 7.41-7.46 (1H, m), 7.86 (1H, dd, J=8.7,
2.7 Hz), 7.96 (1H, d, J=2.7 Hz), 8.46 (1H, s), 8.53 (1H, s).
Example 164
##STR00212##
[1027] Production of
2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}sulfinyl)ethanol
[1028] To a solution of
2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol (100 mg) in
dichloromethane (10 mL) was added dropwise a 70% solution of
3-chloroperbenzoic acid (58 mg) in dichloromethane (5.0 mL) at
-78.degree. C. The mixture was stirred at -78.degree. C. for 1 hr,
and aqueous sodium thiosulfate solution was added. After stirring
at room temperature for 0.5 hr, the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine
and dried over magnesium sulfate. After concentration under reduced
pressure, the residue was separated and purified by silica gel
column chromatography (eluent, ethyl acetate.fwdarw.ethyl
acetate:methanol=4:1) to give the title compound (87 mg) as
colorless crystals.
[1029] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.78-3.01 (2H, m),
3.27-3.40 (1H, m), 3.42-3.58 (1H, m), 3.71-3.79 (2H, m), 4.80-4.90
(2H, m), 5.02-5.09 (1H, m), 6.58-6.63 (1H, m), 7.16-7.25 (2H, m),
7.27-7.31 (1H, m), 7.44-7.50 (1H, m), 7.59-7.64 (1H, m), 7.66-7.72
(1H, m), 7.74-7.82 (1H, m), 7.96-8.03 (1H, m), 8.37 (1H, s), 9.38
(1H, s).
Example 165
##STR00213##
[1030] Production of
2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}sulfonyl)ethanol
[1031] To a solution of
2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol (150 mg), titanium
tetraisopropoxide (43 .mu.L), methanol (24 .mu.L) and water (10
.mu.L) in dichloromethane was stirred at room temperature for 30
min. 70% Aqueous tert-butyl hydroperoxide solution (0.12 mL) was
added to the reaction system, and the mixture was stirred at room
temperature for 2 days. An aqueous sodium thiosulfate solution was
added to the reaction system, and the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure, and the residue was separated and purified by silica gel
column chromatography (eluent, ethyl acetate.fwdarw.ethyl
acetate:methanol=4:1) to give the title compound (118 mg) as
colorless crystals.
[1032] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.09-3.15 (2H, m),
3.62-3.75 (4H, m), 4.92-5.02 (2H, m), 5.09-5.15 (1H, m), 6.50-6.57
(1H, m), 7.16-7.32 (3H, m), 7.45-7.48 (1H, m), 7.58-7.74 (3H, m),
7.91-7.97 (1H, m), 8.37 (1H, br s), 8.69-8.79 (1H, m)
Example 166
##STR00214##
[1033] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}-N-methyl-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}methylcarbamate
[1034] The title compound (665 mg) was obtained as a colorless
amorphous solid by the reaction in the same manner as in Example
155 (ii) using tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]methylcarbamate
(463 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (679 mg)
and isopropyl alcohol (5.0 mL).
[1035] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.51 (9H, s), 3.01 (3H,
s), 3.48-3.61 (2H, m), 4.42-4.50 (2H, m), 6.60 (1H, d, J=3.2 Hz),
6.80-6.83 (1H, m), 6.86-6.95 (2H, m), 7.08 (1H, d, J=8.7 Hz), 7.20
(1H, d, J=3.2 Hz), 7.28-7.33 (1H, m), 7.85-7.95 (1H, m), 7.99-8.05
(1H, m), 8.51 (1H, s), 8.81 (1H, br s).
(ii) Production of
N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5-[2-(methylamino)ethy-
l]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride
[1036] The title compound (557 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 155 (iii)
using tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}methylcarbamate (665 mg), 2N
hydrochloric acid (10 mL) and tetrahydrofuran (20 mL).
[1037] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.52-2.66 (2H, m)),
3.29-3.45 (2H, m), 5.03-5.15 (2H, m), 6.75 (1H, d, J=3.0 Hz),
6.91-7.00 (2H, m), 7.11-7.18 (1H, m), 7.35 (1H, d, J=8.7 Hz),
7.51-7.57 (1H, m), 7.63-7.69 (1H, m), 7.91-7.96 (1H, m), 8.06 (1H,
d, J=3.3 Hz), 8.73 (1H, s), 9.06-9.26 (2H, m), 10.11 (1H, br s)
(iii) Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}-N-methyl-2-(methylsulfonyl)acetamide
[1038] The title compound (147 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5-[2-(methylamino)ethy-
l]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (170 mg),
2-(methylsulfonyl)acetic acid (87 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (179
mg), 1-hydroxybenzotriazole monohydrate (143 mg), triethylamine
(0.43 mL) and N,N-dimethylformamide (5.0 ml).
[1039] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.17 (3H, s), 3.34 (3H,
s), 3.75-3.84 (2H, m), 4.18 (2H, s), 4.43-4.52 (2H, m), 6.64 (1H,
d, J=3.0 Hz), 7.08 (1H, d, J=8.7 Hz), 7.10-7.16 (1H, m), 7.17-7.25
(2H, m), 7.32-7.37 (1H, m), 7.41-7.46 (1H, m), 7.86 (1H, d, J=8.7,
2.7 Hz), 7.96 (1H, d, J=2.7 Hz), 8.46 (1H, s), 8.53 (1H, s).
Example 167
##STR00215##
[1040] Production of
N-{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetamide
hydrochloride
(i) Production of tert-butyl
[3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]carbamate
[1041] The title compound (1.04 g) was obtained as a colorless oil
by the reaction in the same manner as in Example 154 (i) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg), tert-butyl
3-bromopropylcarbamate (1.00 g), cesium carbonate (1.59 g) and
N,N-dimethylacetamide (5.0 mL).
[1042] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46 (9H, s), 2.02-2.12
(2H, m), 3.13-3.25 (2H, m), 4.50-4.66 (3H, m), 6.78 (1H, d, J=3.0
Hz), 7.61-7.69 (1H, m), 8.71 (1H, s).
(ii) Production of tert-butyl
{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]propyl}carbamate
[1043] The title compound (398 mg) was obtained as a colorless
amorphous solid by the reaction in the same manner as in Example
155 (ii) using tert-butyl
[3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]carbamate (546
mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (640 mg) and
isopropyl alcohol (10 mL)
[1044] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42 (9H, s), 2.10-2.21
(2H, m), 3.17-3.27 (2H, m), 4.40 (2H, t, J=7.5 Hz), 4.69-4.79 (1H,
m), 6.62 (1H, d, J=3.0 Hz), 6.81 (1H, br s), 6.85-6.95 (2H, m),
7.04-7.13 (2H, m), 7.29-7.34 (2H, m), 7.54-7.60 (1H, m), 7.89 (1H,
d, J=3.0 Hz), 8.52 (1H, s).
(iii) Production of
5-(3-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-p-
yrrolo[3,2-d]pyrimidin-4-amine dihydrochloride
[1045] The title compound (355 mg) was obtained as colorless powder
crystals by the reaction in the same manner as in Example 155 (iii)
using tert-butyl
{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]propyl}carbamate (398 mg), 2N hydrochloric
acid (10 mL) and tetrahydrofuran (20 ml).
[1046] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.03-2.16 (2H, m),
2.61-2.75 (2H, m), 4.86 (2H, t, J=6.6 Hz), 6.70 (1H, d, J=3.0 Hz),
6.94-7.01 (2H, m), 7.11-7.19 (1H, m), 7.37 (1H, d, J=8.7 Hz),
7.52-7.58 (1H, m), 7.67 (1H, dd, J=8.7, 2.7 Hz), 7.95 (1H, d, J=2.1
Hz), 7.96-815 (4H, m), 8.72 (1H, s), 9.96 (1H, br s).
(iv) Production of
N-{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetamide
hydrochloride
[1047]
N-{3-[4-({3-Chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H--
pyrrolo[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetamide
was obtained by the reaction in the same manner as in Example 155
(iv) using
5-(3-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-p-
yrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (170 mg),
2-(methylsulfonyl)acetic acid (85.0 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (177
mg), 1-hydroxybenzotriazole monohydrate (141 mg), triethylamine
(0.43 mL) and N,N-dimethylformamide (5.0 mL). To a solution of
N-{3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetamide in ethyl
acetate (1.0 mL) was added 4N hydrochloric acid-ethyl acetate (0.50
mL) at room temperature, and the mixture was stirred at room
temperature for 1 hr. After concentration under reduced pressure,
diisopropyl ether was added, and the precipitated crystals were
collected by filtration. The crystals were washed with diisopropyl
ether to give the title compound (128 mg) as colorless powder
crystals.
[1048] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.88-2.00 (2H, m),
2.97-3.08 (2H, m), 3.11 (3H, s), 4.04 (2H, s), 4.63-4.72 (2H, m),
6.67 (1H, d, J=3.0 Hz), 6.94-7.01 (2H, m), 7.13-7.21 (1H, m), 7.36
(1H, d, J=9.0 Hz), 7.49-7.65 (2H, m), 7.91 (1H, d, J=2.4 Hz), 7.96
(1H, d, J=3.0 Hz), 8.45-8.52 (1H, m), 8.70 (1H, s), 9.67 (1H, br
s).
Example 168
##STR00216##
[1049] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-(methylsulfonyl)propanamide
(i) Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-(methylthio)propanamide
[1050] To a mixture of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (230 mg) and
triethylamine (0.61 mL) in tetrahydrofuran (8.0 mL) was added
3-(methylthio)propionyl chloride (0.15 mL) under ice-cooling. After
stirring at room temperature for 20 hrs, water was added, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure, and the residue was separated
and purified by basic silica gel column chromatography (eluent,
ethyl acetate.fwdarw.ethyl acetate:methanol=9:1) to give the title
compound (133 mg) as colorless crystals.
[1051] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.13(3H, s), 2.59 (2H, t,
J=6.9 Hz), 2.83 (2H, t, J=6.9 Hz), 3.57-3.69 (2H, m), 4.45-4.55
(2H, m), 6.39-6.47 (1H, m), 6.62 (1H, d, J=3.0 Hz), 7.08 (1H, d,
J=8.7 Hz), 7.09-7.14 (1H, m), 7.20 (1H, d, J=3.0 Hz), 7.23-7.27
(1H, m), 7.29-7.34 (1H, m), 7.39-7.47 (1H, m), 7.83 (1H, dd, J=8.7,
2.7 Hz), 8.12 (1H, d, J=2.7 Hz), 8.523 (1H, s), 8.63 (1H, s).
(ii) Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-(methylsulfonyl)propanamide
[1052] The title compound (97 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 165 using
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-(methylthio)propanamide (150 mg),
titanium tetraisopropoxide (40.3 .mu.L), methanol (22.2 .mu.L),
water (9.3 .mu.L), 70% aqueous tert-butyl hydroperoxide solution
(0.12 mL) and dichloromethane (8.0 mL).
[1053] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.41-2.57 (2H, m), 2.95
(3H, s), 3.26 (2H, t, J=7.5 Hz), 3.35-3.45 (2H, m), 4.48-4.58 (2H,
m), 6.51 (1H, d, J=3.0 Hz), 7.18-7.32 (3H, m), 7.43-7.50 (1H, m),
7.58-7.67 (2H, m), 7.73-7.82 (1H, m), 8.02-8.07 (1H, m), 8.34-8.45
(2H, m), 8.75 (1H, s).
Example 169
##STR00217##
[1054] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-methyl-2-(methylsulfonyl)propanamide
[1055] To a solution of 2-methyl-2-(methylsulfonyl)propanoic acid
(115 mg) and N,N-dimethylformamide (catalytic amount) in
tetrahydrofuran (5.0 mL) was added thionyl chloride (0.10 mL) at
room temperature. After stirring at room temperature for 3 hrs, the
mixture was concentrated under reduced pressure. A solution of the
residue in tetrahydrofuran (10 mL) was added dropwise to a
suspension of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (180 mg) and
triethylamine (0.48 mL) in tetrahydrofuran (10 mL) at room
temperature. After stirring at room temperature for 20 hrs, water
was added to the reaction system and the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was separated and purified by basic silica
gel column chromatography (eluent, ethyl acetate.fwdarw.ethyl
acetate:methanol=9:1) to give the title compound (205 mg) as
colorless crystals.
[1056] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70 (6H, s), 2.93 (3H,
s), 3.63-3.73 (2H, m), 4.43-4.52 (2H, m), 6.64 (1H, d, J=3.3 Hz),
7.09 (1H, d, J=8.7 Hz), 7.10-7.16 (1H, m), 7.18-7.24 (2H, m),
7.27-7.35 (2H, m), 7.40-7.47 (1H, m), 7.90 (1H, dd, J=8.7, 2.7 Hz),
8.05 (1H, d, J=2.7 Hz), 8.38 (1H, s), 8.54 (1H, s)
[1057] melting point: 167-168.degree. C.
Example 170
##STR00218##
[1058] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}-2-methyl-2-(methylsulfonyl)propanamide
[1059] To a solution of 2-methyl-2-(methylsulfonyl)propanoic acid
(92 mg) and N,N-dimethylformamide (catalytic amount) in
tetrahydrofuran (5.0 mL) was added thionyl chloride (80 .mu.L) at
room temperature. After stirring at room temperature for 3 hrs, the
mixture was concentrated under reduced pressure. A solution of the
residue in tetrahydrofuran-dichloromethane (10 mL-10 mL) was added
dropwise to a suspension of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-py-
rrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg) and
triethylamine (0.39 mL) in tetrahydrofuran (10 mL) at room
temperature. After stirring at room temperature for 20 hrs, aqueous
sodium hydrogen carbonate was added to the reaction system and the
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by basic silica gel column chromatography (eluent, ethyl
acetate.fwdarw.ethyl acetate:methanol=9:1) to give the title
compound (108 mg) as pale-yellow crystals.
[1060] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70 (6H, s), 2.93 (3H,
s), 3.62-3.73 (2H, m) 4.42-4.51 (2H, m), 6.64 (1H, d, J=3.3 Hz),
6.82-6.86 (1H, m), 6.88-6.96 (2H, m), 7.09 (1H, d, J=9.0 Hz), 7.21
(1H, d, J=3.3 Hz), 7.26-7.35 (2H, m), 7.89 (1H, dd, J=9.0, 2.6 Hz),
8.04 (1H, d, J=2.6 Hz), 8.37 (1H, s), 8.54 (1H, s).
Example 171
##STR00219##
[1061] Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(2-methoxyethoxy)e-
thyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride
[1062] 4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) was dissolved
in N,N-dimethylformamide (10 mL), and potassium carbonate (830 mg)
and 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate (920 mg) were
added and the mixture was stirred at room temperature for 12 hrs.
Saturated aqueous sodium hydrogen carbonate was added to the
reaction mixture under ice-cooling, and the mixture was extracted
with ethyl acetate. The organic layer was dried over magnesium
sulfate and concentrated. The residue was purified by silica gel
column chromatography (eluent, hexane:ethyl
acetate=50:50.fwdarw.0:100). The obtained oil was dissolved in
isopropyl alcohol (10 mL), and
3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline was added. The
mixture was stirred at 90.degree. C. for 4 hrs, saturated aqueous
sodium hydrogen carbonate was added to the reaction mixture under
ice-cooling, and the mixture was extracted with ethyl acetate. The
extract was dried over magnesium sulfate and concentrated. The
residue was separated and purified by silica gel column
chromatography (eluent, ethyl acetate:methanol=100:0.fwdarw.ethyl
acetate:methanol=90:10), and crystallized from 4N hydrochloric
acid-ethyl acetate solution/hexane to give the title compound (277
mg).
[1063] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.06 (3H, s), 3.33-3.35
(2H, m), 3.55-3.61 (2H, m), 3.83-3.86 (2H, m), 4.83-4.86 (2H, m),
6.71 (1H, d, J=3 Hz), 7.24-7.72 (7H, m), 7.99-8.04 (2H, m), 8.77
(1H, s), 9.92 (1H, s).
Example 172
##STR00220##
[1064] Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylsulfonyl-
)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylthio)eth-
oxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[1065] The compound (150 mg) of Example 147 was dissolved in
tetrahydrofuran (10 mL) and triethylamine (1.50 mL) and
methanesulfonyl chloride (0.70 mL) were added under ice-cooling,
and the mixture was stirred for 1 hr. Saturated aqueous sodium
hydrogen carbonate was added to this reaction solution under
ice-cooling, and the mixture was extracted with ethyl acetate. The
extract was dried over magnesium sulfate and concentrated, and the
residue was dissolved in a mixed solvent of N,N-dimethylformamide
(5.0 mL) and tetrahydrofuran (4.0 mL). Sodium methanethiolate (180
mg) was added, and the mixture was stirred at room temperature for
1 hr. Saturated aqueous sodium hydrogen carbonate was added to the
reaction mixture under ice-cooling, and the mixture was extracted
with ethyl acetate. The extract was dried over magnesium sulfate
and concentrated. The residue was separated and purified by silica
gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=90:10) to give
the title compound (123 mg).
[1066] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.02 (3H, s), 2.66-2.73
(2H, m), 3.74-3.78 (2H, m), 3.98-4.01 (2H, m), 4.55-4.58 (2H, m),
6.66 (1H, d, J=3 Hz), 7.07-7.63 (6H, m), 7.88 (1H, br s), 8.02 (1H,
s), 8.55 (1H, s), 8.74 (1H, s).
(ii) Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylsulfonyl-
)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[1067]
N-{3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylth-
io)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (70.0 mg) was
dissolved in dichloromethane (5.0 mL), titanium tetraisopropoxide
(0.10 mL), methanol (0.50 mL) and 70% aqueous tert-butyl
hydroperoxide solution (8.0 mL) were added, and the mixture was
stirred at room temperature for 1 hr. Saturated aqueous sodium
thiosulfate solution was added to the reaction mixture under
ice-cooling, and the mixture was stirred at room temperature for 1
hr and extracted with dichloromethane. The extract was dried over
magnesium sulfate and concentrated, and the residue was separated
and purified by silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=90:10).
Crystallization from diethyl ether/ethyl acetate/hexane gave the
title compound (62.5 mg).
[1068] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.62 (3H, s), 4.57-4.61
(2H, m), 6.68 (1H, d, J=3 Hz), 4.16 (1H, m), 5.08 (2H, s), 5.55
(2H, s), 6.33 (1H, br s), 6.66 (1H, d, J=3 Hz), 7.09-7.60 (7H, m),
7.86 (1H, d, J=3 Hz), 8.11 (1H, s), 8.55 (1H, s).
Example 173
##STR00221##
[1069] Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(2,2,2-trifluor-
oethoxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
hydrochloride
[1070] The title compound (107 mg) was obtained as crystals by the
reaction in the same manner as in Example 172 (i) using the
compound (200 mg) of Example 147, sodium 2,2,2-trifluoroethanolate
(1.20 g), tetrahydrofuran (7.0 mL) and N,N-dimethylformamide (10
mL) at a reaction temperature of 50.degree. C., and crystallization
from 4N hydrochloric acid-ethyl acetate solution/hexane.
[1071] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.09 (4H, m), 3.30-3.39
(2H, m), 4.61 (2H, br s), 5.12 (2H, br s), 6.53 (1H, d, J=3 Hz),
7.20-8.56 (10H, m).
Example 174
##STR00222##
[1072] Production of 2-(methylsulfonyl)ethyl
{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}carbamate
[1073]
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}--
5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (64.1 mg) and
triethylamine (1.0 mL) were dissolved in dichloromethane (5.0 mL),
1-({[2-(methylsulfonyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione
(45.6 mg) was added, and the mixture was stirred at room
temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate
was added to the reaction mixture under ice-cooling, and the
mixture was extracted with ethyl acetate. The extract was dried
over magnesium sulfate and concentrated, and the residue was
separated and purified by silica gel column chromatography (eluent,
ethyl acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=95:5).
Crystallization from diethyl ether/hexane gave the title compound
(61.0 mg).
[1074] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.10 (3H, s), 3.48-3.52
(2H, m), 3.70-3.75 (2H, m), 4.62-4.68 (2H, m), 4.75-4.79 (2H, m),
5.57 (1H, m), 6.78 (1H, d, J=3 Hz), 7.22-7.61 (6H, m), 7.92 (1H,
m), 8.11 (1H, m), 8.20 (1H, s), 8.68 (1H, s).
Example 175
##STR00223##
[1075] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N'-[2-(methylsulfonyl)ethyl]urea
[1076]
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}--
5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (54.1 mg) and
triethylamine (0.7 mL) were dissolved in dichloromethane (10 mL),
1,1'-carbonylbis(1H-imidazole) was added, and the mixture was
stirred at room temperature. After 1 hr,
2-(methylsulfonyl)ethanamine (1.0 mL) was added, and the mixture
was further stirred for 1 hr. Saturated aqueous sodium hydrogen
carbonate was added to the reaction mixture under ice-cooling, and
the mixture was extracted with dichloromethane. The extract was
dried over magnesium sulfate and concentrated, and the residue was
separated and purified by silica gel column chromatography (eluent,
ethyl acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=90:10).
crystallized from diethyl ether/ethyl acetate/hexane to give the
title compound (37.6 mg).
[1077] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.84 (3H, s), 3.11-3.17
(2H, m), 3.40-3.50 (2H, m), 3.66-3.72 (2H, m), 4.39-4.44 (2H, m),
5.55 (2H, m), 6.47 (1H, d, J=3 Hz), 7.00-7.39 (6H, m), 7.81-7.88
(1H, m), 7.99 (1H, m), 8.40 (1H, s), 8.73 (1H, s).
Example 176
##STR00224##
[1078] Production of
5-{2-[2-(tert-butylsulfonyl)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluorometh-
yl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of
5-{2-[2-(tert-butylthio)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluoromethyl)p-
henoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[1079]
2-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-p-
yrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol (150 mg) was dissolved
in tetrahydrofuran (6.0 mL), and triethylamine (1.00 mL) and
methanesulfonyl chloride (0.59 mL) were added under ice-cooling and
the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen
carbonate was added to this reaction solution under ice-cooling and
the mixture was extracted with ethyl acetate. The extract was dried
over magnesium sulfate and concentrated, and the residue was
dissolved in a mixed solvent of N,N-dimethylformamide (4.0 mL) and
tetrahydrofuran (6.0 mL). Sodium 2-methylpropane-2-thiolate (220
mg) was added, and the mixture was stirred at room temperature for
1 hr. Saturated aqueous sodium hydrogen carbonate was added to the
reaction mixture under ice-cooling and the mixture was extracted
with ethyl acetate. The extract was dried over magnesium sulfate
and concentrated. The residue was separated and purified by silica
gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=90:10) to give
the title compound (143 mg).
[1080] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (9H, s), 2.69-2.73
(2H, m), 3.73-3.78 (2H, m), 3.97-3.99 (2H, m), 4.54-4.57 (2H, m),
6.66 (1H, d, J=3 Hz), 7.07-7.45 (6H, m), 7.64-7.68 (1H, m), 7.89
(1H, d, J=3 Hz), 8.55 (1H, s), 8.77 (1H, s).
(ii) Production of
5-{2-[2-(tert-butylsulfonyl)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluorometh-
yl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[1081]
5-{2-[2-(tert-Butylthio)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluorome-
thyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (140 mg)
was dissolved in dichloromethane (5.0 mL), titanium
tetraisopropoxide (0.90 mL), methanol (0.20 mL) and 70% aqueous
tert-butyl hydroperoxide solution (7.0 mL) were added, and the
mixture was stirred at room temperature for 1 hr. Saturated aqueous
sodium thiosulfate solution was added to the reaction mixture under
ice-cooling, and the mixture was stirred at room temperature for 1
hr and extracted with dichloromethane. The extract was dried over
magnesium sulfate and concentrated, and the residue was separated
and purified by silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=90:10).
Crystallization from diethyl ether/ethyl acetate/hexane gave the
title compound (10.6 mg).
[1082] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (9H, s), 3.00-3.04
(2H, m), 3.97-4.08 (4H, m), 4.49-4.52 (2H, m), 6.59 (1H, d, J=3
Hz), 7.00-7.56 (7H, m), 7.84 (1H, d, J=3 Hz), 8.27 (1H, s), 8.48
(1H, s).
[1083] melting point: 79.5-81.5.degree. C.
Example 177
##STR00225##
[1084] Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(phenylsulfonyl-
)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(phenylthio)eth-
oxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[1085] The title compound (96.4 mg) was obtained by the reaction in
the same manner as in Example 172 (i) using the compound (100 mg)
of Example 147, sodium benzenethiolate (200 mg), tetrahydrofuran
(5.0 mL) and N,N-dimethylformamide (4.0 mL).
[1086] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.06-3.10 (2H, m),
3.75-3.79 (2H, m), 3.94-3.97 (2H, m), 4.52-4.55 (2H, m), 6.66 (1H,
d, J=3 Hz), 7.01-7.56 (12H, m), 7.88 (1H, d, J=3 Hz), 8.56 (1H, s),
8.71 (1H, s).
(ii) Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(phenylsulfonyl-
)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[1087] The title compound (7.2 mg) was obtained by the reaction in
the same manner as in Example 172 (ii) using
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(phenylthio)eth-
oxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (60 mg),
dichloromethane (5.0 mL), N,N-dimethylformamide (2.0 mL), titanium
tetraisopropoxide (0.90 mL), methanol (0.20 mL) and 70% aqueous
tert-butyl hydroperoxide solution (4.0 mL).
[1088] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.23-3.27 (2H, m),
3.88-4.00 (4H, m), 4.42-4.45 (2H, m), 6.58 (1H, d, J=3 Hz),
7.00-7.70 (12H, m), 7.79 (1H, d, J=3 Hz), 8.13 (1H, s), 8.47 (1H,
s).
Example 178
##STR00226##
[1089] Production of
2-[(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyr-
rolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)sulfinyl]ethanol
[1090] The compound (120 mg) obtained by the reaction in the same
manner as in Example 172 (i) using the compound (200 mg) of Example
147, sodium 2-hydroxyethanethiolate (2.02 g), tetrahydrofuran (6.0
mL) and N,N-dimethylformamide (5.0 mL) was dissolved in
dichloromethane (7.0 mL). m-Chloroperbenzoic acid (110 mg) was
added at -18.degree. C. and the mixture was stirred for 5 hrs.
Saturated aqueous sodium hydrogen carbonate was added to the
reaction mixture under ice-cooling, and the mixture was extracted
with dichloromethane. The extract was dried over magnesium sulfate
and concentrated, and the residue was separated and purified by
silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=80:20).
Crystallization from diethyl ether/ethyl acetate/hexane gave the
title compound (97.0 mg).
[1091] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.66-2.73 (2H, m),
2.90-2.98 (2H, m), 3.93-4.13 (6H, m), 4.56-4.62 (2H, m), 6.68 (1H,
d, J=3 Hz), 7.08-7.59 (7H, m), 7.83 (1H, d, J=3 Hz), 8.37 (1H, m),
8.55 (1H, s).
Example 179
##STR00227##
[1092] Production of
2-[(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyr-
rolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)sulfonyl]ethanol
[1093] The title compound (60.2 mg) was obtained as crystals by the
reaction in the same manner as in Example 172 (ii) using the
compound (87.0 mg) of Example 178, dichloromethane (4.0 mL),
N,N-dimethylformamide (2.0 mL), titanium tetraisopropoxide (0.90
mL), methanol (0.50 mL) and 70% aqueous tert-butyl hydroperoxide
solution (5.0 mL).
[1094] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.78-2.82 (2H, m),
3.34-3.38 (2H, m), 3.79 (2H, m), 4.03-4.13 (4H, m), 4.57-4.60 (2H,
m), 6.68 (1H, d, J=3 Hz), 7.07-7.57 (7H, m), 7.80 (1H, d, J=3 Hz),
8.23 (1H, m), 8.54 (1H, s).
Example 180
##STR00228##
[1095] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-1-(methylsulfonyl)methanesulfonamide
[1096]
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}--
5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (245 mg) and
N-methylmorpholine (1.0 mL) were dissolved in dichloromethane (6.0
mL), (methylsulfonyl)methanesulfonyl chloride (0.40 mL) was added
dropwise under ice-cooling, and the mixture was stirred for 1 hr.
Saturated aqueous sodium hydrogen carbonate was added under
ice-cooling, and the mixture was extracted with dichloromethane.
The extract was dried over magnesium sulfate and concentrated, and
the residue was separated and purified by silica gel column
chromatography (eluent, ethyl acetate:methanol=100:0.fwdarw.ethyl
acetate:methanol=80:20). Crystallization from diethyl ether/ethyl
acetate to give the title compound (79.4 mg) as crystals.
[1097] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.60 (3H, br s), 3.83-3.92
(4H, m), 4.82 (2H, br s), 6.68 (1H, d, J=3 Hz), 7.24-7.99 (8H, m),
8.73 (1H, s), 8.73 (1H, s), 9.72 (1H, s).
Example 181
##STR00229##
[1098] Production of
3-[2-chloro-4-(6,7-dihydro-9H-pyrimido[4',5':4,5]pyrrolo[2,1-c][1,4]oxazi-
n-4-ylamino)phenoxy]benzonitrile hydrochloride
(i) Production of
4-phenoxy-6,7-dihydro-9H-pyrimido[4',5':4,5]pyrrolo[2,1-c][1,4]oxazine
[1099] The compound (130 mg) obtained in Example 21 (ii) was
dissolved in N,N-dimethylformamide (2.16 mL), and cesium carbonate
(1.05 g) and 1,2-dibromoethane (0.255 mL) were sequentially added.
The mixture was stirred at room temperature for 16 hrs. The
reaction mixture was diluted with ethyl acetate (30 mL), and washed
with water (20 mL). The organic layer was separated, dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was dissolved in N,N-dimethylformamide (1.08 mL), potassium
t-butoxide (90.5 mg) was added, and the mixture was stirred at room
temperature for 1 hr. Ethyl acetate (30 mL)/water (20 mL) was
added, and the organic layer was dried over magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl
acetate=70/30.fwdarw.0/100) to give the title compound (76 mg).
[1100] .sup.1H-NMR (CDCl.sub.3) .delta. 4.20 (2H, t, J=5 Hz), 4.55
(2H, t, J=5 Hz), 5.06 (2H, s), 6.40 (1H, s), 7.2-7.5 (5H, m), 8.44
(1H, s).
(ii) Production of
3-[2-chloro-4-(6,7-dihydro-9H-pyrimido[4',5':4,5]pyrrolo[2,1-c][1,4]oxazi-
n-4-ylamino)phenoxy]benzonitrile hydrochloride
[1101] A mixture of
4-phenoxy-6,7-dihydro-9H-pyrimido[4',5':4,5]pyrrolo[2,1-c][1,4]oxazine
(69 mg), 3-(4-amino-2-chlorophenoxy)benzonitrile (95 mg), pyridine
hydrochloride (75 mg) and 1-methyl-2-pyrrolidone (1 mL) was stirred
at 140.degree. C. for 14 hrs. After the completion of the reaction,
the mixture was diluted with ethyl acetate and washed with
saturated aqueous sodium hydrogen carbonate and saturated brine.
The organic layer was dried over magnesium sulfate. After
concentration under reduced pressure, the residue was subjected to
silica gel column chromatography (hexane/ethyl
acetate=50/50.fwdarw.0/100). The obtained fractions were collected
and concentrated, and the residue was dissolved in ethyl acetate (2
mL) and treated with 4N hydrochloric acid/ethyl acetate (0.13 mL)
to give the title compound (81 mg) as hydrochloride crystals.
[1102] .sup.1H-NMR (DMSO-d.sub.6) .delta. 4.17 (2H, t, J=5 Hz),
4.75 (2H, m), 5.07 (2H, s), 6.55 (1H, s), 7.2-7.7 (6H, m), 7.94
(1H, m), 8.70 (1H, s), 9.91 (1H, br s).
Example 182
##STR00230##
[1103] Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-(2-{[2-(methylsulfony-
l)ethyl]amino}ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(i) Production of
4-chloro-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine
[1104] 4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (1 g) was dissolved in
N,N-dimethylformamide (13 mL), cesium carbonate (6.37 g) and
2-bromo-1,1-diethoxyethane (2.94 mL) were sequentially added and
the mixture was stirred at 80.degree. C. for 4.5 hrs. The reaction
mixture was diluted with ethyl acetate (100 mL), and washed with
water (80 mL). The organic layer was separated, dried over
magnesium sulfate and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane/ethyl acetate=50/50.fwdarw.0/100) to give the title
compound (1.26 g) as a yellow oil.
[1105] .sup.1H-NMR (CDCl.sub.3) .delta. 1.14 (6H, t, J=6 Hz), 3.40
(2H, m), 3.72 (2H, m), 4.08 (1H, m), 4.56 (2H, d, J=5 Hz), 6.71
(1H, d, J=3 Hz), 7.55 (1H, d, J=3 Hz), 8.69 (1H, s).
(ii) Production of
4-phenoxy-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine
[1106] A mixture of
4-chloro-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (1 g),
phenol (420 mg), potassium carbonate (617 mg) and
1-methyl-2-pyrrolidone (6.74 mL) was stirred with heating at
140.degree. C. for 6 hrs. The reaction mixture was diluted with
ethyl acetate (100 mL), and washed with water (80 mL). The organic
layer was separated, dried over magnesium sulfate and evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=90/10.fwdarw.40/60) to
give the title compound (1.15 g) as a yellow oil.
[1107] .sup.1H-NMR (CDCl.sub.3) .delta. 1.13 (6H, t, J=7 Hz), 3.40
(2H, m), 3.69 (2H, m), 4.51 (2H, d, J=6 Hz), 4.76 (1H, t, J=6 Hz),
6.65 (1H, d, J=3 Hz), 7.2-7.5 (6H, m), 8.45 (1H, s).
(iii) Production of
2-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethane-1,1-diol
[1108] 4-Phenoxy-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine
(1.1 g) was dissolved in dichloromethane (4.53 mL)/trifluoroacetic
acid (4.53 mL), and the mixture was stirred at room temperature for
16 hrs. The reaction mixture was concentrated under reduced
pressure, and the residue was dissolved in ethyl acetate (100 mL).
The mixture was washed with saturated aqueous sodium hydrogen
carbonate (80 mL), and the organic layer was dried over magnesium
sulfate and concentrated under reduced pressure to give the title
compound (826 mg) as a white solid.
[1109] .sup.1H-NMR (DMSO-d.sub.6) .delta. 4.35 (2H, d, J=6 Hz),
5.17 (1H, t, J=6 Hz), 6.14 (2H, d, J=6 Hz), 6.59 (1H, d, J=3 Hz),
7.2-7.6 (5H, m), 7.75 (1H, d, J=3 Hz), 8.28 (1H, s).
(iv) Production of
2-(methylsulfonyl)-N-[2-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-
ethanamine
[1110] 2-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethane-1,1-diol
(500 mg) and 2-(methylsulfonyl)ethylamine (341 mg) were dissolved
in N,N-dimethylformamide (29 mL)/acetic acid (2.9 mL), and the
mixture was stirred at room temperature for 1.5 hrs. Sodium
triacetoxyborohydride (579 mg) was added, and the mixture was
stirred at room temperature for 16 hrs. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography (ethyl
acetate/methanol=100/0.fwdarw.70/30) to give the title compound
(508 mg) as a candy-like substance.
[1111] .sup.1H-NMR (CDCl.sub.3) .delta. 2.84 (3H, s), 3.0-3.2 (6H,
m), 4.54 (2H, t, J=6 Hz), 6.66 (1H, d, J=3 Hz), 7.2-7.5 (6H, m),
8.45 (1H, s).
(v) Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-(2-{[2-(methylsulfony-
l)ethyl]amino}ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[1112]
2-(Methylsulfonyl)-N-[2-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-
ethyl]ethanamine (500 mg) was dissolved in tetrahydrofuran (5 mL),
and di-tert-butyl dicarbonate (0.478 mL) and triethylamine (0.29
mL) were added, and the mixture was stirred at room temperature for
3 hrs. The reaction mixture was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate=80/20.fwdarw.0/100). A mixture
of a portion (243 mg) taken from the obtained residue (491 mg),
3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (228 mg), pyridine
hydrochloride (183 mg) and phenol (406 mg) was stirred at
140.degree. C. for 14 hrs. After the completion of the reaction,
the mixture was diluted with dichloromethane (50 mL) and washed
with saturated aqueous sodium hydrogen carbonate (30 mL). The
organic layer was dried over magnesium sulfate. After concentration
under reduced pressure, the residue was subjected to silica gel
column chromatography (ethyl acetate/methanol=100/0.fwdarw.70/30)
and crystallized from diisopropyl ether to give the title compound
(123 mg).
[1113] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.88 (3H, s), 2.89 (2H,
m), 2.99 (2H, m), 3.16 (2H, t, J=6 Hz), 4.50 (2H, m), 6.51 (1H, d,
J=3 Hz), 7.22 (2H, m), 7.31 (1H, d, J=9 Hz), 7.46 (1H, d, J=8 Hz),
7.5-7.7 (3H, m), 8.04 (1H, d, J=2 Hz), 8.35 (1H, s).
Example 183
##STR00231##
[1114] Production of
2-[2-(4-{[4-[(6-methylpyridin-3-yl)oxy]-3-(trifluoromethyl)phenyl]amino}--
5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethanol
[1115] A mixture of
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg),
4-[(6-methylpyridin-3-yl)oxy]-3-(trifluoromethyl)aniline (175 mg)
and 1-methyl-2-pyrrolidone (0.863 mL) was stirred with heating at
140.degree. C. for 2.5 hrs. The reaction mixture was diluted with
ethyl acetate (80 mL) and washed with aqueous sodium hydrogen
carbonate (30 mL). The organic layer was separated, dried over
magnesium sulfate and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/methanol=100/0.fwdarw.90/10). The object fraction was
concentrated under reduced pressure. The obtained residue was
dissolved in methanol (1.9 mL), 1N sodium hydroxide (0.433 mL) was
added, and the mixture was stirred at room temperature for 1.5 hrs.
1N hydrochloric acid (0.433 mL) was added, and the mixture was
diluted with ethyl acetate (80 mL) and washed with saturated brine
(30 mL). The organic layer was dried over magnesium sulfate. After
concentration under reduced pressure, the residue was subjected to
silica gel column chromatography (ethyl
acetate/methanol=100/0.fwdarw.90/10) and crystallized from
diisopropyl ether to give the title compound (118 mg).
[1116] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.46 (3H, s), 3.47 (4H,
br s), 3.82 (2H, m), 4.66 (3H, m), 6.51 (1H, d, J=3 Hz), 7.10 (1H,
d, J=9 Hz), 7.31 (2H, m), 7.68 (1H, d, J=3 Hz), 7.90 (1H, dd, J=3
Hz, 9 Hz), 8.10 (1H, d, J=3 Hz), 8.24 (1H, d, J=3 Hz), 8.30 (1H,
s), 8.99 (1H, br s).
Example 184
##STR00232##
[1117] Production of
2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimid-
in-5-yl)ethanol
[1118] The title compound (81 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 183 using
2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (100
mg), 3-chloro-4-(3-chlorophenoxy)aniline (126 mg) and
1-methyl-2-pyrrolidone (0.66 mL).
[1119] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.87 (2H, m), 4.53 (2H,
t, J=4.5 Hz), 6.31 (1H, br s), 6.51 (1H, d, J=3 Hz), 6.88 (1H, d,
J=9 Hz), 6.95 (1H, s), 7.15 (1H, d, J=9 Hz), 7.28 (1H, d, J=9 Hz),
7.38 (1H, t, J=9 Hz), 7.60 (1H, dd, J=2 Hz, 9 Hz), 7.66 (1H, d, J=3
Hz), 7.97 (1H, d, J=2 Hz), 8.34 (1H, s), 9.89 (1H, br s).
Example 185
##STR00233##
[1120] Production of
2-{2-[4-({3-methoxy-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[1121] The title compound (80 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 183 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg), 3-methoxy-4-[3-(trifluoromethyl)phenoxy]aniline
(185 mg) and 1-methyl-2-pyrrolidone (0.863 mL).
[1122] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.52 (4H, m), 3.74 (3H,
s), 3.85 (2H, t, J=5 Hz), 4.65 (2H, t, J=5 Hz), 4.76 (1H, t, J=5
Hz), 6.51 (1H, d, J=3 Hz), 7.13 (3H, m), 7.35 (2H, m), 7.49 (1H, d,
J=2 Hz), 7.55 (1H, t, J=8 Hz), 7.68 (1H, d, J=3 Hz), 8.32 (1H, s),
8.90 (1H, br s).
Example 186
##STR00234##
[1123] Production of
2-{2-[4-({3-(hydroxymethyl)-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-
H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[1124] The title compound (175 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 183 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg),
{5-amino-2-[3-(trifluoromethyl)phenoxy]phenyl}methanol (184 mg) and
1-methyl-2-pyrrolidone (0.863 mL).
[1125] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.52 (4H, m), 3.74 (3H,
s), 3.85 (2H, t, J=5 Hz), 4.65 (2H, t, J=5 Hz), 4.76 (1H, t, J=5
Hz), 6.51 (1H, d, J=3 Hz), 7.13 (3H, m), 7.35 (2H, m), 7.49 (1H, d,
J=2 Hz), 7.55 (1H, t, J=8 Hz), 7.68 (1H, d, J=3 Hz), 8.32 (1H, s),
8.90 (1H, br s).
Example 187
##STR00235##
[1126] Production of
2-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[1127] The title compound (98 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 183 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg), 3-methyl-4-[3-(trifluoromethyl)phenoxy]aniline
(174 mg) and 1-methyl-2-pyrrolidone (0.863 mL).
[1128] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.13 (3H, s), 3.51 (4H,
m), 3.84 (2H, t, J=4.5 Hz), 4.63 (2H, t, J=4.5 Hz), 4.74 (1H, t,
J=4.5 Hz), 6.49 (1H, d, J=3 Hz), 7.04 (1H, d, J=9 Hz), 7.16 (2H,
m), 7.41 (1H, d, J=8 Hz), 7.5-7.7 (4H, m), 8.29 (1H, s), 8.83 (1H,
br s).
Example 188
##STR00236##
[1129] Production of
2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]pheny-
l}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide
(i) Production of tert-butyl
{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}carbamate
[1130] A mixture of tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297
mg), 3-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (401 mg) and
isopropyl alcohol (2.97 mL) was stirred at 80.degree. C. for 16
hrs. The reaction mixture was diluted with ethyl acetate (80 mL),
and washed with aqueous sodium hydrogen carbonate (30 mL). The
organic layer was separated, dried over magnesium sulfate and
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl
acetate=90/10.fwdarw.0/100) to give the title compound (528 mg) as
a white powder.
[1131] .sup.1H-NMR (CDCl.sub.3) .delta. 1.47 (9H, s), 2.21 (3H, s),
3.50 (2H, m), 4.46 (2H, m), 5.11 (1H, m), 6.58 (1H, d, J=3 Hz),
6.97 (1H, d, J=9 Hz), 7.0-7.2 (3H, m), 7.27 (1H, m), 7.39 (1H, t,
J=8 Hz), 7.69 (2H, m), 8.45 (1H, br s), 8.50 (1H, s).
(ii) Production of
5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine
[1132] tert-Butyl
{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}carbamate (494 mg) was dissolved in
dichloromethane (6.4 mL), trifluoroacetic acid (4.8 mL) was added,
and the mixture was stirred at room temperature for 1 hr. The
reaction mixture was concentrated under reduced pressure, and the
residue was diluted with ethyl acetate (50 mL), and washed with
aqueous sodium hydrogen carbonate (30 mL). The organic layer was
separated, dried over magnesium sulfate and concentrated under
reduced pressure to give the title compound (442 mg) as a
powder.
[1133] .sup.1H-NMR (CDCl.sub.3) .delta. 2.20 (3H, s), 3.30 (2H, t,
J=5 Hz), 4.46 (2H, t, J=5 Hz), 6.61 (1H, d, J=3 Hz), 6.95 (1H, d,
J=9 Hz), 7.0-7.5 (6H, m), 7.51 (1H, d, J=3 Hz), 8.50 (1H, s).
(iii) Production of
2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]pheny-
l}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide
[1134] The title compound (89 mg) was obtained as colorless powder
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine (196 mg), 2-(methylsulfonyl)acetic
acid (64 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (133 mg), 1-hydroxybenzotriazole monohydrate (94 mg),
triethylamine (0.319 mL) and N,N-dimethylformamide (5.0 mL).
[1135] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.14 (3H, s), 3.09 (3H,
s), 3.45 (2H, m)), 4.05 (2H, s), 4.56 (2H, t, J=7 Hz), 6.47 (1H, d,
J=3 Hz), 7.04 (1H, d, J=9 Hz), 7.17 (2H, m), 7.47 (1H, m), 7.59
(4H, m), 8.29 (1H, s), 8.55 (1H, br s), 8.67 (1H, t, J=5.5 Hz).
Example 189
##STR00237##
[1136] Production of
2-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[1137] The title compound (128 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 183 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg), 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniline
(184 mg) and 1-methyl-2-pyrrolidone (0.863 mL).
[1138] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.12 (3H, s), 3.51 (4H,
m), 3.84 (2H, t, J=5 Hz), 4.63 (2H, t, J=5 Hz), 4.73 (1H, t, J=5
Hz), 6.49 (1H, d, J=3 Hz), 6.87 (2H, m), 7.04 (2H, m), 7.47 (1H, t,
J=8 Hz), 7.59 (2H, m), 7.66 (1H, d, J=3 Hz), 8.29 (1H, s), 8.82
(1H, br s).
Example 190
##STR00238##
[1139] Production of
2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phen-
yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide
(i) Production of tert-butyl
{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}carbamate
[1140] tert-Butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297
mg) and 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniline (425 mg)
were dissolved in isopropyl alcohol (2.97 mL), and the mixture was
stirred at 80.degree. C. for 16 hrs. After cooling to room
temperature, the mixture was diluted with ethyl acetate (60 mL),
and washed with aqueous sodium hydrogen carbonate (30 mL). The
organic layer was dried over magnesium sulfate and concentrated
under reduced pressure. The residue was subjected to silica gel
column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.0:100) to give the title compound (563 mg) as
a white powder.
[1141] .sup.1H-NMR (CDCl.sub.3) .delta. 1.47 (9H, s), 2.20 (3H, s),
3.49 (2H, m), 4.46 (2H, m), 5.08 (1H, m), 6.59 (1H, d, J=3 Hz),
6.78 (1H, m), 6.86 (2H, m), 6.97 (1H, m), 7.16 (1H, d, J=3 Hz),
7.27 (2H, m), 7.69 (2H, m), 8.43 (1H, br s), 8.50 (1H, s).
(ii) Production of
5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-py-
rrolo[3,2-d]pyrimidin-4-amine
[1142] tert-Butyl
{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}carbamate (523 mg) was dissolved in
dichloromethane (6.4 mL), trifluoroacetic acid (4.8 mL) was added,
and the mixture was stirred at room temperature for 2 hrs. The
reaction mixture was concentrated under reduced pressure, and the
residue was diluted with ethyl acetate (50 mL), and washed with
aqueous sodium hydrogen carbonate (40 mL). The organic layer was
separated, dried over magnesium sulfate and concentrated under
reduced pressure to give the title compound (420 mg) as a white
powder.
[1143] .sup.1H-NMR (CDCl.sub.3) .delta. 2.20 (3H, s), 3.30 (2H, t,
J=4.5 Hz), 4.46 (2H, t, J=4.5 Hz), 6.62 (1H, d, J=3 Hz), 6.85 (3H,
m), 6.96 (1H, d, J=9 Hz), 7.19 (1H, d, J=3 Hz), 7.27 (1H, m), 7.44
(1H, dd, J=2 Hz, 9 Hz), 7.50 (1H, d, J=3 Hz), 8.50 (1H, s).
(iii) Production of
2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phen-
yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide
[1144] A solution of
5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-py-
rrolo[3,2-d]pyrimidin-4-amine (174 mg), 2-(methylsulfonyl)acetic
acid (54 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (79 mg)
and triethylamine (0.273 mL) in N,N-dimethylformamide (7.69 mL) was
stirred at room temperature for 16 hrs. The reaction mixture was
diluted with ethyl acetate (80 mL), and washed with water (60 mL).
The organic layer was dried over magnesium sulfate and concentrated
under reduced pressure. The residue was subjected to silica gel
column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.92:8), and crystallized from
diisopropyl ether to give the title compound (92 mg) as colorless
crystals.
[1145] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.14 (3H, s), 3.10 (3H,
s), 3.46 (2H, q, J=6 Hz), 4.06 (2H, s), 4.56 (2H, t, J=6 Hz), 6.48
(1H, d, J=3 Hz), 6.89 (2H, m), 7.06 (2H, m), 7.48 (1H, t, J=8 Hz),
7.59 (3H, m), 8.30 (1H, s), 8.55 (1H, br s), 8.67 (1H, t, J=6
Hz).
[1146] melting point: 106-108.degree. C.
Example 191
##STR00239##
[1147] Production of
N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyri-
midin-5-yl)ethyl]-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
2-(4-([3-chloro-4-(3-chlorophenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimid-
in-5-yl]ethylcarbamate
[1148] A mixture of tert-butyl
2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethylcarbamate (1.19
g), 3-chloro-4-(3-chlorophenoxy)aniline (1.22 g) and isopropyl
alcohol (12.0 mL) was stirred at 80.degree. C. for 15 hrs. Under
ice-cooling, aqueous sodium hydrogen carbonate was added, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with brine, and dried over anhydrous magnesium sulfate. The
solvent was concentrated under reduced pressure, and the residue
was purified by silica gel chromatography (eluent:hexane/ethyl
acetate=50/50.fwdarw.100/0), and washed with diisopropyl
ether-hexane to give the title compound (1.69 g) as crystals.
[1149] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (9H, s), 3.4-3.6 (2H,
m), 4.4-4.6 (2H, m), 5.0-5.1 (1H, m), 6.61 (1H, d, J=2.6 Hz),
6.85-7.05 (2H, m), 7.07 (2H, d, J=8.8 Hz), 7.18 (1H, d, J=2.6 Hz),
7.2-7.3 (1H, m), 7.85-7.95 (1H, m), 8.0-8.05 (1H, m), 8.52 (1H, s),
8.62 (1H, br s).
(ii) Production of
5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]-
pyrimidin-4-amine dihydrochloride
[1150] To a solution of tert-butyl
2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimid-
in-5-yl)ethylcarbamate (1.69 g) in tetrahydrofuran (32 mL) was
added 2N hydrochloric acid (16 mL). The reaction mixture was
stirred at 65.degree. C. for 18 hrs and concentrated. Ethanol was
added, and the mixture was concentrated again. Ethyl acetate and
diisopropyl ether were added to the residue, and the precipitate
was collected by filtration and washed with diisopropyl ether to
give the title compound (1.50 g) as crystals.
[1151] .sup.1H-NMR (DMSO-d.sub.6+CDCl.sub.3) .delta.: 3.3-3.6 (4H,
m), 5.0-5.15 (2H, m), 6.71 (1H, d, J=3.2 Hz), 6.9-7.0 (2H, m),
7.1-7.2 (1H, m), 7.22 (1H, d, J=8.8 Hz), 7.3-7.45 (1H, m), 7.6-7.7
(1H, m), 7.87 (1H, d, J=2.6 Hz), 8.05 (1H, d, J=2.4 Hz), 8.2-8.4
(2H, m), 8.71 (1H, s).
(iii) Production of
N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyri-
midin-5-yl)ethyl]-2-(methylsulfonyl)acetamide
[1152] To a solution of
5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]-
pyrimidin-4-amine dihydrochloride (200 mg),
2-(methylsulfonyl)acetic acid (113 mg) and 1-hydroxybenzotriazole
(122 mg) in N,N-dimethylformamide (5.0 mL) were added a solution of
triethylamine (419 mg) in N,N-dimethylformamide (1.25 mL) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (173
mg) under ice-cooling. After stirring the reaction mixture at room
temperature for 16 hrs, water was added under ice-cooling, and the
mixture was extracted twice with ethyl acetate. The organic layers
were collected, dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by silica gel column
chromatography (eluent:ethyl acetate/methanol=100/0.fwdarw.80/20),
and recrystallized from ethanol-ethyl acetate-diisopropyl ether to
give the title compound (151 mg) as crystals.
[1153] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.13 (3H, s), 3.6-3.8 (2H,
m), 3.99 (2H, s), 4.4-4.6 (2H, m), 6.62 (1H, d, J=3.4 Hz),
6.85-6.95 (2H, m), 7.0-7.1 (2H, m), 7.2-7.3 (2H, m), 7.7-7.8 (1H,
m), 7.95-8.0 (1H, m), 8.19 (1H, s), 8.52 (1H, s).
[1154] melting point: 206-207.degree. C.
Example 192
##STR00240##
[1155] Production of
2-[{3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d-
]pyrimidin-5-yl]propyl}(methyl)amino]ethanol dihydrochloride
(i) Production of
4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine
[1156] To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.54
g) in N,N-dimethylformamide (20 mL) was added cesium carbonate
(4.89 g) under ice-cooling, and the mixture was stirred under
ice-cooling for 20 min. 1-Bromo-3-chloropropane (1.89 g) was added
and the mixture was stirred under ice-cooling for 1 hr and at room
temperature for 32 hrs. The reaction mixture was poured into water
(40 mL), and the mixture was extracted with ethyl acetate (60
mL.times.2). The organic layers were combined, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=80:20.fwdarw.50:50) to give the title compound
(1.87 g).
[1157] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.35 (2H, m), 3.49 (2H, t,
J=6.0 Hz), 4.69 (2H, t, J=6.6 Hz), 6.73 (1H, d, J=3.0 Hz), 7.56
(1H, d, J=3.0 Hz), 8.70 (1H, s).
(ii) Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[-
3,2-d]pyrimidin-4-amine
[1158] A mixture of
4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine (839 mg),
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and isopropyl
alcohol (5 mL) was stirred at 80.degree. C. for 1.5 hrs. The
mixture was concentrated under reduced pressure, saturated aqueous
sodium hydrogen carbonate (30 mL) was added to the residue, and the
mixture was extracted with ethyl acetate (30 mL.times.3). The
organic layers were combined, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=90:10-20:80) to give the title compound (1.19 g).
[1159] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.36 (2H, m), 3.56 (2H, t,
J=5.7 Hz), 4.47 (2H, t, J=6.9 Hz), 5.14 (2H, s), 6.60 (1H, d, J=3.3
Hz), 6.73 (1H, br s), 6.94 (1H, d, J=8.7 Hz), 7.02 (1H, m),
7.19-7.40 (5H, m), 7.65 (1H, d, J=3.3 Hz), 8.49 (1H, s).
(iii) Production of
2-[{3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d-
]pyrimidin-5-yl]propyl}(methyl)amino]ethanol dihydrochloride
[1160] A mixture of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[-
3,2-d]pyrimidin-4-amine (634 mg), 2-methylaminoethanol (534 mg) and
N,N-dimethylformamide (5 mL) was stirred at room temperature for 64
hrs. After concentration under reduced pressure, saturated aqueous
sodium hydrogen carbonate (10 mL) was added to the residue, and the
mixture was extracted with ethyl acetate (55 mL.times.2). The
organic layer was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
basic silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.0:100). 4N Hydrogen chloride-ethyl acetate
solution (10 mL) was added to the obtained amorphous solid and,
after concentration under reduced pressure, the residue was
recrystallized from ethanol-ethyl acetate to give the title
compound (523 mg).
[1161] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.16-2.32 (2H, m), 2.74
(3H, s), 2.94-3.40 (4H, m), 3.62-3.80 (2H, m), 4.74-4.84 (2H, m),
5.31 (2H, s), 6.69 (1H, m), 7.20 (1H, m), 7.29-7.36 (5H, m),
7.43-7.50 (2H, m), 7.71 (1H, m), 8.03 (1H, br s), 8.64 (1H, s),
9.84 (1H, br s), 10.12 (1H, br s).
Example 193
##STR00241##
[1162] Production of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[3-(dimethylamino)propyl]-5H-
-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride
[1163]
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-py-
rrolo[3,2-d]pyrimidin-4-amine (560 mg) was dissolved in 2.0 M
dimethylamine-tetrahydrofuran solution (5 mL), and the mixture was
stirred at room temperature for 26 hrs. A 2.0 M
dimethylamine-tetrahydrofuran solution (5 mL) was further added and
the mixture was stirred at room temperature for 20 hrs. A 2.0 M
dimethylamine-tetrahydrofuran solution (10 mL) was further added,
and the mixture was stirred at room temperature for 24 hrs. After
concentration of the reaction mixture under reduced pressure,
saturated aqueous sodium hydrogen carbonate (20 mL) was added to
the residue, and the mixture was extracted with ethyl acetate (35
mL.times.2). The organic layer was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by basic silica gel column chromatography (eluent,
hexane:ethyl acetate=90:10.fwdarw.20:80), and 4N hydrogen
chloride-ethyl acetate solution (10 mL) was added to the obtained
amorphous solid. After concentration under reduced pressure, the
residue was recrystallized from ethanol-ethyl acetate to give the
title compound (428 mg).
[1164] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.18-2.26 (2H, m), 2.70
(6H, s), 2.94-3.04 (2H, m), 4.77-4.84 (2H, m), 5.30 (2H, s), 6.67
(1H, m), 7.19 (1H, m), 7.28-7.34 (4H, m), 7.43-7.51 (2H, m), 7.71
(1H, m), 8.04 (1H, m), 8.63 (1H, s), 9.87 (1H, br s), 10.74 (1H, br
s).
Example 194
##STR00242##
[1165] Production of
6-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6,7,8,9-tetrahydro-3,5,6,9a-te-
traazabenzo[cd]azulene
[1166] A mixture of
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[-
3,2-d]pyrimidin-4-amine (839 mg),
3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and
1-methyl-2-pyrrolidone (5 mL) was stirred at 140.degree. C. for 1
hr. The reaction mixture was poured into water (10 mL) and adjusted
to pH 8 with saturated aqueous sodium hydrogen carbonate. The
mixture was extracted with ethyl acetate (40 mL.times.3), and the
organic layers were combined and dried over anhydrous magnesium
sulfate. After concentration under reduced pressure, the residue
was subjected to silica gel column chromatography (eluent,
hexane:ethyl acetate=60:40.fwdarw.50:50) and further subjected to
basic silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.0:100). The object fraction was concentrated
under reduced pressure. Chloroform-diisopropyl ether was added to
the residue, and the solid was collected by filtration and dried.
Recrystallization from ethyl acetate gave the title compound (74.5
mg).
[1167] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.31 (2H, m), 3.88 (2H,
m), 4.31 (2H, m), 5.27 (2H, s), 6.47 (1H, d, J=3.0 Hz), 7.14-7.36
(5H, m), 7.42 (1H, d, J=2.4 Hz), 7.47 (1H, m), 7.65 (1H, d, J=3.0
Hz), 8.02 (1H, s).
Example 195
##STR00243##
[1168] Production of
6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-6,7,8,9-tetrahydro-3,5,-
6,9a-tetraazabenzo[cd]azulene
(i) Production of
5-(3-chloropropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-p-
yrrolo[3,2-d]pyrimidin-4-amine
[1169] A mixture of
4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine (789 mg),
3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (1.09 g) and
isopropyl alcohol (5 mL) was stirred at 80.degree. C. for 4.5 hrs.
The mixture was concentrated under reduced pressure, saturated
aqueous sodium hydrogen carbonate (30 mL) was added to the residue,
and the mixture was extracted with ethyl acetate (40 mL.times.3).
The organic layers were combined, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=90:10.fwdarw.20:80) to give the title compound (1.46
g).
[1170] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.39 (2H, m), 3.60 (2H, t,
J=5.6 Hz), 4.53 (2H, t, J=6.9 Hz), 6.62 (1H, d, J=3.3 Hz), 6.96
(1H, br s), 7.07 (1H, d, J=8.7 Hz), 7.08-7.49 (6H, m), 7.87 (1H,
m), 8.55 (1H, s).
(ii) Production of
6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-6,7,8,9-tetrahydro-3,5,-
6,9a-tetraazabenzo[cd]azulene
[1171] A mixture of
5-(3-chloropropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-p-
yrrolo[3,2-d]pyrimidin-4-amine (470 mg), potassium carbonate (270
mg) and ethylene glycol (10 mL) was stirred at room temperature for
18.5 hrs, and at 60.degree. C. for 4 hrs. The reaction mixture was
poured into aqueous sodium hydrogen carbonate (20 mL), and the
mixture was extracted with ethyl acetate (50 mL.times.2). The
organic layers were combined, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=90:10.fwdarw.0:100), and the obtained solid was
recrystallized from ethanol-water to give the title compound (116
mg).
[1172] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.45 (2H, m), 3.99 (2H,
t, J=4.8 Hz), 4.34 (2H, t, J=5.4 Hz), 6.65 (1H, d, J=3.0 Hz), 7.06
(1H, d, J=9.0 Hz), 7.16-7.22 (2H, m), 7.28 (1H, m), 7.33 (1H, d,
J=3.0 Hz), 7.37 (1H, m), 7.42 (1H, d, J=2.4 Hz), 7.46 (1H, m), 8.36
(1H, s).
Example 196
##STR00244##
[1173] Production of
2-{2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d-
]pyrimidin-1-yl}ethoxy]ethanol
(i) Production of
2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethyl
benzoate
[1174] A mixture of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine
(747 mg), 2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (1.43 g),
potassium carbonate (931 mg) and N,N-dimethylformamide (12 mL) was
stirred at 60.degree. C. for 4 hrs. The reaction mixture was poured
into water (30 mL), and the mixture was extracted with ethyl
acetate (50 mL.times.2). The organic layers were combined, washed
with saturated brine and dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the residue was
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.20:80), and further purified by basic silica
gel column chromatography (eluent, hexane:ethyl
acetate=90:10.fwdarw.40:60) to give the title compound (533
mg).
[1175] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.67 (3H, s), 3.75 (2H,
m), 4.01 (2H, m), 4.38 (2H, m), 4.87 (2H, t, J=5.8 Hz), 7.38-7.48
(3H, m), 7.91-7.95 (2H, m), 8.11 (1H, s), 8.71 (1H, s).
(ii) Production of
2-{2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d-
]pyrimidin-1-yl]ethoxy}ethanol
[1176] A mixture of
2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethyl
benzoate (200 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (140
mg), pyridine hydrochloride (96 mg) and 1-methyl-2-pyrrolidone (5
mL) was stirred at 140.degree. C. for 16.5 hrs. The reaction
mixture was poured into saturated aqueous sodium hydrogen carbonate
(30 mL), and extracted with ethyl acetate (30 mL.times.3). The
organic layers were combined, washed with saturated brine and dried
over anhydrous magnesium sulfate. After concentration under reduced
pressure, the residue was subjected to silica gel column
chromatography (eluent, hexane:ethyl acetate=90:10.fwdarw.20:80).
The object fraction was concentrated under reduced pressure and the
residue was dissolved in methanol (5 mL). 1N Aqueous sodium
hydroxide solution (1 mL) was added and the mixture was stirred at
room temperature for 11.5 hrs. After concentration of the reaction
mixture under reduced pressure, water (30 mL) was added, and the
mixture was extracted with ethyl acetate (45 mL.times.2). The
organic layer was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.0:100) and recrystallized from ethanol-ethyl
acetate to give the title compound (78 mg).
[1177] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.30-3.55 (4H, m), 3.87
(2H, m), 4.67 (1H, m), 4.86 (2H, m), 5.26 (2H, s), 7.14-7.35 (4H,
m), 7.46 (1H, m), 7.60 (1H, d, J=8.4 Hz), 7.92 (1H, m), 8.18 (1H,
s), 8.35 (1H, s), 8.99 (1H, br s).
Example 197
##STR00245##
[1178] Production of
2-{2-[7-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-1H-pyrazol-
o[4,3-d]pyrimidin-1-yl]ethoxy}ethanol
[1179] A mixture of
2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethyl
benzoate (328 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline
(264 mg), pyridine hydrochloride (159 mg) and
1-methyl-2-pyrrolidone (7.5 mL) was stirred at 140.degree. C. for
33.5 hrs. The reaction mixture was poured into saturated aqueous
sodium hydrogen carbonate (15 mL), and extracted with ethyl acetate
(35 mL.times.2). The organic layers were combined and dried over
anhydrous magnesium sulfate. After concentration under reduced
pressure, the residue was subjected to silica gel column
chromatography (eluent, hexane:ethyl acetate=80:20.fwdarw.0:100).
The object fraction was concentrated under reduced pressure and the
residue was dissolved in methanol (5 mL). 1N Aqueous sodium
hydroxide solution (1 mL) was added and the mixture was stirred at
room temperature for 2 hrs. After concentration of the reaction
mixture under reduced pressure, water (30 mL) was added, and the
mixture was extracted with ethyl acetate (40 mL.times.2). The
organic layer was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.0:100) and recrystallized from ethyl
acetate-hexane to give the title compound (50 mg).
[1180] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.40-3.55 (4H, m), 3.88
(2H, m), 4.68 (1H, m), 4.89 (2H, m), 7.20-7.24 (2H, m), 7.33 (1H,
d, J=8.7 Hz), 7.47 (1H, d, J=7.5 Hz), 7.62 (1H, m), 7.77 (1H, m),
8.13 (1H, s), 8.22 (1H, s), 8.44 (1H, m), 9.23 (1H, br s).
Example 198
##STR00246##
[1181] Production of
2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrro-
lo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
(i) Production of 4-phenoxy-6-prop-1-yn-1-ylpyrimidin-5-amine
[1182] 4-Iodo-6-phenoxypyrimidin-5-amine (5.00 g) was dissolved in
a mixed solvent of N,N-dimethylformamide (100 mL)/triethylamine (50
mL), and 1-(trimethylsilyl)-1-propyne (3.3 mL),
trans-dichlorobis(triphenylphosphine)palladium(II) (557.7 mg),
triphenylphosphine (421.1 mg), copper(I) iodide (303.0 mg) and
potassium fluoride (1.29 g) were sequentially added. The mixture
was stirred at 60.degree. C. under an argon stream for 16 hrs. The
reaction mixture was treated with saturated aqueous sodium hydrogen
carbonate solution and extracted with diethyl ether. The organic
layer was washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was separated and purified by silica gel column
chromatography (eluent, hexane:ethyl acetate=80:20.fwdarw.50:50) to
give the title compound (2.64 g) as a orange solid.
[1183] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.19 (3H, s), 4.36 (2H, br
s), 7.07-7.22 (2H, m), 7.22-7.34 (1H, m), 7.35-7.54 (2H, m), 8.08
(1H, s).
(ii) Production of
6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine
[1184] 4-Phenoxy-6-prop-1-yn-1-ylpyrimidin-5-amine (776.0 mg) was
dissolved in tetrahydrofuran (30 mL) and cooled to 0.degree. C. To
this solution was added dropwise a 1.0 M solution (4 mL) of
potassium tert-butoxide in tetrahydrofuran, and the mixture was
stirred at room temperature for 30 min. Water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was separated and purified by silica gel
column chromatography (eluent, hexane:ethyl
acetate=67:33.fwdarw.20:80) to give the title compound (578.6 mg)
as a white solid.
[1185] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.54 (3H, s), 6.44 (1H, q,
J=1.0 Hz), 7.21-7.30 (3H, m), 7.41-7.48 (2H, m), 8.47 (1H, s), 8.55
(1H, br s).
(iii) Production of
2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate
[1186] 6-Methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (299.9 mg)
and 2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (464.1 mg) were
dissolved in N,N-dimethylformamide (7 mL), potassium carbonate (431
mg) was added, and the mixture was stirred at 60.degree. C. for 21
hr. Water was added to the reaction mixture, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.20:80) to give the title compound (517.8 mg)
as a yellow oil.
[1187] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.50 (3H, s), 3.62-3.74
(2H, m), 3.92 (2H, t, J=5 Hz), 4.33-4.44 (2H, m), 4.57 (2H, t, J=5
Hz), 6.36 (1H, s), 7.15-7.34 (3H, m), 7.34-7.51 (4H, m), 7.51-7.65
(1H, m), 7.87-8.00 (2H, m), 8.40 (1H, s).
(iv) Production of
2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrro-
lo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate
[1188] A mixture of
2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (92.3 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (86.3
mg), pyridine hydrochloride (81.6 mg) and phenol (156.1 mg) was
stirred at 120.degree. C. for 3 hrs, and at 140.degree. C. for 5.5
hrs. Further, pyridine hydrochloride (77.6 mg) and phenol (188.7
mg) were added, and the mixture was stirred at 140.degree. C. for
22.5 hrs. The reaction mixture was diluted with dichloromethane,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was separated
and purified by basic silica gel column chromatography (eluent,
hexane:ethyl acetate=50:50.fwdarw.0:100) to give the title compound
(33.3 mg) as a purple oil.
[1189] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.43 (3H, s), 3.88-3.97
(2H, m), 4.00 (2H, t, J=4.4 Hz), 4.42-4.55 (4H, m), 5.04 (2H, s),
6.38 (1H, s), 6.71 (1H, d, J=8.8 Hz), 6.93-7.09 (1H, m), 7.13-7.42
(6H, m), 7.46-7.58 (1H, m), 7.65 (1H, d, J=2.6 Hz), 7.74-7.85 (2H,
m), 8.40 (1H, s), 8.48 (1H, s).
(v) Production of
2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrro-
lo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[1190]
2-{2-[4-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-
-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate (90.0 mg) was
dissolved in methanol (1 mL), 1N aqueous sodium hydroxide solution
(0.3 mL) was added, and the mixture was stirred at room temperature
for 5 hrs. The reaction mixture was neutralized with 1N
hydrochloric acid, and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was separated and purified by basic silica
gel column chromatography (eluent, hexane:ethyl
acetate=33:67.fwdarw.0:100) to give the title compound (43.9 mg) as
a pale-yellow powder.
[1191] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.45 (3H, s), 3.46-3.52
(4H, m), 3.82 (2H, t, J=4.7 Hz), 4.52 (2H, t, J=4.3 Hz), 4.64-4.80
(1H, m), 5.23 (2H, s), 6.30 (1H, s), 7.10-7.24 (2H, m), 7.26-7.38
(2H, m), 7.41-7.55 (2H, m), 7.82 (1H, d, J=2.8 Hz), 8.21 (1H, s),
8.68 (1H, s).
Example 199
##STR00247##
[1192] Production of
2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-6-methyl--
5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
(i) Production of
2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate
[1193] The title compound (288.2 mg) was obtained as a pale pink
oil by the reaction in the same manner as in Example 198 (iv) using
2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (271.0 mg),
3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (297.3 mg),
pyridine hydrochloride (235.0 mg) and phenol (497.9 mg).
[1194] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.45 (3H, s), 3.92-4.00
(2H, m), 4.04 (2H, t, J=4.4 Hz), 4.45-4.55 (4H, m), 6.42 (1H, s),
6.75-6.85 (3H, m), 6.85-6.96 (2H, m), 7.19-7.37 (3H, m), 7.45-7.53
(1H, m), 7.75-7.82 (2H, m), 7.85 (1H, d, J=2.8 Hz), 8.46 (1H, s),
8.73 (1H, br s).
(ii) Production of
2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-6-methyl--
5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[1195] The title compound (119.1 mg) was obtained as a white powder
by the reaction in the same manner as in Example 198 (v) using
2-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate (281.5 mg), 1N aqueous
sodium hydroxide solution (0.6 mL) and methanol (2 mL).
[1196] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.47 (3H, s), 3.44-3.56
(4H, m), 3.81-3.89 (2H, m), 4.56 (2H, t, J=4.5 Hz), 4.71-4.79 (1H,
m), 6.35 (1H, s), 6.88-6.95 (2H, m), 7.06-7.14 (1H, m), 7.26 (1H,
d, J=9 Hz), 7.50 (1H, t, J=9 Hz), 7.66 (1H, dd, J=9 Hz, 2.5 Hz),
8.01 (1H, d, J=2.5 Hz), 8.30 (1H, s), 8.99 (1H, br s).
Example 200
##STR00248##
[1197] Production of
4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-[2-(2-hydroxye-
thoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile
(i) Production of
4-(3,3-diethoxyprop-1-yn-1-yl)-6-phenoxypyrimidin-5-amine
[1198] The title compound (6.20 g) was obtained as a brown oil by
the reaction in the same manner as in Example 9 (iv) using
[1199] 4-iodo-6-phenoxypyrimidin-5-amine (7.0 g),
3,3-diethoxyprop-1-yne (3.8 mL),
trans-dichlorobis(triphenylphosphine)palladium(II) (783.3 mg),
copper(I) iodide (255.2 mg) and acetonitrile (160 mL)/triethylamine
(120 mL).
[1200] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (6H, t, J=7.2 Hz),
3.62-3.77 (2H, m), 3.77-3.91 (2H, m), 4.48 (2H, br s), 5.56 (1H,
s), 7.14-7.21 (2H, m), 7.27-7.33 (1H, m), 7.39-7.50 (2H, m), 8.11
(1H, s).
(ii) Production of
6-(diethoxymethyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine
[1201] 4-(3,3-Diethoxyprop-1-yn-1-yl)-6-phenoxypyrimidin-5-amine
(2.30 g) was dissolved in 1-methyl-2-pyrrolidone (7.5 mL), and the
mixture was cooled to 0.degree. C. A solution (7.6 mL) of potassium
tert-butoxide in 1.0 M tetrahydrofuran was added dropwise to this
solution, and the mixture was stirred at 0.degree. C. for 30 min.
and at room temperature for 1.5 hrs. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was separated and purified by silica gel
column chromatography (eluent, hexane:ethyl acetate=90:10-50:50) to
give the title compound (1.34 g) as a pale orange solid.
[1202] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (6H, t, J=7.1 Hz),
3.52-3.75 (4H, m), 5.78 (1H, s), 6.66 (1H, br d, J=2.2 Hz),
7.26-7.34 (3H, m), 7.42-7.52 (2H, m), 8.52 (1H, s), 8.95 (1H, br
s).
(iii) Production of
4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbaldehyde
[1203] 6-(Diethoxymethyl)-4-phenoxy-5H-pyrrolo[3,2-O]pyrimidine
(3.15 g) was dissolved in tetrahydrofuran (40 mL), 1N hydrochloric
acid (40 mL) was added, and the mixture was stirred at room
temperature for 2 hrs. The reaction mixture was neutralized with 1N
aqueous sodium hydroxide solution, and extracted with a mixed
solvent of ethyl acetate/tetrahydrofuran=1/1. The organic layer was
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The precipitate was
collected by filtration and dried to give the title compound (2.17
g) as a yellow powder.
[1204] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.25-7.40 (3H, m),
7.43-7.58 (3H, m), 8.44 (1H, s), 10.06 (1H, s), 13.26 (1H, s).
(iv) Production of
4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylic acid
[1205] 4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbaldehyde (2.17
g) was dissolved in dimethyl sulfoxide (21 mL) and a solution of
sodium dihydrogen phosphate (5.45 g) in water (14 mL) was added. A
solution of sodium chlorite (2.06 g) in water (14 mL) was added
dropwise to this solution, and the mixture was stirred for 2 hrs.
Saturated aqueous sodium hydrogen carbonate solution was gradually
added to the reaction mixture, and the pH of the solution was
adjusted to 2-3 with 1N hydrochloric acid. The resultant
precipitate was collected by filtration, washed with water and
diisopropyl ether and dried to give the title compound (2.40 g) as
a white powder.
[1206] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.09 (1H, s), 7.23-7.36
(3H, m), 7.41-7.54 (2H, m), 8.36 (1H, s), 12.82 (1H, s).
(v) Production of
4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide
[1207] Thionyl chloride (7 mL) was added to
4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylic acid (465.0 mg)
and the mixture was stirred at 75.degree. C. for 2 hrs. The
reaction mixture was concentrated under reduced pressure and
suspended in tetrahydrofuran (10 mL). The above-mentioned
suspension was gradually added to aqueous ammonia (20 mL) and the
precipitate was collected by filtration. The filtrate was extracted
with a mixed solvent of ethyl acetate/tetrahydrofuran=1/1, washed
with saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The precipitate was collected
by filtration, combined with the precipitate collected earlier by
filtration and dried to give the title compound (427.4 mg) as a
pale-yellow powder.
[1208] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.25 (1H, s), 7.27-7.35
(3H, m), 7.39-7.57 (2H, m), 7.75 (1H, s), 8.17 (1H, s), 8.36 (1H,
s), 12.58 (1H, s).
(vi) Production of
4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile
[1209] 4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (1.67 g)
was suspended in phosphorus oxychloride (20 mL), and the suspension
was stirred at 70.degree. C. for 3 hrs. The reaction mixture was
concentrated under reduced pressure, and the residue was dissolved
in tetrahydrofuran (25 mL). Water and aqueous ammonia were added to
the solution, and the mixture was extracted with a mixed solvent of
ethyl acetate/tetrahydrofuran=1/1. The organic layer was washed
with saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=90:10.fwdarw.67:33) to give the title compound (1.07 g) as
a pale-yellow powder.
[1210] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.29-7.39 (3H, m),
7.46-7.55 (2H, m), 7.59 (1H, s), 8.47 (1H, s), 13.76 (1H, s).
(vii) Production of
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H-
-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate
[1211] 4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile (240.4
mg) was dissolved in N,N-dimethylformamide (5 mL), and
2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (354.1 mg) and
potassium carbonate (354.8 mg) were added. The title compound
(266.5 mg) was obtained as a colorless oil by the reaction in the
same manner as in Example 198 (iii) using the mixture prepared
above.
[1212] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.73-3.79 (2H, m), 3.96
(2H, t, J=4.9 Hz), 4.37-4.43 (2H, m), 4.83 (2H, t, J=4.9 Hz), 7.17
(1H, s), 7.18-7.23 (2H, m), 7.27-7.35 (1H, m), 7.36-7.49 (4H, m),
7.51-7.58 (1H, m), 7.85-7.92 (2H, m), 8.49 (1H, s).
(viii) Production of
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H-
-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate
[1213] The title compound (282.6 mg) was obtained as a yellow oil
by the reaction in the same manner as in Example 198 (iv) using
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H-
-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate (261.5 mg),
3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (264.4 mg), pyridine
hydrochloride (221.6 mg) and phenol (461.6 mg).
[1214] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.96-4.06 (2H, m),
4.16-4.22 (2H, m), 4.45-4.54 (2H, m), 4.68-4.79 (2H, m), 6.80 (1H,
d, J=8.8 Hz), 7.01-7.09 (1H, m), 7.14-7.20 (1H, m), 7.24 (1H, s),
7.27-7.53 (6H, m), 7.68-7.76 (2H, m), 7.92 (1H, d, J=2.5 Hz), 8.53
(1H, s), 8.95 (1H, s).
(ix) Production of
4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-[2-(2-hydroxye-
thoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile
[1215] The title compound (143.2 mg) was obtained as a white powder
by the reaction in the same manner as in Example 198 (v) using
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H-
-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate (282.6 mg), 1N
aqueous sodium hydroxide solution (0.6 mL) and methanol (3 mL).
[1216] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.77 (1H, t, J=4.4 Hz),
3.74-3.88 (4H, m), 4.08-4.16 (2H, m), 4.70-4.80 (2H, m), 7.05-7.15
(2H, m), 7.16-7.21 (1H, m), 7.25 (1H, s), 7.30-7.36 (1H, m), 7.43
(1H, t, J=7.8 Hz), 7.67 (1H, dd, J=8.8 Hz, 2.8 Hz), 7.96 (1H, d,
J=2.8 Hz), 8.58 (1H, s), 9.03 (1H, s).
Example 201
##STR00249##
[1217] Production of
2-{3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]propoxy}ethanol hydrochloride
(i) Production of 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl
methanesulfonate
[1218] 60% Sodium hydride (8.05 g) was suspended in
N,N-dimethylformamide (80 mL), and the suspension was cooled to
0.degree. C. A solution of propane-1,3-diol (7.2 mL) in
N,N-dimethylformamide (10 mL) was added dropwise, and the mixture
was stirred at 0.degree. C. for 1 hr. A solution of
2-(2-bromoethoxy)tetrahydro-2H-pyran (4.0 mL) in
N,N-dimethylformamide (10 mL) was added dropwise to the reaction
solution, and the mixture was stirred at 0.degree. C. for 2
hrs.
[1219] Saturated aqueous ammonium chloride solution was added to
the reaction mixture, and the mixture was extracted with diethyl
ether and ethyl acetate. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was dissolved in
ethyl acetate (100 mL), and triethylamine (9 mL) and
methanesulfonyl chloride (2.3 mL) were added. The mixture was
stirred at room temperature for 3 hrs. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was separated and purified by silica gel
column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.20:80) to give the title compound (3.78 g) as
a colorless oil.
[1220] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45-1.66 (4H, m),
1.66-1.92 (2H, m), 1.96-2.09 (2H, m), 3.02 (3H, s), 3.45-3.68 (6H,
m), 3.81-3.94 (2H, m), 4.36 (2H, t, J=6.2 Hz), 4.62 (1H, dd, J=4.4
Hz, 2.7 Hz).
(ii) Production of
4-chloro-5-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl}-5H-pyrrolo[3-
,2-d]pyrimidine
[1221] 4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (203.6 mg),
3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl methanesulfonate
(559.3 mg) was dissolved in N,N-dimethylformamide (4 mL), cesium
carbonate (1.30 g) was added, and the mixture was stirred at
40.degree. C. for 4.5 hrs. Water was added to the reaction mixture
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
separated and purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=67:33.fwdarw.20:80) to give the title compound
(380.2 mg) as a colorless oil.
[1222] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44-1.70 (4H, m),
1.70-1.95 (2H, m), 1.95-2.24 (2H, m), 3.23-3.43 (2H, m), 3.45-3.69
(2H, m), 3.78-4.02 (2H, m), 4.53-4.75 (3H, m), 6.69 (1H, d, J=3.3
Hz), 7.66 (1H, d, J=3.3 Hz), 8.69 (1H, s).
(iii) Production of
2-{3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]propoxy}ethanol hydrochloride
[1223]
4-Chloro-5-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl}-5H-pyr-
rolo[3,2-d]pyrimidine (380.2 mg) was dissolved in isopropyl alcohol
(7 mL), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (419.2 mg)
was added, and the mixture was stirred at 80.degree. C. for 18 hrs.
Saturated aqueous sodium hydrogen carbonate solution was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was separated and purified by silica gel
column chromatography (eluent, hexane:ethyl
acetate=50:50.fwdarw.0:100), and the mixture was dissolved in ethyl
acetate (4 mL). 4N Hydrochloric acid-ethyl acetate (0.3 mL) was
added to this solution, and the precipitate was collected by
filtration, and dried to give the title compound (398.2 mg) as a
white solid.
[1224] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.86-2.02 (2H, m), 3.22
(2H, t, J=5.8 Hz), 3.27-3.40 (2H, m), 3.41-3.55 (2H, m), 4.53-4.69
(2H, m), 6.50 (1H, d, J=3.0 Hz), 7.16-7.26 (2H, m), 7.30 (1H, d,
J=8.9 Hz), 7.47 (1H, d, J=7.7 Hz), 7.56-7.76 (2H, m), 7.97 (1H, s),
8.35 (1H, s), 8.61 (1H, s).
Example 202
##STR00250##
[1225] Production of
2-[4-({3-chloro-4-{3-(trifluoromethyl)phenoxy}phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]acetamide
(i) Production of ethyl
[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2--
d]pyrimidin-5-yl]acetate
[1226] The title compound (221.2 mg) was obtained as an orange oil
by the reaction in the same manner as in Example 201 (iii) using
ethyl (4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (119.3 mg),
3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (171.3 mg) and
isopropyl alcohol (3 mL).
[1227] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.37 (3H, t, J=7 Hz), 4.37
(2H, q, J=7 Hz), 4.98 (2H, s), 6.66 (1H, d, J=3.3 Hz), 7.09 (1H, d,
J=8.8 Hz), 7.09-7.14 (1H, m), 7.17-7.22 (1H, m), 7.24 (1H, d, J=3.3
Hz), 7.32 (1H, d, J=7.8 Hz), 7.42 (1H, t, J=7.8 Hz), 7.53 (1H, dd,
J=8.8 Hz, 2.8 Hz), 7.83 (1H, d, J=2.8 Hz), 8.52-8.63 (2H, m)
(ii) Production of
[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2--
d]pyrimidin-5-yl]acetic acid
[1228] Ethyl
[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2--
d]pyrimidin-5-yl]acetate (221.2 mg) was dissolved in a mixed
solvent of tetrahydrofuran (1.5 mL)/ethanol (1.5 mL), 1N aqueous
sodium hydroxide solution (0.6 mL) was added, and the mixture was
stirred at room temperature for 30 min. The reaction mixture was
adjusted to pH 2-3 with 1N hydrochloric acid and extracted with a
mixed solvent of ethyl acetate/tetrahydrofuran=1/1. The organic
layer was washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was collected by filtration and dried to give the title
compound (169.8 mg) as a yellow powder.
[1229] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 5.62 (2H, s), 6.70 (1H,
d, J=3.0 Hz), 7.22-7.31 (2H, m), 7.35 (1H, d, J=8.8 Hz), 7.51 (1H,
d, J=8 Hz), 7.59 (1H, dd, J=8.8 Hz, 2.5 Hz), 7.65 (1H, t, J=8 Hz),
7.86 (1H, d, J=2.5 Hz), 7.95 (1H, d, J=3.0 Hz), 8.70 (1H, s), 9.99
(1H, s).
(iii) Production of
2-[4-({3-chloro-4-{3-(trifluoromethyl)phenoxy}phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]acetamide
[1230]
[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]acetic acid (149.3 mg) was dissolved in
N,N-dimethylformamide (1.6 mL), 2-(methylsulfonyl)ethanamine (60.3
mg), 1H-1,2,3-benzotriazol-1-ol (67.8 mg), triethylamine (0.15 mL)
and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride
(93.0 mg) were added, and the mixture was stirred at room
temperature for 17 hrs. Moreover, 2-(methylsulfonyl)ethanamine
(120.6 mg), 1H-1,2,3-benzotriazol-1-ol (134.6 mg), triethylamine
(0.3 mL) and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide
hydrochloride (181.4 mg) were added, and the mixture was stirred at
room temperature for 24 hrs. Water was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was separated and purified by silica gel column
chromatography (eluent, ethyl acetate:methanol=100:0.fwdarw.90:10),
and basic silica gel column chromatography (eluent, hexane:ethyl
acetate=33:67.fwdarw.0:100.fwdarw.ethyl acetate:methanol=90:10) to
give the title compound (20.3 mg) as a white powder.
[1231] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.98 (3H, s), 3.27 (2H,
t, J=6.9 Hz), 3.50-3.61 (2H, m), 5.12 (2H, s), 6.54 (1H, d, J=3.0
Hz), 7.15-7.26 (2H, m), 7.33 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=8.0
Hz), 7.56-7.68 (3H, m), 8.04 (1H, d, J=2.5 Hz), 8.38 (1H, s), 9.07
(1H, t, J=5.8 Hz), 9.97 (1H, s).
Example 203
##STR00251##
[1232] Production of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]but-2-yn-1-ol
(i) Production of
4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-ol
[1233] 60% Sodium hydride (1.39 g) was suspended in tetrahydrofuran
(50 mL), and the suspension was cooled to 0.degree. C., a solution
of but-2-yne-1,4-diol (3.0 g) in tetrahydrofuran (20 mL) was added
dropwise, and the mixture was stirred at room temperature for 1 hr.
tert-Butyldimethylsilyl chloride (5.26 g) was added to the reaction
mixture, and the mixture was stirred at room temperature for 24
hrs. Water was added to the reaction mixture and the mixture was
extracted with diethyl ether. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=100:0.fwdarw.80:20) to give the title compound (1.48 g) as
a colorless oil.
[1234] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.12 (6H, s), 0.91 (9H,
s), 1.60-1.66 (1H, m), 4.27-4.33 (2H, m), 4.36 (2H, t, J=1.8
Hz).
(ii) Production of 4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl
methanesulfonate
[1235] 4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-ol (701.4 mg)
was dissolved in ethyl acetate (15 mL), and the solution was cooled
to 0.degree. C. Triethylamine (1.1 mL) and methanesulfonyl chloride
(0.3 mL) were added, and the mixture was stirred at 0.degree. C.
for 3 hrs. Water was added to the reaction mixture and the mixture
was extracted with diethyl ether. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=90:10.fwdarw.50:50) to give the title compound (469.7 mg)
as a colorless oil.
[1236] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.12 (6H, s), 0.91 (9H,
s), 3.12 (3H, s), 4.37 (2H, t, J=1.9 Hz), 4.89 (2H, t, J=1.9
Hz).
(iii) Production of
5-(4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)-4-chloro-5H-pyrrolo[3-
,2-d]pyrimidine
[1237] The title compound (431.1 mg) was obtained as a yellow oil
by the reaction in the same manner as in Example 201 (ii) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (211.9 mg),
4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl methanesulfonate
(464.0 mg), cesium carbonate (672.7 mg) and N,N-dimethylformamide
(5 mL).
[1238] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.07 (6H, s), 0.87 (9H,
s), 4.35 (2H, t, J=2 Hz), 5.33 (2H, t, J=2 Hz), 6.76 (1H, d, J=3.3
Hz), 7.69 (1H, d, J=3.3 Hz), 8.72 (1H, s).
(iv) Production of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]but-2-yn-1-ol
[1239]
5-(4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)-4-chloro-5H-pyr-
rolo[3,2-d]pyrimidine (408.3 mg) was dissolved in isopropyl alcohol
(7 mL), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421.0 mg)
was added, and the mixture was stirred at 80.degree. C. for 6 hrs.
Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The obtained oil was dissolved
in tetrahydrofuran (6 mL), a 1.0 M solution (2 mL) of
tetrabutylammonium fluoride in tetrahydrofuran was added, and the
mixture was stirred at room temperature for 1 hr. To the reaction
mixture was added saturated aqueous ammonium chloride solution and
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was separated
and purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=67:33.fwdarw.20:80) and crystallized from
hexane/ethyl acetate to give the title compound (425 mg) as white
crystals.
[1240] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.07-4.13 (1H, m),
4.45-4.52 (2H, m), 5.01-5.06 (2H, m), 6.44 (1H, d, J=3.3 Hz),
7.06-7.16 (3H, m), 7.18-7.22 (1H, m), 7.33 (1H, d, J=8 Hz), 7.43
(1H, t, J=8 Hz), 7.57 (1H, dd, J=8.8 Hz, 2.5 Hz), 7.82 (1H, s),
7.95 (1H, d, J=2.5 Hz), 8.40 (1H, s).
Example 204
##STR00252##
[1241] Production of
(2E)-4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrro-
lo[3,2-d]pyrimidin-5-yl]but-2-en-1-ol
[1242] 70% Sodium bis(2-methoxyethoxy)aluminum hydride in toluene
solution (0.8 mL) was dissolved in tetrahydrofuran (4 mL), and the
solution was cooled to 0.degree. C. A solution of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]but-2-yn-1-ol (262.4 mg) in tetrahydrofuran (10
mL) was added dropwise, and the mixture was stirred at 0.degree. C.
for 2 hrs. To the reaction mixture was added 10% aqueous potassium
carbonate solution and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was separated and purified by silica gel
column chromatography (eluent, hexane:ethyl
acetate=33:67.fwdarw.0:100) and crystallized from hexane/ethyl
acetate to give the title compound (195.9 mg) as white
crystals.
[1243] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.81-3.92 (2H, m), 4.75
(1H, t, J=5.5 Hz), 5.17 (2H, m), 5.56 (1H, br d, J=15 Hz), 5.80
(1H, br d, J=15 Hz), 6.53 (1H, d, J=3.0 Hz), 7.16-7.26 (2H, m),
7.30 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=7.7 Hz), 7.57-7.74 (3H, m),
7.98 (1H, d, J=2.2 Hz), 8.36 (1H, s), 8.48 (1H, s).
Example 205
##STR00253##
[1244] Production of
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]propane-1,2-diol
(i) Production of
3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propane-1,2-diyl
dibenzoate
[1245] A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg),
3-bromopropane-1,2-diyl dibenzoate (1.77 g), cesium carbonate (1.59
g) and N,N-dimethylformamide (6.5 mL) was stirred at 80.degree. C.
for 4 hrs. The reaction mixture was diluted with ethyl acetate (100
mL) and washed with water (80 mL). The organic layer was separated,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=90/10.fwdarw.40/60) to give
the title compound (401 mg) as a white powder.
[1246] .sup.1H-NMR (CDCl.sub.3) .delta. 4.58 (1H, dd, J=5 Hz, 12
Hz), 4.73 (1H, dd, J=5 Hz, 12 Hz), 4.84 (1H, dd, J=9 Hz, 15 Hz),
5.11 (1H, dd, J=15 Hz, 5 Hz), 5.84 (1H, m), 6.69 (1H, d, J=3 Hz),
7.3-7.7 (7H, m), 7.91 (2H, m), 8.02 (2H, m), 8.69 (1H, s).
(ii) Production of
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]propane-1,2-diol
[1247] The title compound (180 mg) was obtained as colorless
crystals by the method in the same manner as in Example 183 using
3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propane-1,2-diyl
dibenzoate (250 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline
(280 mg) and 1-methyl-2-pyrrolidone (1.14 mL).
[1248] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.47 (2H, m), 3.94 (1H,
m), 4.50 (2H, m), 5.18 (1H, br s), 6.52 (2H, d, J=3 Hz), 7.20 (2H,
m), 7.33 (1H, d, J=9 Hz), 7.45 (1H, d, J=8 Hz), 7.64 (3H, m), 8.04
(1H, d, J=3 Hz), 8.35 (1H, s), 10.03 (1H, br s).
Example 206
##STR00254##
[1249] Production of
2-(2-{4-[{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}(methyl)amino]-5H-
-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol
[1250] The title compound (127 mg) was obtained by the method in
the same manner as in Example 183 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg),
3-chloro-N-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (196 mg)
and 1-methyl-2-pyrrolidone (0.863 mL).
[1251] .sup.1H-NMR (CDCl.sub.3) .delta. 3.38 (2H, t, J=4.5 Hz),
3.48 (2H, t, J=4.5 Hz), 3.58 (3H, s), 3.62 (2H, m), 4.00 (2H, t,
J=5 Hz), 5.08 (1H, br s), 6.64 (1H, dd, J=3 Hz, 9 Hz), 6.70 (1H, d,
J=3 Hz), 6.72 (1H, s), 6.97 (2H, m), 7.09 (2H, m), 7.40 (2H, m),
8.79 (1H, s).
Example 207
##STR00255##
[1252] Production of
N-(2-{4-[{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}(methyl)amino]-5H-
-pyrrolo[3,2-d]pyrimidin-5-yl}ethyl)-2-(methylsulfonyl)acetamide
hydrochloride
[1253] A mixture of tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297
mg), 3-chloro-N-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (453
mg) and 1-methyl-2-pyrrolidone (1.99 mL) was stirred at 120.degree.
C. for 16 hrs. To the reaction mixture was added 2N hydrochloric
acid (1 mL), and the mixture was stirred at 80.degree. C. for 2.5
hrs. The reaction mixture was diluted with ethyl acetate (80 mL)
and washed with aqueous sodium hydrogen carbonate (30 mL). The
organic layer was separated, dried over magnesium sulfate and
evaporated under reduced pressure. The residue,
2-(methylsulfonyl)acetic acid (207 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (429
mg), 1-hydroxybenzotriazole monohydrate (304 mg), triethylamine
(0.697 mL) and N,N-dimethylformamide (7.69 mL) were reacted in the
same manner as in Example 155 (iv). The obtained compound was
treated with 4N hydrochloric acid/ethyl acetate to give the title
compound (149 mg) as colorless crystals.
[1254] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.02 (3H, s), 3.20 (2H,
s), 3.51 (2H, m), 3.71 (3H, s), 3.90 (2H, s), 6.72 (1H, d, J=3 Hz),
7.2-7.4 (4H, m), 7.52 (1H, d, J=8 Hz), 7.68 (2H, m), 7.86 (1H, d,
J=2 Hz), 8.40 (1H, m), 8.94 (1H, s).
Example 208
##STR00256##
[1255] Production of
N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyri-
midin-5-yl)ethyl]-3-hydroxy-3-methylbutanamide
[1256] The title compound (145 mg) was obtained as crystals by the
reaction in the same manner as in Example 155 (iv) using
5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]-
pyrimidin-4-amine dihydrochloride (200 mg) and
3-hydroxy-3-methylbutyric acid (104 mg).
[1257] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (6H, s), 2.49 (2H,
s), 3.55-3.7 (2H, m), 4.4-4.55 (2H, m), 6.60 (1H, d, J=3.4 Hz),
6.85-7.1 (4H, m), 7.1-7.3 (2H, m), 7.7-7.8 (1H, m), 8.05 (1H, d,
J=2.6 Hz), 8.52 (1H, s), 8.64 (1H, s).
Example 209
##STR00257##
[1258] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(isopropylsulfonyl)acetamide
[1259]
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}--
5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (300 mg) and
4-methylmorpholine (3.0 mL) were dissolved in tetrahydrofuran (7.0
mL), chloroacetyl chloride (0.7 mL) was added, and the mixture was
stirred at 0.degree. C. for 2 hrs. To the reaction mixture was
added saturated aqueous sodium hydrogen carbonate under ice-cooling
and the mixture was extracted with ethyl acetate. The extract was
dried over magnesium sulfate and concentrated, and the residue was
dissolved in a mixed solvent of N,N-dimethylformamide (3.5 mL) and
tetrahydrofuran (6.0 mL). To the mixture was added sodium
2-methylpropane-2-thiolate (180 mg), and the mixture was stirred at
room temperature for 1 hr. To the reaction mixture was added
saturated aqueous sodium hydrogen carbonate under ice-cooling and
the mixture was extracted with ethyl acetate.
[1260] The extract was dried over magnesium sulfate and
concentrated, and the residue was separated and purified by silica
gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=90:10) to give
an oil. The title compound (165 mg) was obtained as crystals by the
reaction in the same manner as in Example 172 (ii) using the oil
obtained above and titanium tetraisopropoxide (0.15 mL), methanol
(0.52 mL) and 70% aqueous tert-butyl hydroperoxide solution (12.0
mL).
[1261] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24 (6H, d, J=6.8 Hz),
3.45-3.58 (3H, m), 4.03 (2H, s), 4.56 (2H, m), 6.52 (1H, m),
7.20-7.99 (8H, m), 8.35 (1H, s), 8.72 (1H, s).
Example 210
##STR00258##
[1262] Production of
N-{2-[4-{(3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-[(cyclopentyl)sulfonyl]acetamide
[1263] The title compound (115 mg) was obtained as crystals by the
reaction in the same manner as in Example 209 using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (350 mg),
4-methylmorpholine (3.50 mL), chloroacetyl chloride (0.9 mL),
sodium cyclopentanethiolate (890 mg), titanium tetraisopropoxide
(0.25 mL), methanol (0.55 mL) and 70% aqueous tert-butyl
hydroperoxide solution (15.0 mL).
[1264] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.63 (4H, m), 1.89
(4H, m), 3.47 (2H, m), 3.79 (1H, m), 3.99 (2H, s), 4.56 (2H, m),
6.52 (1H, m), 7.20-7.99 (8H, m), 8.35 (1H, s), 8.72 (1H, s).
Example 211
##STR00259##
[1265] Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(2,2,2-trifluoroet-
hoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[1266] The title compound (175 mg) was obtained as crystals by the
reaction in the same manner as in Example 171 using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (340 mg), potassium carbonate
(530 mg) and 2-(2,2,2-trifluoroethoxy)ethyl methanesulfonate (550
mg).
[1267] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.91-4.09 (4H, m),
3.73-3.76 (2H, m), 6.53 (1H, d, J=3 Hz), 7.21-7.92 (8H, m), 8.36
(1H, s), 8.62 (1H, s).
Example 212
##STR00260##
[1268] Production of
(2E)-N-[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H--
pyrrolo[3,2-d]pyrimidin-6-yl)prop-2-en-1-yl]-4-(dimethylamino)but-2-enamid-
e
(i) Production of
N-(4,6-diiodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide
[1269] 4,6-Diiodopyrimidin-5-amine (20 g) was dissolved in
dichloromethane (200 mL), and trifluoroacetic anhydride (47.3 mL)
and triethylamine (8.04 mL) were successively added dropwise. The
mixture was stirred at room temperature for 1 hr, and the reaction
mixture was concentrated under reduced pressure. The residue was
dissolved in methanol (150 mL), and concentrated again under
reduced pressure to give a colorless solid. The obtained solid was
dissolved in N,N-dimethylformamide (106 mL), potassium carbonate
(15.9 g) and iodomethane (10.8 mL) were added, and the mixture was
stirred at room temperature for 16 hrs. The reaction mixture was
diluted with diethyl ether (400 mL) and washed with water (400 mL).
The organic layer was dried over magnesium sulfate and concentrated
under reduced pressure to give the title compound (25.1 g) as a
colorless solid.
[1270] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.34 (2H, s), 3.48 (1H,
s), 8.44 (1H, d, J=2 Hz).
(ii) Production of
N-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-6-iodopyrimidin-5-yl)-2,2-
,2-trifluoro-N-methylacetamide
[1271]
N-(4,6-Diiodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide (3
g) and 3-(4-amino-2-chlorophenoxy)benzonitrile (1.69 g) were
dissolved in 1-methyl-2-pyrrolidone (11.4 mL), and the mixture was
stirred with heating at 100.degree. C. for 16 hrs. To the reaction
mixture was added aqueous sodium hydrogen carbonate (80 mL) and the
mixture was extracted with ethyl acetate (100 mL.times.2). The
organic layer was washed with saturated brine (80 mL), dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=90:10->hexane:ethyl acetate=50:50) and
crystallized from diisopropyl ether to give the title compound
(1.67 g) as colorless crystals.
[1272] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.39 (3H, s), 7.1-7.6 (6H,
m), 7.90 (1H, d, J=3 Hz), 8.37 (1H, s).
(iii) Production of
3-(2-chloro-4-{[6-iodo-5-(methylamino)pyrimidin-4-yl]amino}phenoxy)benzon-
itrile
[1273] To a solution of
N-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-6-iodopyrimidin-5-yl)-2,2-
,2-trifluoro-N-methylacetamide (1.0 g) in
isopropanol-tetrahydrofuran (5.0 mL-10 mL) was added sodium
borohydride (70 mg) at room temperature. The mixture was stirred at
room temperature for 1.5 hrs, and ethyl acetate was added. The
mixture was washed with water and saturated brine and the organic
layer was dried over magnesium sulfate. After concentration under
reduced pressure, the residue was separated and purified by silica
gel column chromatography (eluent, hexane:ethyl acetate=4:1-3:2) to
give the title compound (755 mg) as a white amorphous solid.
[1274] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.72 (3H, d, J=6.3 Hz),
2.86-2.98 (1H, m), 7.15-7.21 (3H, m), 7.31-7.45 (2H, m), 7.58 (1H,
dd, J=9.0, 2.7 Hz), 7.73 (1H, br s), 7.99 (1H, d, J=2.7 Hz), 8.20
(1H, s).
(iv) Production of tert-butyl
{(2E)-5-[6-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-(methylamino)pyri-
midin-4-yl]pent-2-en-4-yn-1-yl}carbamate
[1275] The title compound (366 mg) was obtained as brown powder
crystals by the reaction in the same manner as in Example 81 (ii)
using
3-(2-chloro-4-{[6-iodo-5-(methylamino)pyrimidin-4-yl]amino}phenoxy)benzon-
itrile (755 mg), tert-butyl pent-2-en-4-ynylcarbamate (0.43 g),
bis(triphenylphosphine)palladium(II) dichloride (55.5 mg),
copper(I) iodide (18 mg), acetonitrile (16 mL) and triethylamine
(12 mL).
[1276] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.47 (9H, s), 2.78 (3H, d,
J=6.3 Hz), 3.15-3.27 (1H, m), 3.84-3.95 (2H, m), 4.53-4.65 (1H, m),
5.84-5.93 (1H, m), 6.34-6.43 (1H, m), 7.09 (1H, d, J=8.7 Hz),
7.10-7.22 (2H, m), 7.32-7.44 (2H, m), 7.55 (1H, br s), 7.59 (1H,
dd, J=8.7, 2.7 Hz), 7.99 (1H, d, J=2.7 Hz), 8.46 (1H, s).
(v) Production of tert-butyl
[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H-pyrrolo-
[3,2-d]pyrimidin-6-yl)prop-2-en-1-yl]carbamate
[1277] The title compound (200 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 81 (iii)
using tert-butyl
{(2E)-5-[6-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-(methylamino)pyri-
midin-4-yl]pent-2-en-4-yn-1-yl}carbamate (366 mg), copper(I) iodide
(13 mg) and N,N-dimethylformamide (4.0 mL).
[1278] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.48 (9H, s), 3.92-4.03
(5H, m), 4.71-4.86 (1H, m), 6.31-6.45 (1H, m), 6.56 (1H, d, J=15.9
Hz), 6.67 (1H, s), 6.74 (1H, s), 7.06-7.22 (3H, m), 7.31-7.46 (3H,
m), 7.75 (1H, d, J=2.7 Hz), 8.49 (1H, s).
(vi) Production of
3-[4-({6-[(1E)-3-aminoprop-1-en-1-yl]-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-
-4-yl}amino)-2-chlorophenoxy]benzonitrile dihydrochloride
[1279] The title compound (170 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 81 (iv)
using tert-butyl
[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H-pyrrolo-
[3,2-d]pyrimidin-6-yl)prop-2-en-1-yl]carbamate (190 mg), 2N
hydrochloric acid (4.5 mL) and tetrahydrofuran (9.0 mL).
[1280] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.75 (2H, t, J=5.3 Hz),
4.17 (3H, s), 6.62-6.72 (1H, m), 6.87 (1H, s), 7.13 (1H, d, J=16.5
Hz), 7.25-7.34 (2H, m), 7.43-7.46 (1H, m), 7.55-7.67 (3H, m), 7.93
(1H, d, J=2.4 Hz), 8.16-8.31 (3H, m), 8.64 (1H, s), 9.83 (1H, br
s).
(vii) Production of
(2E)-N-[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H--
pyrrolo[3,2-d]pyrimidin-6-yl)prop-2-en-1-yl]-4-(dimethylamino)but-2-enamid-
e
[1281] The title compound (74 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 82 using
3-[4-({6-[(1E)-3-aminoprop-1-en-1-yl]-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-
-4-yl}amino)-2-chlorophenoxy]benzonitrile dihydrochloride (160 mg),
(2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (182 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (420
mg), 1-hydroxybenzotriazole monohydrate (340 mg), triethylamine
(0.80 mL) and N,N-dimethylformamide (5.0 mL).
[1282] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.15 (6H, s), 3.00 (2H,
dd, J=6.0, 1.2 Hz), 3.95-4.08 (5H, m), 6.05-6.14 (1H, m), 6.42-6.53
(1H, m), 6.60 (1H, dt, J=15.6, 6.6 Hz), 6.72 (1H, s), 6.78 (1H, d,
J=15.6 Hz), 7.20-7.28 (2H, m), 7.39-7.43 (1H, m), 7.53-7.59 (2H,
m), 7.60-7.68 (1H, m), 7.68-7.92 (1H, m), 8.28 (1H, s), 8.32 (1H,
t, J=5.4 Hz), 8.77 (1H, s).
Example 213
##STR00261##
[1283] Production of
(2E)-N-{[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5-meth-
yl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl}-4-(dimethylamino)but-2-enamide
(i) Production of 4,6-diiodo-N-methylpyrimidin-5-amine
[1284] To a solution of 4,6-diiodopyrimidin-5-amine (1.0 g) in
tetrahydrofuran (10 mL) was added sodium hydride (60%, 138 mg)
under ice-cooling. The mixture was stirred at room temperature for
30 min. To the reaction system was added dropwise a solution of
methyl methanesulfonate (0.256 mL) in tetrahydrofuran (4.0 mL). The
mixture was stirred at room temperature for 3 hrs and ethyl acetate
was added. The mixture was washed with water and saturated brine
and dried over magnesium sulfate. After concentration under reduced
pressure, the residue was separated and purified by silica gel
column chromatography (hexane:ethyl acetate=9:1.fwdarw.3:1) to give
the title compound (600 mg) as pale-yellow crystals.
[1285] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.02 (3H, d, J=5.7 Hz),
3.71-3.83 (1H, m), 8.04 (1H, s).
(ii) Production of
N4-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-6-iodo-N-5-methylpyri-
midine-4,5-diamine
[1286] The title compound (552 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 212 (ii)
using 4,6-diiodo-N-methylpyrimidin-5-amine (600 mg),
3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (504 mg) and
1-methyl-2-pyrrolidone (10 mL).
[1287] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.71 (3H, d, J=5.7 Hz),
2.87-2.98 (1H, m), 6.76-6.85 (2H, m), 6.90-6.96 (1H, m), 7.09 (1H,
d, J=8.7 Hz), 7.29-7.34 (1H, m), 7.52-7.56 (1H, m), 7.70 (1H, br
s), 7.96 (1H, d, J=1.5 Hz), 8.19 (1H, s).
(iii) Production of tert-butyl
{[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5-methyl-5H-p-
yrrolo[3,2-d]pyrimidin-6-yl]methyl}carbamate
[1288] To a solution of
N4-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-6-iodo-N-5-methylpyri-
midine-4,5-diamine (1.53 g), tert-butyl prop-2-ynylcarbamate (0.67
g) and triethylamine (1.19 mL) in acetonitrile (28 mL) were added
bis(triphenylphosphine)palladium(II) dichloride (100 mg) and
copper(I) iodide (32.5 mg) at room temperature. Under an argon
atmosphere, the mixture was stirred at room temperature for 4.5
hrs, heated at 50.degree. C., and the mixture was stirred for 6
hrs. After concentration under reduced pressure, the residue was
separated and purified by silica gel column chromatography
(hexane:ethyl acetate=7:3.fwdarw.3:7.fwdarw.basic silica gel,
hexane:ethyl acetate=1:1 ethyl acetate) to give the title compound
(1.05 g) as colorless crystals.
[1289] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.48 (9H, s), 4.04 (3H,
s), 4.52 (2H, d, J=6.0 Hz), 4.83-4.95 (1H, m), 6.49 (1H, s),
6.76-6.96 (4H, m), 7.08 (1H, d, J=8.7 Hz), 7.31 (1H, t, J=8.3 Hz),
7.43 (1H, dd, J=8.3 Hz), 7.78 (1H, d, J=2.4 Hz), 8.48 (1H, s).
(iv) Production of
6-(aminomethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5-meth-
yl-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride
[1290] The title compound (1.01 g) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 81 (iv)
using tert-butyl
{[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5-methyl-5H-p-
yrrolo[3,2-d]pyrimidin-6-yl]methyl}carbamate (1.05 g), 2N
hydrochloric acid (20 mL) and tetrahydrofuran (40 mL).
[1291] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.18 (3H, s), 4.39-4.48
(2H, m), 6.89 (1H, s), 6.94-6.99 (2H, m), 7.15 (1H, d, J=9.0 Hz),
7.35 (1H, d, J=8.7 Hz), 7.50-7.56 (1H, m), 7.67 (1H, dd, J=9.0, 2.4
Hz), 7.94 (1H, d, J=2.4 Hz), 8.72 (1H, s), 8.77-8.92 (3H, m), 10.04
(1H, br s).
(v) Production of
(2E)-N-{[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5-meth-
yl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methyl}-4-(dimethylamino)but-2-enamide
[1292] The title compound (105 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 82 using
6-(aminomethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5-meth-
yl-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg),
(2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (124 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (214
mg), 1-hydroxybenzotriazole monohydrate (171 mg), triethylamine
(0.52 mL) and N,N-dimethylformamide (5.0 mL).
[1293] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.14 (6H, s), 3.00 (2H, d,
J=6.3 Hz), 4.00 (3H, s), 4.58 (2H, d, J=5.4 Hz), 6.11 (1H, d,
J=15.3 Hz), 6.39 (1H, s), 6.58-6.68 (1H, m), 6.87-6.95 (2H, m),
7.04-7.11 (1H, m), 7.25 (1H, d, J=8.7 Hz), 7.45-7.51 (1H, m),
7.60-7.68 (1H, m), 7.91 (1H, d, J=2.7 Hz), 8.28 (1H, s), 8.54-8.61
(1H, m), 8.71 (1H, s).
Example 214
##STR00262##
[1294] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-2,2-dimethylpropanamide
hydrochloride
[1295] A solution of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
3-hydroxy-2,2-dimethylpropanoic acid (68 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166
mg), 1-hydroxybenzotriazole monohydrate (132 mg) and triethylamine
(0.40 mL) in N,N-dimethylformamide (5.0 mL) was stirred at room
temperature for 20 hrs. Water was added to the reaction system and
the mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine and dried over magnesium
sulfate. After concentration under reduced pressure, the residue
was separated and purified by basic silica gel column
chromatography (eluent, ethyl acetate.fwdarw.methanol:ethyl
acetate=15:85). After concentration under reduced pressure, ethyl
acetate (2.0 mL) and 4N hydrochloric acid/ethyl acetate (0.5 mL)
were added, and the mixture was stirred at room temperature for 15
hrs. After concentration under reduced pressure, the precipitated
crystals were collected by filtration. To a solution of the
collected crystals in ethanol (2.0 mL) was added 1N aqueous sodium
hydroxide solution at room temperature, and the mixture was stirred
for 2 days. The mixture was concentrated under reduced pressure and
a solution of the residue in ethyl acetate was washed with water
and saturated brine and dried over magnesium sulfate. After
concentration under reduced pressure, 4N hydrochloric acid/ethyl
acetate (0.5 mL) was added to a solution of the residue in ethyl
acetate (1.0 mL). After concentration under reduced pressure, the
precipitated crystals were collected by filtration. The crystals
were washed with diisopropyl ether to give the title compound (119
mg) as colorless crystals.
[1296] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.96 (6H, s), 3.23-3.52
(4H, m), 4.56-4.68 (2H, m), 6.64 (1H, d, J=3.0 Hz), 7.23-7.30 (2H,
m), 7.38 (1H, d, J=8.4 Hz), 7.52 (1H, d, J=8.1 Hz), 7.61-7.69 (1H,
m), 7.72-7.80 (1H, m), 7.85-7.92 (2H, m), 8.00-8.03 (1H, m), 8.70
(1H, s), 9.95-10.06 (1H, m).
Example 215
##STR00263##
[1298] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)propanamide
[1299] To a mixture of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
triethylamine (0.39 mL) and tetrahydrofuran (5.0 mL) was added
2-chloropropionyl chloride (54 .mu.L) at room temperature. The
mixture was stirred at room temperature for 3 days, water was added
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine and dried over magnesium sulfate.
After concentration under reduced pressure, sodium methanesulfinate
(85 mg) and pyridine (67 .mu.L) were added to a solution of the
residue in N,N-dimethylformamide (5.0 mL), and the mixture was
stirred at 70.degree. C. for 2 days. Water was added to the
reaction system and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over
magnesium sulfate. After concentration under reduced pressure, the
residue was separated and purified by basic silica gel column
chromatography (eluent, ethyl acetate.fwdarw.ethyl
acetate:methanol=9:1) and recrystallized from ethyl
acetate-diisopropyl ether to give the title compound (114 mg) as
colorless crystals.
[1300] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.71 (3H, d, J=7.2 Hz),
2.98 (3H, s), 3.63-3.75 (2H, m), 3.81 (1H, q, J=7.2 Hz), 4.44-4.55
(2H, m), 6.64 (1H, d, J=3.0 Hz), 7.09 (1H, d, J=8.7 Hz), 7.11-7.18
(2H, m), 7.19-7.25 (2H, m), 7.30-7.36 (1H, m), 7.40-7.47 (1H, m),
7.85 (1H, dd, J=8.7, 2.7 Hz), 8.01 (1H, d, J=2.7 Hz), 8.30 (1H, s),
8.54 (1H, s).
Example 216
##STR00264##
[1301] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide
[1302] The title compound (128 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
2-hydroxy-2-(trifluoromethyl)propionic acid (88.2 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160
mg), 1-hydroxybenzotriazole monohydrate (128 mg), triethylamine
(0.39 mL) and N,N-dimethylformamide (5.0 mL).
[1303] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.68 (3H, s), 3.65-3.77
(2H, m), 3.80-3.89 (1H, m), 4.43-4.57 (2H, m), 6.63 (1H, d, J=3.0
Hz), 7.08 (1H, d, J=8.7 Hz), 7.11-7.16 (1H, m), 7.19-7.28 (3H, m),
7.30-7.36 (1H, m), 7.40-7.43 (1H, m), 7.79 (1H, dd, J=8.7, 2.4 Hz),
8.08 (1H, d, J=2.4 Hz), 8.31 (1H, s), 8.53 (1H, s).
Example 217
##STR00265##
[1304] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
4-methylbenzenesulfonate
[1305] To a solution of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide (150 mg)
in ethyl acetate (10 mL) was added 4-methylbenzenesulfonic acid
monohydrate (55.4 mg) at room temperature. The mixture was stirred
at room temperature for 20 hrs, and the solvent was evaporated
under reduced pressure. The precipitated crystals were collected by
filtration and washed with ethyl acetate and diisopropyl ether to
give the title compound (150.3 mg) as colorless crystals.
[1306] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.29 (3H, s), 3.07 (3H,
s), 3.44-3.60 (2H, m), 4.06 (2H, s), 4.61-4.70 (2H, m), 6.66 (1H,
d, J=3.0 Hz), 7.11 (2H, d, J=8.4 Hz), 7.22-7.28 (2H, m), 7.38 (1H,
d, J=8.7 Hz), 7.47 (2H, d, J=8.4 Hz), 7.50-7.55 (1H, m), 7.62-7.72
(2H, m), 7.89-7.96 (2H, m), 8.65-8.74 (2H, m), 9.70-9.80 (1H,
m).
Example 218
##STR00266##
[1307] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
hydrochloride
[1308] The title compound (147 mg) was obtained as colorless
crystals in the same manner as in Example 217 using
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide (150 mg),
4N hydrochloric acid/ethyl acetate (0.13 mL) and ethyl acetate
(10-mL).
[1309] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.06 (3H, s), 3.35-3.59
(2H, m), 4.07 (2H, s), 4.63-4.74 (2H, m), 6.67 (1H, d, J=3.0 Hz),
7.25-7.30 (2H, m), 7.38 (1H, d, J=8.7 Hz), 7.51-7.54 (1H, m),
7.62-7.72 (2H, m), 7.92-7.99 (2H, m), 8.70-8.79 (2H, m), 9.78-9.89
(1H, m).
Example 219
##STR00267##
[1310] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
methanesulfonate
[1311] The title compound (1.14 g) was obtained as colorless
crystals in the same manner as in Example 217 using
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide (1.0 g),
methanesulfonic acid (0.126 mL) and ethyl acetate (50 mL).
[1312] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.30 (3H, s), 3.06 (3H,
s), 3.47-3.61 (2H, m), 4.06 (2H, s), 4.63-4.72 (2H, m), 6.67 (1H,
d, J=3.3 Hz), 7.23-7.29 (2H, m), 7.37-7.40 (2H, m), 7.63-7.73 (2H,
m), 7.91-7.98 (2H, m), 8.68-8.78 (2H, m), 9.80 (1H, br s).
Example 220
##STR00268##
[1313] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]-1-methylethyl}-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1-methylethyl]carbamate
[1314] To a solution of 2-aminopropan-1-ol (1.0 g) in
tetrahydrofuran (50 mL) was added di-tert-butyl dicarbonate (3.1
mL) at room temperature. The mixture was stirred at room
temperature for 3 days and concentrated under reduced pressure.
[1315] To a solution of the residue and triethylamine (3.7 mL) in
tetrahydrofuran (30 mL) was added methanesulfonyl chloride (1.54
mL) under ice-cooling, and the mixture was stirred at 30 min. To
the reaction system was added aqueous sodium hydrogen carbonate and
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over magnesium sulfate. After
concentration under reduced pressure,
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.02 g), cesium carbonate
(6.49 g) and N,N-dimethylformamide (10 mL) were added to the
residue, and the mixture was stirred at 40.degree. C. for 3 days.
Water was added to the reaction system and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine and dried over magnesium sulfate. After
concentration under reduced pressure, the residue was separated and
purified by silica gel column chromatography (hexane:ethyl
acetate=3:1.fwdarw.2:3) to give the title compound (1.16 g) as a
pale-yellow oil.
[1316] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93-1.35 (12H, m),
4.02-4.18 (1.5H, m), 4.39-4.53 (1.5H, m), 4.57-4.70 (1H, m), 6.74
(1H, d, J=3.0 Hz), 7.50 (1H, d, J=3.0 Hz), 8.71 (1H, s).
(ii) Production of
5-(2-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-py-
rrolo[3,2-d]pyrimidin-4-amine dihydrochloride
[1317] A solution of tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1-methylethyl]carbamate
(350 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (423
mg) in 1-methyl-2-pyrrolidone (3.5 mL) was stirred at 120.degree.
C. for 4 hrs. After cooling to room temperature, triethylamine
(0.24 mL) and di-tert-butyl dicarbonate (0.13 mL) were added, and
the mixture was stirred for 20 hrs. Water was added to the reaction
system and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine and dried
over magnesium sulfate. The residue was separated and purified by
silica gel column chromatography (hexane:ethyl
acetate=19:1.fwdarw.3:2.fwdarw.ethyl acetate) to give a brown
solid. To a solution of the obtained solid in tetrahydrofuran (20
mL) was added 2N hydrochloric acid (10 mL) at room temperature, and
the mixture was stirred at 60.degree. C. for 20 hrs. After
concentration under reduced pressure, ethanol was added and the
mixture was further concentrated. To the residue was added
diisopropyl ether, and the precipitated crystals were collected by
filtration. The crystals were washed with diisopropyl ether to give
the title compound (225 mg) as pale-yellow crystals.
[1318] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.17 (3H, d, J=6.6 Hz),
3.35-3.77 (1H, m), 4.75-4.89 (1H, m), 4.98-5.09 (1H, m), 6.75 (1H,
d, J=2.7 Hz), 7.23-7.30 (2H, m), 7.37 (1H, d, J=8.7 Hz), 7.52-7.54
(1H, m), 7.64-7.69 (2H, m), 7.89-7.97 (1H, m), 8.04-8.10 (1H, m),
8.24-8.43 (3H, m), 8.74 (1H, s), 10.04 (1H, br s).
(iii) Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]-1-methylethyl}-2-(methylsulfonyl)acetamide
[1319] The title compound (34 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-py-
rrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
2-(methylsulfonyl)acetic acid (77 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160
mg), 1-hydroxybenzotriazole monohydrate (128 mg), triethylamine
(0.39 mL) and N,N-dimethylformamide (5.0 mL).
[1320] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (3H, d, J=6.6 Hz),
3.14 (3H, s), 3.71-3.80 (1H, m), 4.00 (2H, s), 4.12-4.26 (1H, m),
4.98-5.04 (1H, m), 6.62 (1H, d, J=3.3 Hz), 6.82-6.88 (1H, m), 7.07
(1H, d, J=8.7 Hz), 7.12-7.24 (3H, m), 7.30-7.35 (1H, m), 7.41-7.49
(1H, m), 7.79 (1H, dd, J=8.7, 2.7 Hz), 7.95 (1H, d, J=2.7 Hz), 8.52
(1H, s), 8.54 (1H, br s).
Example 221
##STR00269##
[1321] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide
methanesulfonate
[1322] To a solution of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide (200 mg)
in ethyl acetate (10 mL) was added methanesulfonic acid (26 .mu.L)
at room temperature. The mixture was stirred at room temperature
for 1 hr and concentrated under reduced pressure. To the residue
were added ethanol and ethyl acetate, and the precipitated crystals
were collected by filtration to give the title compound (223 mg) as
colorless crystals.
[1323] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.12 (6H, s), 2.21 (2H,
s), 2.29 (3H, s), 3.41-3.54 (2H, m), 4.56-4.68 (2H, m), 6.66 (1H,
d, J=3.3 Hz), 7.26-7.28 (2H, m), 7.37 (1H, d, J=9.0 Hz), 7.51-7.54
(1H, m), 7.61-7.75 (2H, m), 7.95-8.03 (2H, m), 8.31-8.40 (1H, m),
8.72 (1H, s), 10.11-10.19 (1H, m).
Example 222
##STR00270##
[1324] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N-ethyl-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]ethylcarbamate
[1325] The title compound (630 mg) was obtained as a pale-yellow
oil by the reaction in the same manner as in Example 163 (i) using
2-(ethylamino)ethanol (1.00 g), di-tert-butyl dicarbonate (2.58
mL), tetrahydrofuran (100 mL), methanesulfonyl chloride (1.30 mL),
triethylamine (3.12 mL), tetrahydrofuran (50 mL),
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.86 g), cesium carbonate
(7.5 g) and N,N-dimethylformamide (20 mL).
[1326] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.84-1.48 (12H, m),
2.80-2.93 (1H, m), 3.07-3.22 (1H, m), 3.51-3.67 (2H, m), 4.52-4.72
(2H, m), 6.73 (1H, d, J=3.3 Hz), 7.29-7.47 (1H, m), 8.71 (1H,
s).
(ii) Production of tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}ethylcarbamate
[1327] The title compound (950 mg) was obtained as a colorless
solid by the reaction in the same manner as in Example 155 (ii)
using tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]ethylcarbamate
(630 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (725 mg)
and isopropyl alcohol (6.0 mL).
[1328] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, t, J=7.2 Hz),
1.52 (9H, s), 3.35 (2H, q, J=7.2 Hz), 3.49-3.58 (2H, m), 4.41-4.51
(2H, m), 6.60 (1H, d, J=3.0 Hz), 7.07 (1H, d, J=9.0 Hz), 7.09-7.15
(1H, m), 7.18-7.22 (2H, m), 7.29-7.33 (1H, m), 7.39-7.45 (1H, m),
7.93 (1H, d, J=9.0, 2.4 Hz), 8.04 (1H, d, J=2.4 Hz), 8.51 (1H, s),
8.92 (1H, br s).
(iii) Production of
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(ethylamino)ethyl]-
-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride
[1329] The title compound (861 mg) was obtained as pale-yellow
crystals by the reaction in the same manner as in Example 155 (iii)
using tert-butyl
{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}ethylcarbamate (950 mg), 2N hydrochloric
acid (5.0 mL) and tetrahydrofuran (10 mL).
[1330] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.18 (3H, t, J=7.5 Hz),
2.89-3.02 (2H, m), 3.33-3.47 (2H, m), 5.03-5.12 (2H, m), 6.72-6.77
(1H, m), 7.22-7.29 (2H, m), 7.37 (1H, d, J=9.0 Hz), 7.51-7.54 (1H,
m), 7.61-7.71 (2H, m), 7.91-7.98 (1H, m), 8.04-8.10 (1H, m), 8.72
(1H, s), 9.05-9.21 (2H, m), 9.95-10.05 (1H, m).
(iv) Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N-ethyl-2-(methylsulfonyl)acetamide
[1331] The title compound (94 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(ethylamino)ethyl]-
-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
2-(methylsulfonyl)acetic acid (76 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158
mg), 1-hydroxybenzotriazole monohydrate (126 mg), triethylamine
(0.38 mL) and N,N-dimethylformamide (5.0 mL).
[1332] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36 (3H, t, J=7.2 Hz),
3.20 (3H, s), 3.61 (2H, q, J=7.2 Hz), 3.71-3.80 (2H, m), 4.15 (2H,
s), 4.45-4.53 (2H, m), 6.64 (1H, d, J=3.3 Hz), 7.08 (1H, d, J=8.7
Hz), 7.10-7.17 (1H, m), 7.19-7.23 (2H, m), 7.30-7.35 (1H, m),
7.40-7.46 (1H, m), 7.89 (1H, dd, J=8.7, 2.7 Hz), 7.96 (1H, d, J=2.7
Hz), 8.53 (1H, s), 8.60 (1H, s).
Example 223
##STR00271##
[1333] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N-ethyl-3-hydroxy-3-methylbutanamide
[1334] The title compound (106 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(ethylamino)ethyl]-
-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
3-hydroxy-3-methylbutyric acid (64.6 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (157
mg), 1-hydroxybenzotriazole monohydrate (125 mg), triethylamine
(0.38 mL) and N,N-dimethylformamide (5.0 mL).
[1335] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, t, J=7.2 Hz),
1.34 (6H, s), 2.56 (2H, s), 3.47 (2H, q, J=7.2 Hz), 3.65-3.75 (2H,
m), 4.42-4.52 (3H, m), 6.62 (1H, d, J=3.0 Hz), 7.08 (1H, d, J=8.7
Hz), 7.10-7.15 (1H, m), 7.20 (1H, d, J=3.0 Hz), 7.24-7.33 (2H, m),
7.39-7.46 (1H, m), 7.72 (1H, dd, J=8.7, 2.4 Hz), 8.03 (1H, d, J=2.4
Hz), 8.50 (1H, s), 8.81 (1H, s).
Example 224
##STR00272##
[1336] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-(dimethylamino)acetamide
[1337] The title compound (84 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
N,N-dimethylglycine (59.4 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166
mg), 1-hydroxybenzotriazole monohydrate (132 mg), triethylamine
(0.40 mL) and N,N-dimethylformamide (5.0 mL).
[1338] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.29 (6H, s), 3.05 (2H,
s), 3.58-3.70 (2H, m), 4.45-4.54 (2H, m), 6.63 (1H, d, J=3.0 Hz),
7.08 (1H, d, J=9.0 Hz), 7.10-7.15 (1H, m), 7.20 (1H, d, J=3.0 Hz),
7.23-7.34 (2H, m), 7.36-7.45 (1H, m), 7.70-7.79 (2H, m), 8.10 (1H,
d, J=2.7 Hz), 8.52 (1H, s), 8.63 (1H, s).
Example 225
##STR00273##
[1339] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-methyl-1,3-oxazole-4-carboxamide
[1340] The title compound (112.1 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (210 mg),
2-methyl-1,3-oxazole-4-carboxylic acid (210 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (560
mg), 1-hydroxybenzotriazole monohydrate (100 mg), triethylamine
(2.0 mL) and tetrahydrofuran (10 mL).
[1341] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.41 (3H, s), 3.56 (2H,
m), 4.67 (2H, m), 6.53 (1H, d, J=3 Hz), 7.21-7.91 (8H, m), 8.30
(1H, s), 8.42 (2H, m), 8.87 (1H, br s).
Example 226
##STR00274##
[1342] Production of
N-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-2,2,2-trifluoroethanesulfonamide
(i) Production of
2-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione
[1343] The title compound (5.20 g) was obtained by the reaction in
the same manner as in Example 172 (i) using
2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethoxy}ethanol (4.00 g), tetrahydrofuran (25
mL), triethylamine (13.0 mL), methanesulfonyl chloride (7.25 mL),
potassium phthalimide (4.51 g), tetrahydrofuran (60 mL) and
N,N-dimethylformamide (50 mL).
[1344] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.69 (4H, s), 3.83 (2H,
m), 4.61 (2H, m), 6.33 (1H, m), 7.13-7.23 (3H, m), 7.42-7.95 (9H,
m), 8.24 (1H, s), 8.75 (1H, s).
(ii) Production of
N-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-2,2,2-trifluoroethanesulfonamide
[1345]
2-(2-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-
H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione
(100 mg) was dissolved in ethanol (2.0 mL), hydrazine monohydrate
(0.45 mL) was added, and the mixture was stirred for 1 hr. To the
reaction mixture was added saturated aqueous sodium hydrogen
carbonate under ice-cooling, and the mixture was extracted with
ethyl acetate. The extract was dried over magnesium sulfate and
concentrated, and the residue was separated and purified by basic
silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=95:5). The
obtained oil was dissolved in tetrahydrofuran (5.0 mL).
N-Methylmorpholine (2.0 mL) was added,
2,2,2-trifluoroethanesulfonyl chloride (0.10 mL) was added dropwise
under ice-cooling, and the mixture was stirred for 1 hr. Under
ice-cooling, saturated aqueous sodium hydrogen carbonate was added,
and the mixture was extracted with dichloromethane. The extract was
dried over magnesium sulfate and concentrated, and the residue was
separated and purified by silica gel column chromatography (eluent,
ethyl acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=80:20).
Crystallization from diethyl ether/ethyl acetate gave the title
compound (36.0 mg) as crystals.
[1346] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.10 (2H, m), 3.47 (2H,
m), 3.79 (2H, m), 4.30 (2H, m), 4.68 (2H, m), 6.52 (1H, m),
7.20-8.02 (9H, m), 8.35 (1H, s), 8.79 (1H, s).
Example 227
##STR00275##
[1347] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}acetamide
[1348] The title compound (62.1 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (270 mg), acetic acid
(0.20 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (500 mg), 1-hydroxybenzotriazole monohydrate (100
mg), triethylamine (2.0 mL) and tetrahydrofuran (10 mL).
[1349] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.79 (3H, s), 3.37 (2H,
m), 4.51 (2H, m), 6.51 (1H, d, J=3 Hz), 7.20-7.81 (7H, m), 8.06
(1H, m), 8.26 (1H, m), 8.34 (1H, s), 8.81 (1H, s).
Example 228
##STR00276##
[1350] Production of
N-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-2-(methylsulfonyl)acetamide
hydrochloride
[1351]
2-(2-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-
H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione
(600 mg) was dissolved in ethanol (30 mL), hydrazine monohydrate
(8.0 mL) was added, and the mixture was stirred for 1 hr. To the
reaction mixture was added saturated aqueous sodium hydrogen
carbonate under ice-cooling and the mixture was extracted with
ethyl acetate. The extract was dried over magnesium sulfate and
concentrated, and the residue was separated and purified by basic
silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=95:5). The
title compound (312 mg) was obtained as colorless crystals by the
reaction in the same manner as in Example 155 (iv) using the
obtained oil, 2-(methylsulfonyl)acetic acid (500 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.50
g), 1-hydroxybenzotriazole monohydrate (200 mg), triethylamine (2.0
mL) and tetrahydrofuran (20 mL).
[1352] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.06 (3H, s), 3.16-3.47
(4H, m), 3.81 (2H, m), 3.98 (2H, s), 4.86 (2H, s), 6.70 (1H, m),
7.25-7.68 (6H, m), 7.97-8.01 (2H, m), 8.44 (1H, m), 8.75 (1H, s),
9.90 (1H, s).
Example 229
##STR00277##
[1353] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-1H-pyrazole-3-carboxamide
[1354] The title compound (67.0 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (250 mg),
1H-pyrazole-3-carboxylic acid (210 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (500
mg), 1-hydroxybenzotriazole monohydrate (100 mg), triethylamine
(2.0 mL) and tetrahydrofuran (15 mL).
[1355] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.58 (2H, m), 4.64 (2H,
m), 6.49 (1H, m), 6.57 (1H, s), 7.21-7.79 (8H, m), 8.01 (1H, s),
8.33 (1H, s), 8.49 (1H, m), 8.77 (1H, s), 13.25 (1H, s).
Example 230
##STR00278##
[1356] Production of
(2R)--N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-p-
yrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,3-dihydroxypropanamide
[1357] The title compound (197.3 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (350 mg),
(2R)-2,3-dihydroxypropanoic acid (400 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.70
g), 1-hydroxybenzotriazole monohydrate (1.0 g), triethylamine (2.0
mL) and tetrahydrofuran (10 mL).
[1358] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.33-3.58 (4H, m), 3.87
(1H, m), 4.53 (2H, m), 4.69 (1H, m), 5.62 (1H, d, J=5 Hz), 6.48
(1H, d, J=3 Hz), 7.20-7.81 (7H, m), 8.05 (1H, d, J=2 Hz), 8.14 (1H,
m), 8.34 (1H, s), 8.77 (1H, s).
Example 231
##STR00279##
[1359] Production of
N-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)methanesulfonamide
[1360] The title compound (18.2 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 226 (ii)
using
2-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione
(200 mg), hydrazine monohydrate (1.50 mL), methanesulfonyl chloride
(0.70 mL), N-methylmorpholine (1.20 mL), ethanol (7.0 mL) and
tetrahydrofuran (10 mL).
[1361] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.78 (3H, s), 3.04 (2H,
m), 3.48 (2H, m), 3.79 (2H, m), 4.68 (2H, m), 6.52 (1H, d, J=3 Hz),
7.03-7.70 (8H, m), 8.02 (1H, s), 8.35 (1H, s), 8.81 (1H, s).
Example 232
##STR00280##
[1362] Production of
N-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)acetamide
[1363]
2-(2-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5-
H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione
(200 mg) was dissolved in ethanol (5.0 mL), hydrazine monohydrate
(3.0 mL) was added, and the mixture was stirred for 1 hr. To the
reaction mixture was added saturated aqueous sodium hydrogen
carbonate under ice-cooling and the mixture was extracted with
ethyl acetate. The extract was dried over magnesium sulfate and
concentrated, and the residue was separated and purified by basic
silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=95:5). The
title compound (146.0 mg) was obtained as colorless crystals by the
reaction in the same manner as in Example 180 using the obtained
oil, acetic anhydride (1.0 mL), N-methylmorpholine (1.0 mL) and
tetrahydrofuran (5.0 mL).
[1364] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.69 (3H, s), 3.12 (2H,
m), 3.44 (2H, m), 3.79 (2H, m), 4.66 (2H, m), 6.52 (1H, d, J=3 Hz),
7.20-7.78 (8H, m), 8.00 (1H, s), 8.36 (1H, s), 8.85 (1H, s).
Example 233
##STR00281##
[1365] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N2-(methylsulfonyl)glycinamide
[1366] Using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (450 mg),
N-(tert-butoxy carbonyl)glycine (500 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (960
mg), 1-hydroxybenzotriazole monohydrate (300 mg), triethylamine
(4.0 mL) and tetrahydrofuran (25 mL), the reaction was performed in
the same manner as in Example 155 (iv). The obtained compound was
dissolved in methanol (5.0 mL), 4N hydrochloric acid/ethyl acetate
(8 mL) was added, and the mixture was stirred for 5 hrs. 8N Aqueous
sodium hydroxide solution (8 mL) and water (10 mL) were added and
the mixture was extracted with dichloromethane. The extract was
dried over magnesium sulfate and concentrated, and the residue was
dissolved in tetrahydrofuran (5.0 mL). N-Methylmorpholine (1.0 mL)
was added, methanesulfonyl chloride (0.70 mL) was added dropwise
under ice-cooling, and the mixture was stirred for 1 hr. Under
ice-cooling, saturated aqueous sodium hydrogen carbonate was added
and the mixture was extracted with dichloromethane. The extract was
dried over magnesium sulfate and concentrated, and the residue was
separated and purified by silica gel column chromatography (eluent,
ethyl acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=80:20),
and crystallized from diethyl ether/ethyl acetate to give the title
compound (47.9 mg) as crystals.
[1367] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.89 (3H, s), 3.46 (2H,
m), 3.58 (2H, m), 4.54 (2H, m), 6.51 (1H, d, J=3 Hz), 7.20-7.78
(8H, m), 8.02 (1H, s), 8.27 (1H, m), 8.36 (1H, s), 8.77 (1H,
s).
Example 234
##STR00282##
[1368] Production of tert-butyl
4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)acetyl]amino}ethyl)-5H-pyrrolo[3,2-
-d]pyrimidin-4-yl]amino}phenoxy)piperidine-1-carboxylate
(i) Production of
N-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)a-
cetamide
[1369] tert-Butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (300
mg) was dissolved in trifluoroacetic acid (5.0 mL), and the mixture
was stirred for 15 min. Toluene (5 mL) was added, the solvent was
evaporated, and the residue was separated and purified by basic
silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=75:25). The
title compound (64.0 mg) as colorless crystals were obtained by the
reaction in the same manner as in Example 155 (iv) using obtained
oil, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(2.50 g), triethylamine (2.0 mL), 2-(methylsulfonyl)acetic acid
(180 mg) and tetrahydrofuran (10 mL).
[1370] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.07 (3H, s), 3.57 (2H,
m), 4.00 (2H, s), 4.57 (2H, m), 6.74 (1H, d, J=3 Hz), 7.92 (1H, d,
J=3 Hz), 8.49 (1H, m), 8.63 (1H, s).
(ii) Production of tert-butyl
4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)acetyl]amino}ethyl)-5H-pyrrolo[3,2-
-d]pyrimidin-4-yl]amino}phenoxy)piperidine-1-carboxylate
[1371] The title compound (24.0 mg) was obtained as colorless
crystals by the reaction in the same manner as in Example 155 (ii)
using
N-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)a-
cetamide (60.0 mg) and tert-butyl
4-(4-amino-2-chlorophenoxy)piperidine-1-carboxylate (160 mg).
[1372] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.41 (9H, s), 1.50-1.70
(2H, m), 1.81-1.95 (2H, m), 3.10 (3H, s), 3.22-3.60 (6H, m), 4.04
(2H, s), 4.45-4.65 (3H, m), 6.47 (1H, d, J=3 Hz), 7.23 (1H, d, J=9
Hz), 7.55-7.58 (2H, m), 7.75 (1H, d, J=3 Hz), 8.27 (1H, s), 8.48
(1H, s), 8.66 (1H, m).
Example 235
##STR00283##
[1373] Production of
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]propanamide
hydrochloride
(i) Production of ethyl
3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propanoate
[1374] 4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (303 mg) was dissolved
in N,N-dimethylformamide (9 mL), ethyl acrylate (0.3 mL) and
potassium carbonate (538 mg) were sequentially added, and the
mixture was stirred at room temperature for 7.5 hrs. Ethyl acrylate
(0.2 mL) was added, and the mixture was stirred for 16 hrs. Ethyl
acrylate (0.3 mL) and potassium carbonate (526 mg) were further
added, and the mixture was stirred for 6 hrs. The reaction mixture
was treated with saturated aqueous ammonium chloride solution and
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was separated
and purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=66:34.fwdarw.20:80) to give the title compound
(404 mg) as a colorless oil.
[1375] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, t, J=7.1 Hz),
2.92 (2H, t, J=6.3 Hz), 4.13 (2H, q, J=7.1 Hz), 4.80 (2H, t, J=6.3
Hz), 6.70 (1H, d, J=3.3 Hz), 7.61 (1H, d, J=3.3 Hz), 8.71 (1H,
s).
(ii) Production of ethyl
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]propanoate
[1376] The title compound (687 mg) was obtained as a pale-yellow
oil by the reaction in the same manner as in Example 201 (iii)
using ethyl 3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propanoate
(404 mg), isopropyl alcohol (10 mL) and
3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (555 mg).
[1377] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (3H, t, J=7 Hz),
2.99-3.10 (2H, m), 4.24 (2H, q, J=7 Hz), 4.53-4.65 (2H, m), 6.69
(1H, d, J=3.3 Hz), 7.06-7.17 (2H, m), 7.18-7.24 (1H, m), 7.27-7.35
(2H, m), 7.43 (1H, t, J=7.9 Hz), 7.65 (1H, dd, J=8.8 Hz, 2.6 Hz),
7.92 (1H, d, J=2.6 Hz), 8.54 (1H, s), 9.14 (1H, s).
(iii) Production of
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]propanoic acid
[1378] The title compound (595 mg) was obtained as a pale-yellow
powder by the reaction in the same manner as in Example 202 (ii)
using a mixed solvent of ethyl
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]propanoate (683 mg), 1N aqueous sodium hydroxide
solution (2 mL) and tetrahydrofuran (6 mL)/ethanol (6 mL).
[1379] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.84 (2H, t, J=6.4 Hz),
4.69 (2H, t, J=6.4 Hz), 6.52 (1H, d, J=3.0 Hz), 7.14-7.29 (2H, m),
7.32 (1H, d, J=8.9 Hz), 7.47 (1H, d, J=7.7 Hz), 7.56-7.80 (3H, m)
7.94 (1H, s), 8.35 (1H, s), 9.10 (1H, s), 12.72 (1H, s)
(iv) Production of
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]propanamide
hydrochloride
[1380]
3-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]propanamide
(140 mg) was obtained by the reaction in the same manner as in
Example 202 (iii) using
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrr-
olo[3,2-d]pyrimidin-5-yl]propanoic acid (199 mg),
2-(methylsulfonyl)ethanamine (106 mg), 1-hydroxybenzotriazole
monohydrate (84.7 mg),
N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride
(128.6 mg), triethylamine (0.1 mL) and N,N-dimethylformamide (2
mL). The obtained
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-p-
yrrolo[3,2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]propanamide
was dissolved in ethyl acetate (2 mL), 4N hydrochloric acid-ethyl
acetate (0.1 mL) was added, and the precipitate was collected by
filtration and dried to give the title compound (119 mg) as a white
powder.
[1381] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.82-2.90 (2H, m), 2.91
(3H, s), 3.18 (2H, t, J=6.6 Hz), 3.40-3.51 (2H, m), 4.72-4.83 (2H,
m), 6.70 (1H, d, J=3.0 Hz), 7.23-7.32 (2H, m), 7.41 (1H, d, J=8.8
Hz), 7.52 (1H, d, J=7.7 Hz), 7.66 (1H, t, J=7.7 Hz), 7.74 (1H, dd,
J=8.8 Hz, 2.5 Hz), 8.01-8.08 (2H, m), 8.67 (1H, t, J=5.6 Hz), 8.76
(1H, s), 10.80 (1H, s).
Example 236
##STR00284##
[1382] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide
hydrochloride
[1383]
N-{2-[4-({3-Chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H--
pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide was
obtained by the reaction in the same manner as in Example 202 (iii)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-py-
rrolo[3,2-d]pyrimidin-4-amine dihydrochloride (303 mg), 3.6M
aqueous solution (0.25 mL) of 3-hydroxypropanoic acid,
1-hydroxybenzotriazole monohydrate (231 mg),
N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (322
mg), triethylamine (0.8 mL) and N,N-dimethylformamide (3 mL). The
obtained
N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrol-
o[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide was dissolved in
ethyl acetate (2 mL), 4N hydrochloric acid-ethyl acetate (0.1 mL)
was added, and the obtained product was crystallized from ethyl
acetate to give the title compound (80.9 mg) as white crystals.
[1384] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.21 (2H, t, J=6.5 Hz),
3.39-3.51 (2H, m), 3.54 (2H, t, J=6.5 Hz), 4.67 (2H, t, J=7.0 Hz),
6.68 (1H, t, J=3.0 Hz), 6.94-7.04 (2H, m), 7.16 (1H, d, J=8.3 Hz),
7.36 (1H, d, J=8.8 Hz), 7.54 (1H, t, J=8.3 Hz), 7.72 (1H, dd, J=8.8
Hz, 2.6 Hz), 7.93-8.04 (2H, m), 8.36 (1H, t, J=5.8 Hz), 8.74 (1H,
s), 10.23 (1H, s).
Example 237
##STR00285##
[1385] Production of
5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]pentane-1,2-diol
(i) Production of 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol
[1386] Pentane-1,2,5-triol (5.00 g) was dissolved in acetone (150
mL), 2,2-dimethoxypropane (10.5 mL) and 4-methylbenzenesulfonic
acid (794 mg) were added, and the mixture was stirred at room
temperature for 1.5 hrs. The reaction mixture was concentrated
under reduced pressure, and the residue was separated and purified
by silica gel column chromatography (eluent, hexane:ethyl
acetate=80:20.fwdarw.50:50) to give the title compound (3.79 g) as
a colorless oil.
[1387] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.37 (3H, s), 1.42 (3H,
s), 1.57-1.77 (4H, m), 2.05 (1H, br s), 3.53 (1H, t, J=7.3 Hz),
3.60-3.77 (2H, m), 4.00-4.21 (2H, m).
(ii) Production of 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl
methanesulfonate
[1388] The title compound (2.13 g) was obtained as a colorless oil
by the reaction in the same manner as in Example 203 (ii) using
3-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol (2.30 g),
methanesulfonyl chloride (0.8 mL), triethylamine (3.0 mL) and ethyl
acetate (50 mL).
[1389] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35 (3H, s), 1.41 (3H,
s), 1.62-1.73 (2H, m), 1.75-2.02 (2H, m), 3.02 (3H, m), 3.50-3.57
(1H, m), 4.02-4.17 (2H, m), 4.21-4.36 (2H, m).
(iii) Production of
4-chloro-5-[3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3,2-d]py-
rimidine
[1390] The title compound (176 mg) was obtained as a white powder
by the reaction in the same manner as in Example 201 (ii) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (151 mg),
3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl methanesulfonate (319 mg),
cesium carbonate (574 mg) and N,N-dimethylformamide (1.5 mL).
[1391] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34 (3H, s), 1.40 (3H,
s), 1.53-1.73 (2H, m) 1.80-2.13 (2H, m), 3.47-3.53 (1H, m),
3.97-4.18 (2H, m), 4.41-4.70 (2H, m), 6.72 (1H, d, J=3.3 Hz), 7.51
(1H, d, J=3.3 Hz), 8.70 (1H, s).
(iv) Production of
5-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]pentane-1,2-diol
[1392] The crude product was obtained by the reaction in the same
manner as in Example 201 (iii) using
4-chloro-5-[3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3,2-d]py-
rimidine (171 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline
(195 mg) and isopropyl alcohol (3.5 mL). The crude product was
dissolved in methanol (1 mL), 1N hydrochloric acid (0.5 mL) was
added, and the mixture was stirred at room temperature for 3.5 hrs.
The reaction mixture was treated with 1N aqueous sodium hydroxide
solution, extracted with ethyl acetate, washed with saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was separated and purified by
silica gel column chromatography (eluent, ethyl
acetate:methanol=100:0.fwdarw.95:5) to give the title compound (179
mg) as white crystals.
[1393] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.03-1.41 (2H, m),
1.61-1.93 (2H, m), 3.08-3.28 (2H, m), 3.28-3.43 (1H, m), 4.44 (1H,
t, J=5.5 Hz), 4.47-4.59 (3H, m), 6.49 (1H, d, J=3.0 Hz), 7.17-7.27
(2H, m), 7.30 (1H, d, J=9.1 Hz), 7.47 (1H, d, J=8.5 Hz), 7.57-7.74
(3H, m), 7.97 (1H, d, J=2.4 Hz), 8.34 (1H, s), 8.61 (1H, s).
Example 238
##STR00286##
[1394] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide hydrochloride
[1395]
N-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-p-
yrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide was
obtained by the reaction in the same manner as in Example 202 (iii)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (300 mg), 3.6 M
aqueous solution (0.25 mL) of 3-hydroxypropanoic acid,
1-hydroxybenzotriazole monohydrate (231 mg),
N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (330
mg), triethylamine (0.8 mL) and N,N-dimethylformamide (3 mL). The
obtained
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide was dissolved in
ethyl acetate (2 mL), and 4N hydrochloric acid-ethyl acetate (0.1
mL) was added. The obtained product was recrystallized from ethyl
acetate to give the title compound (63.1 mg) as a white powder.
[1396] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.22 (2H, t, J=6.5 Hz),
3.39-3.52 (2H, m), 3.55 (2H, t, J=6.5 Hz), 4.65 (2H, t, J=6.7 Hz),
6.67 (1H, d, J=3.0 Hz), 7.24-7.32 (2H, m), 7.37 (1H, d, J=8.8 Hz),
7.53 (1H, d, J=8.0 Hz), 7.66 (1H, t, J=8.0 Hz), 7.72 (1H, dd, J=8.8
Hz, 2.5 Hz), 7.96-8.01 (2H, m), 8.34 (1H, t, J=5.8 Hz), 8.74 (1H,
s), 10.17 (1H, s).
Example 239
##STR00287##
[1397] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3,3,3-trifluoropropanamide
[1398] The title compound (64.0 mg) was obtained as yellow crystals
by the reaction in the same manner as in Example 202 (iii) using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg),
3,3,3-trifluoropropanoic acid (0.06 mL), 1-hydroxybenzotriazole
monohydrate (142 mg),
N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (200
mg), triethylamine (0.4 mL) and N,N-dimethylformamide (1.5 mL) and
crystallization from diisopropyl ether.
[1399] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.19 (2H, q, J=11.2 Hz)
3.43 (2H, m), 4.58 (2H, t, J=6.4 Hz), 6.52 (1H, d, J=3.0 Hz),
7.18-7.26 (2H, m), 7.30 (1H, d, J=9 Hz), 7.47 (1H, d, J=7.5 Hz),
7.57-7.67 (2H, m), 7.76 (1H, dd, J=9 Hz, 2.5 Hz), 8.00 (1H, d,
J=2.5 Hz), 8.36 (1H, s), 8.50 (1H, t, J=5.3 Hz), 8.72 (1H, s).
Example 240
##STR00288##
[1400] Production of
3-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethoxy}propane-1,2-diol hydrochloride
(i) Production of tert-butyl
{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethoxy}dimethylsilane
[1401] 60% Sodium hydride (890 mg) was suspended in
N,N-dimethylformamide (60 mL), and the suspension was cooled to
0.degree. C. (2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (2.3 mL) was
added dropwise and the mixture was stirred at 0.degree. C. for 1
hr. To the reaction mixture was added
(2-bromoethoxy)(tert-butyl)dimethylsilane (3 mL), and the mixture
was stirred at 0.degree. C. for 2 hrs. To the reaction mixture was
added saturated aqueous ammonium chloride solution, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was separated and
purified by silica gel column chromatography (eluent, hexane:ethyl
acetate=100:0.fwdarw.90:10) to give the title compound (1.04 g) as
a yellow oil.
[1402] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.06 (6H, s), 0.89 (9H,
s), 1.36 (3H, s), 1.42 (3H, s), 3.47-3.63 (4H, m) 3.71-3.79 (3H,
m), 4.06 (1H, dd, J=8.2 Hz, 6.3 Hz), 4.20-4.35 (1H, m).
(ii) Production of 2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl
methanesulfonate
[1403]
tert-Butyl{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethoxy}dimeth-
ylsilane (1.03 g) was dissolved in tetrahydrofuran (20 mL), a 1.0 M
solution (4 mL) of tetrabutylammonium fluoride in tetrahydrofuran
was added, and the mixture was stirred at room temperature for 1
hr. To the reaction mixture was added saturated aqueous ammonium
chloride solution, and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was dissolved in ethyl acetate (20 mL) and
subjected the reaction similar to that in Example 203 (ii) using
methanesulfonyl chloride (0.3 mL) and triethylamine (2 mL) to give
the title compound (857 mg) as a yellow oil.
[1404] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36 (3H, s), 1.42 (3H,
s), 3.07 (3H, s), 3.56 (1H, d, J=1.4 Hz), 3.58 (1H, d, J=1.9 Hz),
3.73 (1H, dd, J=8.3 Hz, 6.3 Hz), 3.77-3.82 (2H, m), 4.06 (1H, dd,
J=8.3 Hz, 6.3 Hz), 4.24-4.33 (1H, m), 4.35-4.41 (2H, m).
(iii) Production of
4-chloro-5-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5H-pyrrolo[-
3,2-d]pyrimidine
[1405] The title compound (298 mg) was obtained as a colorless oil
by the reaction in the same manner as in Example 201 (ii) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (152 mg),
2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl methanesulfonate
(327 mg), cesium carbonate (576 mg) and N,N-dimethylformamide (1.5
mL).
[1406] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (3H, s), 1.38 (3H,
s), 3.37-3.50 (2H, m), 3.59 (1H, dd, J=8.3 Hz, 6.6 Hz), 3.87 (2H,
dt, J=5.1 Hz, 2.2 Hz), 3.96 (1H, dd, J=8.3 Hz, 6.6 Hz), 4.11-4.22
(1H, m), 4.66-4.72 (2H, m), 6.71 (1H, d, J=3 Hz), 7.57 (1H, d, J=3
Hz), 8.70 (1H, s).
(iv) Production of
3-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethoxy}propane-1,2-diol hydrochloride
[1407]
3-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-p-
yrrolo[3,2-d]pyrimidin-5-yl]ethoxy}propane-1,2-diol was obtained by
the reaction in the same manner as in Example 237 (iv) using
4-chloro-5-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5H-pyrrolo[-
3,2-d]pyrimidine (295 mg),
3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (359 mg) and
isopropyl alcohol (6 mL). The obtained
3-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-O]pyrimidin-5-yl]ethoxy}propane-1,2-diol was dissolved in
ethyl acetate (6 mL), 4N hydrochloric acid-ethyl acetate (0.2 mL)
was added, and the mixture was concentrated under reduced pressure.
The residue was crystallized from ethyl acetate to give the title
compound (360 mg) as a white powder.
[1408] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.10-3.26 (2H, m),
3.31-3.42 (1H, m), 3.42-3.56 (2H, m), 3.78-3.89 (2H, m), 4.77-4.89
(2H, m), 6.71 (1H, d, J=3.0 Hz), 7.22-7.31 (2H, m), 7.36 (1H, d,
J=8.8 Hz), 7.52 (1H, d, J=7.7 Hz), 7.60-7.73 (2H, m), 7.96-8.06
(2H, m), 8.75 (1H, s), 9.96 (1H, s).
Example 241
##STR00289##
[1409] Production of
N-[2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl]amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-2-cyanoacetamide
[1410] The title compound (104 mg) was obtained as a yellow powder
by the reaction in the same manner as in Example 202 (iii) using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (201 mg), cyanoacetic
acid (65.9 mg), 1-hydroxybenzotriazole monohydrate (215 mg),
N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (300
mg), triethylamine (0.55 mL) and N,N-dimethylformamide (2.0 mL) and
crystallization from diisopropyl ether.
[1411] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.36-3.47 (2H, m), 3.56
(2H, s), 4.58 (2H, t, J=6.3 Hz), 6.52 (1H, d, J=3.3 Hz), 7.18-7.28
(2H, m), 7.31 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=7.7 Hz), 7.56-7.68
(2H, m), 7.73 (1H, dd, J=8.8 Hz, 2.5 Hz), 7.99 (1H, d, J=2.5 Hz),
8.36 (1H, s), 8.44 (1H, t, J=5.8 Hz), 8.67 (1H, s).
Example 242
##STR00290##
[1412] Production of
N-{4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]but-2-yn-1-yl}-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl (4-chlorobut-2-yn-1-yl)carbamate
[1413] 4-Chlorobut-2-yn-1-amine hydrochloride (10.5 g) was
dissolved in a mixed solvent of water (200 mL)/methanol (40 mL),
di-tert-butyl dicarbonate (19 mL) was added, and the mixture was
stirred at room temperature for 2 hrs. In this case, the reaction
solution was maintained at pH 10-11 with 4N aqueous sodium
hydroxide solution. Water was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was separated
and purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=100:0.fwdarw.80:20) to give the title compound
(14.5 g) as a pale-yellow oil.
[1414] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (9H, s), 3.89-4.06
(2H, m), 4.14 (2H, t, J=2.1 Hz), 4.71 (1H, br s).
(ii) Production of tert-butyl
[4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)but-2-yn-1-yl]carbamate
[1415] A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.51 g),
tert-butyl (4-chlorobut-2-yn-1-yl)carbamate (2.60 g), cesium
carbonate (4.80 g) and N,N-dimethylformamide (15 mL) was stirred at
room temperature for 2 hrs. Water was added to the reaction mixture
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
separated and purified by silica gel column chromatography (eluent,
hexane:ethyl acetate=80:20.fwdarw.33:67) to give the title compound
(2.61 g) as an orange oil.
[1416] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (9H, s), 3.87-4.05
(2H, m), 4.71 (1H, s), 5.29 (2H, t, J=2.1 Hz), 6.76 (1H, d, J=3.3
Hz), 7.70 (1H, d, J=3.3 Hz), 8.72 (1H, s).
(iii) Production of tert-butyl
{4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]but-2-yn-1-yl}carbamate
[1417] The title compound (1.86 g) was obtained as a colorless
powder by the reaction in the same manner as in Example 201 (iii)
using tert-butyl
[4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)but-2-yn-1-yl]carbamate
(1.32 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (1.43 g)
and isopropyl alcohol (25 mL) and crystallization from
hexane/diisopropyl ether.
[1418] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (9H, s), 4.03-4.08
(2H, m), 4.80 (1H, br s), 5.08 (2H, t, J=2.1 Hz), 6.60 (1H, d,
J=3.3 Hz), 7.09 (1H, d, J=8.8 Hz), 7.10-7.15 (1H, m), 7.18-7.23
(2H, m), 7.33 (1H, d, J=7.8 Hz), 7.43 (1H, t, J=7.8 Hz), 7.51 (1H,
dd, J=8.8 Hz, 2.5 Hz), 7.68 (1H, s), 7.97 (1H, d, J=2.5 Hz), 8.56
(1H, s).
[1419] (iv) Production of
5-(4-aminobut-2-yn-1-yl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl-
}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride
[1420] tert-Butyl
{4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]but-2-yn-1-yl}carbamate (1.90 g) was dissolved
in tetrahydrofuran (35 mL), 2N hydrochloric acid (18 mL) was added,
and the mixture was stirred at 60.degree. C. for 16 hrs. To the
reaction mixture was added ethanol, and the mixture was
concentrated under reduced pressure. The residue was crystallized
from ethyl acetate to give the title compound (802 mg) as a white
powder.
[1421] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.71-3.84 (2H, m), 5.97
(2H, s), 6.74 (1H, d, J=3 Hz), 7.23-7.32 (2H, m), 7.36 (1H, d,
J=8.8 Hz), 7.52 (1H, d, J=8.0 Hz), 7.66 (1H, t, J=8.0 Hz), 7.76
(1H, dd, J=8.8 Hz, 2.5 Hz), 8.05 (1H, d, J=2.5 Hz), 8.21 (1H, d,
J=3 Hz), 8.42-8.60 (3H, m), 8.76 (1H, s), 10.49 (1H, s).
(v) Production of
N-{4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]but-2-yn-1-yl}-2-(methylsulfonyl)acetamide
[1422] The title compound (55.8 mg) was obtained as a pale-yellow
powder by the reaction in the same manner as in Example 202 (iii)
using
5-(4-aminobut-2-yn-1-yl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl-
}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (204 mg),
methanesulfonylacetic acid (102 mg), 1-hydroxybenzotriazole
monohydrate (204 mg),
N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (287
mg), triethylamine (0.5 mL) and N,N-dimethylformamide (2 mL) and
crystallization from diisopropyl ether/ethyl acetate.
[1423] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.07 (3H, s), 3.92-4.00
(2H, m), 4.02 (2H, s), 5.50 (2H, s), 6.55 (1H, d, J=3 Hz),
7.18-7.28 (2H, m), 7.32 (1H, d, J=9.1 Hz), 7.48 (1H, d, J=7.1 Hz),
7.57-7.70 (2H, m), 7.76 (1H, d, J=3 Hz), 8.02 (1H, d, J=2.5 Hz),
8.39 (1H, s), 8.62 (1H, s), 8.77 (1H, t, J=5.5 Hz).
Example 243
##STR00291##
[1424] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide
[1425] The title compound (104 mg) was obtained as white crystals
by the reaction in the same manner as in Example 202 (iii) using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (201 mg),
4,4,4-trifluoro-3-hydroxy-3-methylbutanoic acid (131 mg),
1-hydroxybenzotriazole monohydrate (159 mg),
N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (372
mg), triethylamine (0.55 mL) and tetrahydrofuran (2 mL) and
crystallization from diisopropyl ether/ethyl acetate.
[1426] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.36 (3H, s), 2.26-2.48
(2H, m), 3.36-3.56 (2H, m), 4.53 (2H, t, J=6.7 Hz), 6.18 (1H, s),
6.51 (1H, d, J=3.0 Hz), 7.15-7.26 (2H, m), 7.30 (1H, d, J=8.8 Hz),
7.47 (1H, d, J=8.0 Hz), 7.56-7.72 (2H, m), 7.81 (1H, dd, J=8.8 Hz,
2.5 Hz), 8.04 (1H, d, J=2.5 Hz), 8.35 (1H, s), 8.42 (1H, t, J=5.9
Hz), 8.83 (1H, s).
Example 244
##STR00292##
[1427] Production of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]butanoic acid
(i) Production of ethyl
4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butanoate
[1428] The title compound (1.70 g) was obtained as a yellow oil by
the reaction in the same manner as in Example 201 (ii) using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.01 g), ethyl
4-bromobutanoate (1.2 mL), cesium carbonate (3.23 g) and
N,N-dimethylfonmamide (10 mL).
[1429] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (3H, t, J=7 Hz),
2.09-2.44 (4H, m), 4.13 (2H, q, J=7 Hz), 4.56 (2H, t, J=7.0 Hz),
6.73 (1H, d, J=3 Hz), 7.50 (1H, d, J=3 Hz), 8.71 (1H, s).
(ii) Production of ethyl
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]butanoate
[1430] The title compound (2.69 g) was obtained as a yellow solid
by the reaction in the same manner as in Example 201 (iii) using
ethyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butanoate (1.70
g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (2.19 g) and
isopropyl alcohol (35 mL).
[1431] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.2 Hz),
2.12-2.27 (2H, m), 2.50-2.61 (2H, m), 4.24 (2H, q, J=7.2 Hz),
4.34-4.48 (2H, m), 6.60 (1H, d, J=3.3 Hz), 7.08 (1H, d, J=8.0 Hz),
7.11-7.17 (1H, m), 7.19-7.25 (2H, m), 7.32 (1H, d, J=8.0 Hz), 7.43
(1H, t, J=8.0 Hz), 7.82 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.00 (1H, d,
J=2.6 Hz), 8.16 (1H, s), 8.52 (1H, s).
(iii) Production of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]butanoic acid
[1432] The title compound (2.02 g) was obtained as a white solid by
the reaction in the same manner as in Example 202 (ii) using ethyl
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]butanoate (2.69 g), 1N aqueous sodium hydroxide
solution (7 mL) and a mixed solvent of tetrahydrofuran (20
mL)/ethanol (20 mL).
[1433] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.87-2.00 (2H, m), 2.20
(2H, t, J=6.9 Hz), 4.52 (2H, t, J=7.6 Hz), 6.50 (1H, d, J=3.0 Hz),
7.17-7.28 (2H, m), 7.30 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=7.7 Hz),
7.57-7.76 (3H, m), 7.99 (1H, d, J=2.5 Hz), 8.34 (1H, s), 8.61 (1H,
s), 12.33 (1H, s).
Example 245
##STR00293##
[1434] Production of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]butanamide
[1435] The title compound (142 mg) was obtained as white crystals
by the reaction in the same manner as in Example 202 (iii) using
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]butanoic acid (250 mg),
2-(methylsulfonyl)ethanamine (128 mg), 1-hydroxybenzotriazole
monohydrate (114 mg),
N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (492
mg), triethylamine (0.15 mL) and a mixed solvent of tetrahydrofuran
(1.5 mL)/N,N-dimethylformamide (1.5 mL) and crystallization from
ethyl acetate.
[1436] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.90-2.03 (2H, m),
2.08-2.19 (2H, m), 2.97 (3H, s), 3.20-3.30 (2H, m), 3.40-3.52 (2H,
m), 4.49 (2H, t, J=7.2 Hz), 6.50 (1H, d, J=3 Hz), 7.17-7.24 (1H,
m), 7.24-7.27 (1H, m), 7.30 (1H, d, J=9 Hz), 7.47 (1H, d, J=8 Hz),
7.62 (1H, t, J=8 Hz), 7.67 (1H, d, J=3 Hz), 7.82 (1H, dd, J=9 Hz,
2.5 Hz), 8.09 (1H, d, J=2.5 Hz), 8.29 (1H, t, J=5.6 Hz), 8.34 (1H,
s), 8.79 (1H, s).
Example 246
##STR00294##
[1437] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide
methanesulfonate
[1438]
N-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-p-
yrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide was
obtained by the reaction in the same manner as in Example 202 (iii)
using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (3.50 g), a 3.6 M
aqueous solution (5.6 mL) of 3-hydroxypropanoic acid,
1-hydroxybenzotriazole monohydrate (4.56 g),
N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (10.1
g), triethylamine (10 mL) and a mixed solvent of tetrahydrofuran
(17 mL)/N,N-dimethylformamide (17 mL). The obtained
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxypropanamide was dissolved in
ethyl acetate (50 mL), methanesulfonic acid (0.155 mL) was added,
and the mixture was stirred for 2 hrs. The reaction mixture was
concentrated under reduced pressure and recrystallized from ethyl
acetate to give the title compound (1.04 g) as white crystals.
[1439] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.22 (2H, t, J=6.3 Hz),
2.31 (3H, s), 3.41-3.51 (4H, m), 3.56 (2H, t, J=6.5 Hz), 6.67 (1H,
d, J=3.0 Hz), 7.25-7.32 (2H, m), 7.37 (1H, d, J=8.8 Hz), 7.50-7.56
(1H, m), 7.62-7.74 (2H, m), 7.98 (1H, d, J=2.8 Hz), 8.33 (1H, t,
J=5.5 Hz), 8.75 (1H, s), 10.11 (1H, s).
Example 247
##STR00295##
[1440] Production of
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]-N-methoxybutanamide
[1441] The title compound (98.1 mg) was obtained as white crystals
by the reaction in the same manner as in Example 202 (iii) using
4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,
2-d]pyrimidin-5-yl]butanoic acid (252 mg), O-methylhydroxylamine
hydrochloride (85 mg), 1-hydroxybenzotriazole monohydrate (105 mg),
N-[3-(dimethylamino)propy]-N-ethylcarbodiimide hydrochloride (484
mg), triethylamine (0.7 mL) and a mixed solvent of tetrahydrofuran
(1 mL)/N,N-dimethylformamide (1 mL).
[1442] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.92-1.99 (4H, m), 3.55
(3H, s), 4.46-4.56 (2H, m), 6.51 (1H, d, J=2.8 Hz), 7.18-7.27 (2H,
m), 7.30 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=7.7 Hz), 7.58-7.69 (2H,
m), 7.74-7.81 (1H, m), 8.03 (1H, s), 8.34 (1H, s), 8.75 (1H, br s),
11.02 (1H, br s).
Example 248
##STR00296##
[1443] Production of
3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phen-
yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}butanamide
[1444] The title compound (203 mg) was obtained as colorless powder
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-py-
rrolo[3,2-d]pyrimidin-4-amine (238 mg), 3-hydroxy-3-methylbutanoic
acid (0.0865 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (154 mg), 1-hydroxybenzotriazole monohydrate (109
mg), triethylamine (0.374 mL) and N,N-dimethylformamide (10.5
mL).
[1445] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.13 (6H, s), 2.12 (3H,
s), 2.21 (2H, s), 3.41 (2H, m), 4.51 (2H, t, J=6 Hz), 4.70 (1H, s),
6.47 (1H, d, J=3 Hz), 6.88 (2H, m), 7.04 (2H, m), 7.47 (1H, t, J=8
Hz), 7.61 (1H, d, J=3 Hz), 7.65 (2H, m), 8.28 (2H, m), 8.73 (1H, br
s).
Example 249
##STR00297##
[1446] Production of
3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]pheny-
l}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}butanamide
(i) Production of
5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride
[1447] tert-Butyl
{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3-
,2-d]pyrimidin-5-yl]ethyl}carbamate (2.9 g) obtained in Example 188
(i) was dissolved in tetrahydrofuran (80 mL)/2N hydrochloric acid
(40 mL), and the mixture was stirred at 60.degree. C. for 16 hrs.
The reaction mixture was concentrated under reduced pressure,
ethanol (80 mL) was added to the residue and the mixture was
concentrated again under reduced pressure. Ethyl acetate was added
to the residue and the solid was collected by filtration and dried
under reduced pressure to give the title compound (2.58 g) as a
solid powder.
[1448] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.20 (3H, s), 3.29 (2H,
m), 5.06 (2H, m), 6.73 (1H, d, J=3 Hz), 7.11 (1H, d, J=9 Hz), 7.22
(2H, m), 7.48 (2H, m), 7.61 (2H, m), 8.08 (1H, d, J=3 Hz), 8.42
(3H, br s), 8.70 (1H, s), 10.04 (1H, br s).
(ii) Production of
3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]pheny-
l}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}butanamide
[1449] The title compound (203 mg) was obtained as colorless powder
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg),
3-hydroxy-3-methylbutanoic acid (0.0644 mL),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115
mg), 1-hydroxybenzotriazole monohydrate (81 mg), triethylamine
(0.279 mL) and N,N-dimethylformamide (7.82 mL).
[1450] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.13 (6H, s), 2.13 (3H,
s), 2.21 (2H, s), 3.42 (2H, m), 4.52 (2H, t, J=7 Hz), 4.69 (1H, s),
6.47 (1H, d, J=3 Hz), 7.03 (1H, m), 7.18 (2H, m), 7.42 (1H, d, J=8
Hz), 7.5-7.7 (4H, m), 8.26 (2H, m), 8.73 (1H, br s).
Example 250
##STR00298##
[1451] Production of
2-{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[1452] The title compound (132 mg) was obtained colorless crystals
by the method in the same manner as in Example 183 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline
(139 mg) and 1-methyl-2-pyrrolidone (0.863 mL).
[1453] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.17 (3H, s), 2.43 (3H,
s), 3.51 (4H, br s), 3.84 (2H, t, J=4.5 Hz), 4.63 (2H, t, J=4.5
Hz), 4.73 (1H, t, J=4.5 Hz), 6.49 (1H, d, J=3 Hz), 6.93 (1H, d, J=8
Hz), 7.16 (1H, dd, J=9 Hz, 3 Hz), 7.23 (1H, d, J=8 Hz), 7.56 (2H,
m), 7.65 (1H, d, J=3 Hz), 8.17 (1H, d, J=3 Hz), 8.28 (1H, s), 8.78
(1H, br s).
Example 251
##STR00299##
[1454] Production of
N-{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]ethyl}carbamate
[1455] The title compound (799 mg) was obtained as a white powder
by the method in the same manner as in Example 188 (i) using
tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (500
mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (542 mg) and
isopropyl alcohol (5 mL).
[1456] .sup.1H-NMR (CDCl.sub.3) .delta. 1.47 (9H, s), 2.24 (3H, s),
2.52 (3H, s), 3.49 (2H, m), 4.46 (2H, m), 5.18 (1H, m), 6.58 (1H,
d, J=3 Hz), 6.89 (1H, d, J=9 Hz), 7.0-7.2 (3H, m), 7.65 (2H, m),
8.27 (1H, d, J=2 Hz), 8.41 (1H, br s), 8.48 (1H, s).
(ii) Production of
5-(2-aminoethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrr-
olo[3,2-d]pyrimidin-4-amine trihydrochloride
[1457] tert-Butyl
{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]ethyl}carbamate (790 mg) was dissolved in
tetrahydrofuran (24 mL)/2N hydrochloric acid (12 mL), and the
mixture was stirred at 60.degree. C. for 16 hrs. The reaction
mixture was concentrated under reduced pressure, ethanol (30 mL)
was added to the residue and the mixture was concentrated again
under reduced pressure. Ethyl acetate was added to the residue and
the solid was collected by filtration and dried under reduced
pressure to give the title compound (701 mg) as a solid powder.
[1458] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.23 (3H, s), 2.68 (3H,
s), 3.29 (2H, m), 5.11 (2H, m), 6.74 (1H, d, J=3 Hz), 7.16 (1H, d,
J=8 Hz), 7.52 (1H, d, J=9 Hz), 7.62 (1H, s), 7.80 (1H, m), 7.96
(1H, m), 8.10 (1H, m), 8.37 (1H, d, J=3 Hz), 8.51 (3H, br s), 8.71
(1H, s).
(iii) Production of
N-{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
[1459] The title compound (205 mg) was obtained as colorless powder
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrr-
olo[3,2-d]pyrimidin-4-amine trihydrochloride (250 mg),
2-(methylsulfonyl)acetic acid (107 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149
mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine
(0.360 mL) and N,N-dimethylformamide (10 mL).
[1460] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.17 (3H, s), 2.44 (3H,
s), 3.34 (3H, s), 3.45 (2H, q, J=6 Hz), 4.05 (2H, s), 4.55 (2H, t,
J=6 Hz), 6.47 (1H, d, J=3 Hz), 6.94 (1H, d, J=9 Hz), 7.1-7.3 (2H,
m), 7.55 (3H, m), 8.18 (1H, d, J=3 Hz), 8.28 (1H, s), 8.51 (1H, br
s), 8.67 (1H, t, J=5 Hz).
Example 252
##STR00300##
[1461] Production of
2-[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]-
pyrimidin-5-yl)ethoxy]ethanol
[1462] The title compound (149 mg) was obtained as colorless
crystals by the method in the same manner as in Example 183 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg), 3-chloro-4-(pyridin-2-ylmethoxy)aniline (152 mg)
and 1-methyl-2-pyrrolidone (0.863 mL).
[1463] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.47 (4H, m), 3.81 (2H,
t, J=4.5 Hz), 4.61 (2H, t, J=4.5 Hz), 4.70 (1H, t, J=4.5 Hz), 5.27
(2H, s), 6.48 (1H, d, J=3 Hz), 7.20 (1H, d, J=9 Hz), 7.37 (1H, dd,
J=7 Hz, 4.5 Hz), 7.49 (1H, dd, J=9 Hz, 3 Hz), 7.58 (1H, d, J=8 Hz),
7.64 (1H, d, J=3 Hz), 7.84 (1H, d, J=3 Hz), 7.88 (1H, m), 8.27 (1H,
s), 8.59 (1H, dd, J=3 Hz, 1 Hz), 8.70 (1H, br s).
Example 253
##STR00301##
[1464] Production of
N-[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]-
pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)ethyl]carbamate
[1465] The title compound (812 mg) was obtained as a white powder
by the method in the same manner as in Example 188 (i) using
tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (500
mg), 3-chloro-4-(pyridin-2-ylmethoxy)aniline (594 mg) and isopropyl
alcohol (5 mL).
[1466] .sup.1H-NMR (CDCl.sub.3) .delta. 1.48 (9H, s), 3.46 (2H, m),
4.43 (2H, m), 5.19 (1H, t, J=5 Hz), 5.29 (2H, s), 6.56 (1H, d, J=3
Hz), 6.98 (1H, d, J=9 Hz), 7.14 (1H, d, J=3 Hz), 7.2-7.3 (2H, m),
7.6-7.8 (3H, m), 7.87 (1H, d, J=3 Hz), 8.46 (1H, s), 8.51 (1H, br
s), 8.59 (1H, m).
(ii) Production of
5-(2-aminoethyl)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5H-pyrrolo[3,-
2-d]pyrimidin-4-amine trihydrochloride
[1467] tert-Butyl
[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)ethyl]carbamate (790 mg) was dissolved in
tetrahydrofuran (24 mL)/2N hydrochloric acid (12 mL), and the
mixture was stirred at 60.degree. C. for 16 hrs. The reaction
mixture was concentrated under reduced pressure, ethanol (30 mL)
was added to the residue and the mixture was concentrated again
under reduced pressure. Ethyl acetate was added to the residue and
the solid was collected by filtration and dried under reduced
pressure to give the title compound (826 mg) as a solid powder.
[1468] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.29 (2H, m), 5.07 (2H,
m), 5.49 (2H, s), 6.73 (1H, dd, J=3 Hz, 1 Hz), 7.34 (1H, d, J=9
Hz), 7.52 (1H, dd, J=9 Hz, 3 Hz), 7.68 (1H, m), 7.74 (1H, d, J=2
Hz), 7.85 (1H, m), 8.09 (1H, d, J=3 Hz), 8.24 (1H, m), 8.47 (3H, br
s), 8.69 (1H, s), 8.77 (1H, m), 10.19 (1H, br s).
(iii) Production of
N-[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]-
pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide
[1469] The title compound (182 mg) was obtained as colorless powder
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5H-pyrrolo[3,-
2-d]pyrimidin-4-amine trihydrochloride (261 mg),
2-(methylsulfonyl)acetic acid (107 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149
mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine
(0.360 mL) and N,N-dimethylformamide (10 mL).
[1470] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.10 (3H, s), 3.44 (2H,
q, J=6 Hz), 4.06 (2H, s), 4.53 (2H, t, J=6 Hz), 5.28 (2H, s), 6.46
(1H, d, J=3 Hz), 7.22 (1H, d, J=9 Hz), 7.37 (1H, dd, J=8 Hz, 6 Hz),
7.57 (3H, m), 7.78 (1H, d, J=2 Hz), 7.89 (1H, dt, J=2 Hz, 8 Hz),
8.26 (1H, s), 8.49 (1H, br s), 8.60 (1H, d, J=5 Hz), 8.67 (1H, t,
J=6 Hz).
Example 254
##STR00302##
[1471] Production of tert-butyl
(2S,4R)-4-hydroxy-2-[({2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phen-
yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}amino)carbonyl]pyrrolidine-
-1-carboxylate
[1472] The title compound (310 mg) was obtained as a colorless
powder by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (300 mg),
(4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (118 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (172
mg), 1-hydroxybenzotriazole monohydrate (122 mg), triethylamine
(0.418 mL) and N,N-dimethylformamide (11.73 mL).
[1473] .sup.1H-NMR (CDCl.sub.3) .delta. 1.43 (9H, s), 1.9-2.1 (2H,
m), 2.22 (3H, s), 2.50 (1H, br s), 3.44 (2H, m), 3.61 (2H, m), 4.44
(4H, m), 6.58 (1H, d, J=3 Hz), 6.94 (1H, d, J=9 Hz), 7.10 (1H, m),
7.18 (2H, m), 7.27 (2H, m), 7.39 (1H, d, J=8 Hz), 7.65 (1H, d, J=9
Hz), 7.73 (1H, m), 8.39 (1H, br s), 8.48 (1H, s).
Example 255
##STR00303##
[1474] Production of
(4R)-4-hydroxy-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}am-
ino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-L-prolinamide
dihydrochloride
[1475] tert-Butyl
(2S,4R)-4-hydroxy-2-[({2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phen-
yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}amino)carbonyl]pyrrolidine-
-1-carboxylate (230 mg) was dissolved in dichloromethane (2.39 mL),
trifluoroacetic acid (1.79 mL) was added, and the mixture was
stirred at room temperature for 2 hrs. The reaction mixture was
concentrated under reduced pressure, and the residue was dissolved
in ethyl acetate/tetrahydrofuran (1:1, 50 mL). The organic layer
was washed with saturated aqueous sodium hydrogen carbonate (30
mL), dried over magnesium sulfate and concentrated under reduced
pressure. The residue was subjected to basic silica gel
chromatography (ethyl acetate/methanol=100/0.fwdarw.80/20). The
fractions containing the title compound were collected and
concentrated under reduced pressure. The residue was dissolved in
ethyl acetate, 4N hydrochloric acid (0.252 mL) was added, and the
mixture was crystallized to give the title compound (136 mg).
[1476] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.66 (1H, m), 2.14 (1H,
m), 2.21 (3H, s), 3.04 (1H, m), 3.23 (1H, m), 3.49 (3H, m), 3.67
(1H, m), 4.16 (2H, m), 4.36 (1H, m), 4.83 (2H, m), 5.55 (1H, br s),
6.66 (1H, d, J=3 Hz), 7.13 (1H, d, J=9 Hz), 7.23 (2H, m), 7.49 (2H,
m), 7.61 (2H, m), 7.94 (1H, m), 8.56 (1H, m), 8.68 (1H, s), 8.95
(1H, m), 10.02 (2H, m).
Example 256
##STR00304##
[1477] Production of
2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]pheny-
l}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide
methanesulfonate
[1478]
2-(Methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy-
]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide (680
mg) was dissolved in ethyl acetate (3.4 mL), methanesulfonic acid
(0.0887 mL) was added at 50.degree. C., and the mixture was stirred
for 10 min. and further stirred at room temperature for 2 hrs. The
precipitated crystals were collected by filtration and washed with
diisopropyl ether to give the title compound (797 mg) as colorless
crystals.
[1479] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.20 (3H, s), 2.31 (3H,
s), 3.05 (3H, s), 3.55 (2H, q, J=6 Hz), 4.06 (2H, s), 4.68 (2H, t,
J=6 Hz), 6.65 (1H, d, J=3 Hz), 7.13 (1H, d, J=9 Hz), 7.23 (2H, m),
7.49 (2H, m), 7.62 (2H, m), 7.91 (1H, d, J=3 Hz), 8.70 (2H, m),
9.84 (1H, br s).
Example 257
##STR00305##
[1480] Production of
2-{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[1481] The title compound (133 mg) was obtained as colorless
crystals by the method in the same manner as in Example 183 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg), 3-chloro-4-[(6-methylpyridin-3-yl)oxy]aniline
(152 mg) and 1-methyl-2-pyrrolidone (0.863 mL).
[1482] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.44 (3H, s), 3.48 (4H,
m), 3.83 (2H, t, J=4.5 Hz), 4.64 (2H, t, J=4.5 Hz), 4.71 (1H, t,
J=4.5 Hz), 6.52 (1H, d, J=3 Hz), 7.18 (1H, d, J=9 Hz), 7.24 (2H,
m), 7.62 (1H, dd, J=9 Hz, 2 Hz), 7.69 (1H, d, J=3 Hz), 8.00 (1H, d,
J=2 Hz), 8.20 (1H, d, J=1 Hz), 8.34 (1H, s), 8.96 (1H, br s).
Example 258
##STR00306##
[1483] Production of
N-{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]ethyl}carbamate
[1484] The title compound (673 mg) was obtained as a white powder
by the method in the same manner as in Example 188 (i) using
tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (500
mg), 3-chloro-4-[(6-methylpyridin-3-yl)oxy]aniline (594 mg) and
isopropyl alcohol (5 mL).
[1485] .sup.1H-NMR (CDCl.sub.3) .delta. 1.49 (9H, s), 2.53 (3H, s),
3.48 (2H, m), 4.46 (2H, m), 5.26 (1H, t, J=6 Hz), 6.59 (1H, d, J=3
Hz), 7.01 (1H, d, J=9 Hz), 7.09 (1H, d, J=8 Hz), 7.18 (2H, m), 7.85
(1H, dd, J=9 Hz, 3 Hz), 8.00 (1H, d, J=3 Hz), 8.30 (1H, d, J=3 Hz),
8.50 (1H, s), 8.63 (1H, br s).
(ii) Production of
5-(2-aminoethyl)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrr-
olo[3,2-d]pyrimidin-4-amine trihydrochloride
[1486] tert-Butyl
{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]ethyl}carbamate (643 mg) was dissolved in
tetrahydrofuran (19.5 mL)/2N hydrochloric acid (9.75 mL), and the
mixture was stirred at 60.degree. C. for 16 hrs. The reaction
mixture was concentrated under reduced pressure, ethanol (50 mL)
was added to the residue and the mixture was concentrated again
under reduced pressure. Ethyl acetate was added to the residue and
the solid was collected by filtration and dried under reduced
pressure to give the title compound (646 mg) as a solid powder.
[1487] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.68 (3H, d, J=6 Hz),
3.30 (2H, m), 5.14 (2H, m), 6.77 (1H, d, J=3 Hz), 7.40 (1H, m),
7.6-7.9 (2H, m), 8.00 (2H, m), 8.12 (1H, m), 8.52 (4H, m), 8.77
(1H, s), 10.50 (1H, m).
(iii) Production of
N-{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
[1488] The title compound (230 mg) was obtained as colorless powder
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrr-
olo[3,2-d]pyrimidin-4-amine trihydrochloride (261 mg),
2-(methylsulfonyl)acetic acid (107 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149
mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine
(0.360 mL) and N,N-dimethylformamide (10 mL).
[1489] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.45 (3H, s), 3.10 (3H,
s), 3.45 (2H, q, J=6 Hz), 4.04 (2H, s), 4.56 (2H, t, J=6 Hz), 6.50
(1H, d, J=3 Hz), 7.18 (1H, d, J=9 Hz), 7.25 (1H, d, J=2 Hz), 7.62
(1H, d, J=3 Hz), 7.70 (1H, dd, J=9 Hz, 3 Hz), 7.95 (1H, d, J=2 Hz),
8.22 (1H, m), 8.34 (1H, s), 8.67 (2H, m).
Example 259
##STR00307##
[1490] Production of
2-{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethoxy}ethanol
[1491] The title compound (145 mg) was obtained as colorless
crystals by the method in the same manner as in Example 183 using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (150 mg), 3-chloro-4-[(5-chloropyridin-3-yl)oxy]aniline
(165 mg) and 1-methyl-2-pyrrolidone (0.863 mL).
[1492] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.49 (4H, m), 3.84 (2H,
t, J=4.5 Hz), 4.65 (2H, t, J=4.5 Hz), 4.72 (1H, t, J=4.5 Hz), 6.53
(1H, d, J=3 Hz), 7.33 (1H, d, J=9 Hz), 7.49 (1H, m), 7.69 (2H, m),
8.04 (1H, d, J=2 Hz), 8.32 (1H, d, J=2 Hz), 8.36 (1H, s), 8.40 (1H,
d, J=2 Hz), 9.02 (1H, br s).
Example 260
##STR00308##
[1493] Production of
N-{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
(i) Production of tert-butyl
{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]ethyl}carbamate
[1494] The title compound (769 mg) was obtained as a white powder
by the method in the same manner as in Example 188 (i) using
tert-butyl
[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (500
mg), 3-chloro-4-[(5-chloropyridin-3-yl)oxy]aniline (643 mg) and
isopropyl alcohol (5 mL).
[1495] .sup.1H-NMR (CDCl.sub.3) .delta. 1.50 (9H, s), 3.49 (2H, m),
4.48 (2H, m), 5.21 (1H, t, J=6 Hz), 6.60 (1H, d, J=3 Hz), 7.11 (1H,
d, J=9 Hz) 7.21 (2H, m), 7.94 (1H, dd, J=9 Hz, 3 Hz), 8.06 (1H, d,
J=3 Hz), 8.29 (2H, m), 8.53 (1H, s), 8.69 (1H, br s).
(ii) Production of
5-(2-aminoethyl)-N-{3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}-5H-pyrr-
olo[3,2-d]pyrimidin-4-amine trihydrochloride
[1496] tert-Butyl
{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]ethyl}carbamate (700 mg) was dissolved in
tetrahydrofuran (19.5 mL)/2N hydrochloric acid (9.75 mL), and the
mixture was stirred at 60.degree. C. for 16 hrs. The reaction
mixture was concentrated under reduced pressure, ethanol (50 mL)
was added to the residue and the mixture was concentrated again
under reduced pressure. Ethyl acetate was added to the residue and
the solid was collected by filtration and dried under reduced
pressure to give the title compound (663 mg) as a solid powder.
[1497] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.30 (2H, m), 5.09 (2H,
m), 6.77 (1H, d, J=3 Hz), 7.40 (1H, d, J=9 Hz), 7.61 (1H, m), 7.69
(1H, dd, J=9 Hz, 2 Hz), 7.96 (1H, d, J=2 Hz), 8.12 (1H, d, J=3 Hz),
8.35 (1H, d, J=2 Hz), 8.40 (3H, s), 8.46 (1H, d, J=2 Hz), 8.77 (1H,
s), 10.36 (1H, m).
(iii) Production of
N-{2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[-
3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide
[1498] The title compound (255 mg) was obtained as colorless powder
crystals by the reaction in the same manner as in Example 155 (iv)
using
5-(2-aminoethyl)-N-{3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}-5H-pyrr-
olo[3,2-d]pyrimidin-4-amine trihydrochloride (271 mg),
2-(methylsulfonyl)acetic acid (107 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149
mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine
(0.360 mL) and N,N-dimethylformamide (10 mL).
[1499] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.09 (3H, s), 3.45 (2H,
m), 4.04 (2H, s), 4.56 (2H, t, J=6 Hz), 6.50 (1H, d, J=3 Hz), 7.34
(1H, d, J=9 Hz), 7.50 (1H, m), 7.63 (1H, d, J=3 Hz), 7.76 (1H, dd,
J=9 Hz, 2 Hz), 7.99 (1H, d, J=3 Hz), 8.32 (1H, d, J=2 Hz), 8.35
(1H, s), 8.40 (1H, d, J=2 Hz), 8.66 (1H, m), 8.73 (1H, br s).
Example 261
##STR00309##
[1500] Production of tert-butyl
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]piperidine-1-carboxylate
(i) Production of tert-butyl
4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-
amino]-2-chlorophenoxy}piperidine-1-carboxylate
[1501] A mixture of
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (3.46 g), tert-butyl
4-(4-amino-2-chlorophenoxy)piperidine-1-carboxylate (3.27 g) and
isopropyl alcohol (50 mL) was stirred at 80.degree. C. overnight.
The reaction mixture was concentrated under reduced pressure, water
and saturated aqueous sodium hydrogen carbonate solution were
added, and the mixture was extracted with ethyl acetate. The ethyl
acetate layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure and the obtained residue was subjected to silica
gel column chromatography (eluent, methanol:ethyl
acetate=0:100.fwdarw.10:90). The object fraction was concentrated
under reduced pressure. The residue was crystallized from ethyl
acetate-diisopropyl ether to give the title compound (4.70 g) as a
white powder.
[1502] .sup.1H-NMR (CDCl.sub.3) .delta. 1.48 (9H, s), 1.71-1.92
(4H, m), 3.33-3.45 (2H, m), 3.62-3.73 (2H, m), 3.90-3.97 (2H, m),
4.05 (2H, t, J=4.4 Hz), 4.29-4.39 (1H, m), 4.46-4.52 (2H, m), 4.56
(2H, t, J=4.4 Hz), 6.61 (1H, d, J=3.3 Hz), 6.72 (1H, d, J=8.7 Hz),
7.19 (1H, d, J=3.3 Hz), 7.29 (1H, dd, J=8.7, 2.7 Hz), 7.33-7.40
(2H, m), 7.50-7.57 (1H, m), 7.69 (1H, d, J=2.7 Hz), 7.78-7.83 (2H,
m), 8.47 (1H, s), 8.55 (1H, br s).
(ii) Production of tert-butyl
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]piperidine-1-carboxylate
[1503] tert-Butyl
4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-
amino]-2-chlorophenoxy}piperidine-1-carboxylate (636 mg) was
dissolved in a mixed solvent of methanol (10 mL) and
tetrahydrofuran (10 mL), 1N aqueous sodium hydroxide solution (2
mL) was added, and the mixture was stirred overnight at room
temperature. Water was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The ethyl acetate layer
was washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure and the
obtained residue was subjected to basic silica gel column
chromatography (eluent, methanol:ethyl acetate=0:100.fwdarw.10:90).
The object fraction was concentrated under reduced pressure. The
solvent was evaporated under reduced pressure and the obtained
residue was crystallized from ethyl acetate-diethyl ether to give
the title compound (498 mg) as a white powder.
[1504] .sup.1H-NMR (CDCl.sub.3) .delta. 1.47 (9H, s), 1.75-1.96
(4H, m), 2.27 (1H, br s), 3.33-3.45 (2H, m), 3.63-3.82 (6H, m),
4.00 (2H, t, J=4.5 Hz), 4.39-4.47 (1H, m), 4.54 (2H, t, J=4.5 Hz),
6.58 (1H, d, J=3.3 Hz), 6.95 (1H, d, J=8.8 Hz), 7.17 (1H, d, J=3.3
Hz), 7.52 (1H, dd, J=8.8, 2.7 Hz), 7.70 (1H, d, J=2.7 Hz), 8.46
(1H, s), 8.60 (1H, br s).
Example 262
##STR00310##
[1505] Production of
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]-N-(2,6-difluorophenyl)piperidine-1-carboxamide
hydrochloride
(i) Production of
2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride
[1506] 4N Hydrochloric acid/ethyl acetate solution (20 mL) and
ethanol (10 mL) were added to tert-butyl
4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-
amino]-2-chlorophenoxy}piperidine-1-carboxylate (3.82 g), and the
mixture was stirred at room temperature for 5 hrs. The reaction
mixture was concentrated under reduced pressure, and the obtained
residue was crystallized from ethanol-ethyl acetate to give the
title compound (3.68 g) as a white powder.
[1507] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.85-2.00 (2H, m),
2.07-2.21 (2H, m), 3.02-3.28 (4H, m), 3.77 (2H, m), 3.88 (2H, m),
4.29 (2H, m), 4.70-4.79 (1H, m), 4.89 (2H, m), 6.60 (1H, d, J=3.0
Hz), 7.25 (1H, d, J=8.7 Hz), 7.42-7.51 (3H, m), 7.61-7.73 (4H, m),
7.98 (1H, d, J=3.0 Hz), 8.57 (1H, s), 9.20-9.50 (2H, m), 9.85 (1H,
br s).
(ii) Production of
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]-N-(2,6-difluorophenyl)piperidine-1-carboxamide
hydrochloride
[1508] To a mixture of
2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10%
aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL)
and tetrahydrofuran (5 mL) was added 2,6-difluorophenyl isocyanate
(93 mg) with vigorous stirring. The mixture was stirred at room
temperature for 2 hrs, water was added and the mixture was
extracted with ethyl acetate. The ethyl acetate layer was washed
with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure and the obtained
residue was dissolved in methanol (8 mL) and tetrahydrofuran (2
mL). 1N Aqueous sodium hydroxide solution (1 mL) was added, and the
mixture was stirred at room temperature for 3 hrs. Water was added
to the reaction mixture and the mixture was extracted with ethyl
acetate. The ethyl acetate layer was washed with saturated brine
and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure and the obtained residue was
subjected to basic silica gel column chromatography (eluent,
methanol:ethyl acetate=0:100.fwdarw.15:85). The object fraction was
concentrated under reduced pressure. The residue was dissolved in
ethyl acetate-ethanol, and 1N hydrochloric acid/ethyl acetate
solution (0.5 mL) was added. The solvent was evaporated under
reduced pressure and the obtained residue was crystallized from
ethanol-ethyl acetate to give the title compound (202 mg) as a
white powder.
[1509] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.60-1.75 (2H, m),
1.91-2.04 (2H, m), 3.20-3.55 (6H, m), 3.68-3.81 (2H, m), 3.84 (2H,
m), 4.72-4.85 (3H, m), 6.67 (1H, d, J=3.0 Hz), 7.06-7.17 (2H, m),
7.23-7.32 (1H, m), 7.35 (1H, d, J=8.9 Hz), 7.51 (1H, dd, J=8.9, 2.5
Hz), 7.77 (1H, d, J=2.5 Hz), 7.99 (1H, d, J=3.0 Hz), 8.34 (1H, s),
8.68 (1H, s), 9.79 (1H, br s).
Example 263
##STR00311##
[1510] Production of
2-(2-{4-[(3-chloro-4-{[1-(cyclopentylcarbonyl)piperidin-4-yl]oxy}phenyl)a-
mino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol
hydrochloride
[1511] The title compound (207 mg) was obtained as a white powder
by the method in the same manner as in Example 262 (ii) using
2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10%
aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL),
tetrahydrofuran (5 mL) and cyclopentanecarbonyl chloride (80
mg).
[1512] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.45-2.06 (12H, m),
2.95-3.08 (1H, m), 3.30-3.55 (6H, m), 3.69-3.80 (2H, m), 3.83 (2H,
t, J=4.4 Hz), 4.70-4.85 (3H, m), 6.67 (1H, d, J=3.0 Hz), 7.34 (1H,
d, J=9.0 Hz), 7.50 (1H, dd, J=9.0, 2.7 Hz), 7.76 (1H, d, J=2.7 Hz),
7.99 (1H, d, J=3.0 Hz), 8.68 (1H, s), 9.82 (1H, br s).
Example 264
##STR00312##
[1513] Production of
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]-N-cyclopentylpiperidine-1-carboxamide
hydrochloride
[1514] To a solution of 1,1'-carbonylbis(1H-imidazole) (162 mg) in
tetrahydrofuran (5 mL) was added a solution of cyclopentylamine (85
mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room
temperature for 1 hr. A solution of
2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg) and
triethylamine (0.153 mL) in tetrahydrofuran (1 mL) was added, and
the mixture was stirred overnight at room temperature. Water was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The ethyl acetate layer was washed with saturated
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure and the obtained residue was
dissolved in methanol (8 mL) and tetrahydrofuran (2 mL). 1N Aqueous
sodium hydroxide solution (1 mL) was added, and the mixture was
stirred overnight at room temperature. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated brine and dried
over anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure and the obtained residue was subjected to basic
silica gel column chromatography (eluent, methanol:ethyl
acetate=0:100.fwdarw.10:90). The object fraction was concentrated
under reduced pressure. The residue was dissolved in ethyl
acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution
(0.5 mL) was added. The solvent was evaporated under reduced
pressure and the obtained residue was crystallized from
ethanol-ethyl acetate to give the title compound (188 mg) as a
white powder.
[1515] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.30-1.95 (12H, m),
3.15-3.27 (2H, m), 3.40-3.50 (4H, m), 3.55-3.67 (2H, m), 3.83 (2H,
t, J=4.6 Hz), 3.82-3.98 (1H, m), 4.62-4.72 (1H, m), 4.80 (2H, m),
6.30 (1H, d, J=6.4 Hz), 6.67 (1H, d, J=3.0 Hz), 7.32 (1H, d, J=9.0
Hz), 7.50 (1H, dd, J=9.0, 2.6 Hz), 7.75 (1H, d, J=2.6 Hz), 7.99
(1H, d, J=3.0 Hz), 8.68 (1H, s), 9.82 (1H, br s).
Example 265
##STR00313##
[1516] Production of
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]-N-(4-methoxyphenyl)piperidine-1-carboxamide
hydrochloride
[1517] The title compound (209 mg) was obtained as a white powder
by the method in the same manner as in Example 262 (ii) using
2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10%
aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL),
tetrahydrofuran (5 mL) and 4-methoxyphenyl isocyanate (75 mg).
[1518] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.60-1.75 (2H, m),
1.90-2.03 (2H, m), 3.34-3.51 (6H, m), 3.68-3.80 (2H, m), 3.70 (3H,
s), 3.84 (2H, t, J=4.5 Hz), 4.70-4.85 (3H, m), 6.68 (1H, d, J=3.2
Hz), 6.82 (2H, d, J=9.1 Hz), 7.31-7.40 (3H, m), 7.51 (1H, dd,
J=8.9, 2.6 Hz), 7.77 (1H, d, J=2.6 Hz), 7.99 (1H, d, J=3.2 Hz),
8.44 (1H, br s), 8.68 (1H, s), 9.81 (1H, br s).
Example 266
##STR00314##
[1519] Production of
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]-N-(4-methylphenyl)piperidine-1-carboxamide
hydrochloride
[1520] The title compound (190 mg) was obtained as a white powder
by the method in the same manner as in Example 262 (ii) using
2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]py-
rimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10%
aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL),
tetrahydrofuran (5 mL) and 4-methylphenyl isocyanate (67 mg).
[1521] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.60-1.75 (2H, m),
1.90-2.03 (2H, m), 2.23 (3H, s), 3.34-3.51 (6H, m), 3.69-3.80 (2H,
m), 3.84 (2H, t, J=4.5 Hz), 4.69-4.84 (3H, m), 6.67 (1H, d, J=3.0
Hz), 7.03 (2H, d, J=8.5 Hz), 7.31-7.39 (3H, m), 7.51 (1H, dd,
J=8.9, 2.7 Hz), 7.76 (1H, d, J=2.7 Hz), 7.99 (1H, d, J=3.0 Hz),
8.50 (1H, br s), 8.68 (1H, s), 9.82 (1H, br s).
Example 267
##STR00315##
[1522] Production of tert-butyl
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]benzoate hydrochloride
(i) Production of tert-butyl
4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-
amino]-2-chlorophenoxy}benzoate
[1523] A mixture of
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (1.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)benzoate
(1.35 g) and isopropyl alcohol (30 mL) was stirred at 80.degree. C.
overnight. The reaction mixture was concentrated under reduced
pressure, water and saturated aqueous sodium hydrogen carbonate
solution were added, and the mixture was extracted with ethyl
acetate. The ethyl acetate layer was washed with saturated brine
and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure and the obtained residue was
subjected to silica gel column chromatography (eluent, ethyl
acetate). The object fraction was concentrated under reduced
pressure and the residue was crystallized from ethyl
acetate-diethyl ether to give the title compound (1.54 g) as a
white powder.
[1524] .sup.1H-NMR (CDCl.sub.3) .delta. 1.59 (9H, s), 3.93-3.99
(2H, m), 4.05-4.11 (2H, m), 4.46-4.52 (2H, m), 4.55-4.61 (2H, m),
6.64 (1H, d, J=3.2 Hz), 6.82-6.90 (3H, m), 7.22 (1H, d, J=3.2 Hz),
7.30-7.40 (3H, m), 7.47-7.54 (1H, m), 7.76-7.81 (2H, m), 7.90 (1H,
d, J=2.6 Hz), 7.94 (2H, d, J=9.1 Hz), 8.51 (1H, s), 8.78 (1H, br
s).
(ii) Production of tert-butyl
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]benzoate hydrochloride
[1525] tert-Butyl
4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-
amino]-2-chlorophenoxy}benzoate (189 mg) was dissolved in a mixed
solvent of methanol (5 mL) and tetrahydrofuran (1 mL), 1N aqueous
sodium hydroxide solution (0.6 mL) was added, and the mixture was
stirred overnight at room temperature. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated brine and dried
over anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure and the obtained residue was subjected to basic
silica gel column chromatography (eluent, methanol:ethyl
acetate=0:100.fwdarw.10:90). The object fraction was concentrated
under reduced pressure. The residue was dissolved in ethyl
acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution
(0.3 mL) was added. The solvent was evaporated under reduced
pressure and the obtained residue was crystallized from
ethanol-ethyl acetate to give the title compound (163 mg) as a
white powder.
[1526] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.54 (9H, s), 3.41-3.52
(4H, m), 3.85 (2H, m), 4.84 (2H, m), 6.71 (1H, d, J=3.2 Hz), 7.02
(2H, d, J=8.9 Hz), 7.36 (1H, d, J=8.9 Hz), 7.69 (1H, dd, J=8.9, 2.4
Hz), 7.93 (2H, d, J=8.9 Hz), 8.00 (1H, d, J=2.4 Hz), 8.04 (1H, d,
J=3.2 Hz), 8.75 (1H, s), 10.00 (1H, br s).
Example 268
##STR00316##
[1527] Production of
N-(tert-butyl)-4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,-
2-d]pyrimidin-4-yl}amino)phenoxy]benzamide hydrochloride
(i) Production of
4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-
amino]-2-chlorophenoxy}benzoic acid hydrochloride
[1528] Trifluoroacetic acid (10 mL) was added to tert-butyl
4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-
amino]-2-chlorophenoxy}benzoate (1.26 g), and the mixture was
stirred at room temperature for 3 hrs. The reaction mixture was
concentrated under reduced pressure, 4N hydrochloric acid/ethyl
acetate solution was added, and the mixture was concentrated again
under reduced pressure. The obtained residue was crystallized from
ethyl acetate to give the title compound (1.16 g) as a white
powder.
[1529] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.76-3.83 (2H, m), 3.92
(2H, t, J=4.4 Hz), 4.26-4.34 (2H, m), 4.89 (2H, m), 6.63 (1H, d,
J=3.4 Hz), 6.98 (2H, d, J=8.8 Hz), 7.27 (1H, d, J=8.8 Hz),
7.41-7.50 (2H, m), 7.55-7.73 (4H, m), 7.92-8.03 (4H, m), 8.66 (1H,
s), 9.91 (1H, br).
(ii) Production of
N-(tert-butyl)-4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,-
2-d]pyrimidin-4-yl}amino)phenoxy]benzamide hydrochloride
[1530] A mixture of
4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-
amino]-2-chlorophenoxy}benzoic acid hydrochloride (183 mg),
2-methylpropan-2-amine (0.038 mL),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69
mg), 1-hydroxybenzotriazole monohydrate (55 mg), triethylamine
(0.050 mL) and N,N-dimethylformamide (3 mL) was stirred overnight
at room temperature. Water was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The ethyl acetate
layer was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced
pressure and the obtained residue was subjected to silica gel
column chromatography (eluent, methanol:ethyl
acetate=0:100.fwdarw.10:90). The object fraction was concentrated
under reduced pressure. The residue was dissolved in a mixed
solvent of methanol (5 mL) and tetrahydrofuran (1 mL), 1N aqueous
sodium hydroxide solution (0.6 mL) was added and the mixture was
stirred at room temperature for 3 days. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated brine and dried
over anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure and the obtained residue was subjected to basic
silica gel column chromatography (eluent, methanol:ethyl
acetate=0:100.fwdarw.10:90). The object fraction was concentrated
under reduced pressure. The residue was dissolved in ethyl
acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution
(0.3 mL) was added. The solvent was evaporated under reduced
pressure and the obtained residue was crystallized from
ethanol-ethyl acetate to give the title compound (118 mg) as a
white powder.
[1531] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.37 (9H, s), 3.41-3.52
(4H, m), 3.85 (2H, m), 4.84 (2H, m), 6.71 (1H, d, J=3.2 Hz), 6.97
(2H, d, J=8.8 Hz), 7.29 (1H, d, J=8.8 Hz), 7.67 (1H, dd, J=8.8, 2.5
Hz), 7.72 (1H, s), 7.85 (2H, d, J=8.8 Hz), 7.99 (1H, d, J=2.5 Hz),
8.04 (1H, d, J=3.2 Hz), 8.75 (1H, s), 10.00 (1H, br s).
Example 269
##STR00317##
[1532] Production of
4-[2-chloro-4-((5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl)amino)phenoxy]-N-(2,2-dimethylpropyl)benzamide
[1533] The title compound (140 mg) was obtained as a white powder
by the method in the same manner as in Example 268 (ii) using
4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-
amino]-2-chlorophenoxy}benzoic acid hydrochloride (183 mg),
neopentylamine (0.042 mL),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69
mg), 1-hydroxybenzotriazole monohydrate (55 mg), triethylamine
(0.050 mL), N,N-dimethylformamide (3 mL), methanol (5 mL),
tetrahydrofuran (1 mL) and 1N aqueous sodium hydroxide solution
(0.6 mL).
[1534] .sup.1H-NMR (DMSO-d.sub.6) .delta. 0.90 (9H, s), 3.10 (2H,
d, J=6.4 Hz), 3.42-3.52 (4H, m), 3.86 (2H, t, J=4.6 Hz), 4.83 (2H,
t, J=4.6 Hz), 6.71 (1H, d, J=2.9 Hz), 7.01 (2H, d, J=8.5 Hz), 7.32
(1H, d, J=8.8 Hz), 7.66 (1H, dd, J=8.8, 2.2 Hz), 7.91 (2H, d, J=8.5
Hz), 7.99 (1H, d, J=2.2 Hz), 8.03 (1H, d, J=2.9 Hz), 8.32 (1H, t,
J=6.4 Hz), 8.75 (1H, s), 9.95 (1H, br s).
Example 270
##STR00318##
[1535] Production of
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]-N-(2,2,2-trifluoroethyl)piperidine-1-carboxamide
hydrochloride
[1536] The title compound (101 mg) was obtained as a white powder
by the method in the same manner as in Example 264 using
1,1'-carbonylbis(1H-imidazole) (97 mg), 2,2,2-trifluoroethylamine
(0.048 mL),
2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-
-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (244 mg),
triethylamine (0.123 mL) and 1N aqueous sodium hydroxide solution
(0.6 mL).
[1537] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.53-1.68 (2H, m),
1.84-1.98 (2H, m), 3.25-3.70 (8H, m), 3.77-3.92 (4H, m), 4.66-4.77
(1H, m), 4.79 (2H, t, J=4.8 Hz), 6.67 (1H, d, J=3.1 Hz), 7.23 (1H,
t, J=6.2 Hz), 7.33 (1H, d, J=9.0 Hz), 7.50 (1H, dd, J=9.0, 2.6 Hz),
7.76 (1H, d, J=2.6 Hz), 7.99 (1H, d, J=3.1 Hz), 8.68 (1H, s), 9.78
(1H, br s).
Example 271
##STR00319##
[1538] Production of 2,2,2-trifluoroethyl
4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-
-yl}amino)phenoxy]piperidine-1-carboxylate hydrochloride
[1539] The title compound (135 mg) was obtained as a white powder
by the method in the same manner as in Example 264 using
1,1'-carbonylbis(1H-imidazole) (97 mg), 2,2,2-trifluoroethanol
(0.044 mL),
2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-
-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (244 mg),
triethylamine (0.123 mL) and 1N aqueous sodium hydroxide solution
(0.6 mL).
[1540] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.62-1.77 (2H, m),
1.89-2.02 (2H, m), 3.38-3.52 (6H, m), 3.58-3.73 (2H, m), 3.83 (2H,
t, J=4.7 Hz), 4.67-4.85 (5H, m), 6.68 (1H, d, J=2.9 Hz), 7.34 (1H,
d, J=9.0 Hz), 7.51 (1H, dd, J=9.0, 2.5 Hz), 7.76 (1H, d, J=2.5 Hz),
7.99 (1H, d, J=2.9 Hz), 8.68 (1H, s), 9.82 (1H, br s).
Example 272
##STR00320##
[1541] Production of
N-(tert-butyl)-4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)acetyl]amino}ethyl)-
-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}phenoxy)piperidine-1-carboxamide
[1542] tert-Butyl
4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)acetyl]amino}ethyl)-5H-pyrrolo[3,2-
-d]pyrimidin-4-yl]amino}phenoxy)piperidine-1-carboxylate (120.0 mg)
was dissolved in methanol (4.0 mL), 4N hydrochloric acid/ethyl
acetate (5 mL) was added, and the mixture was stirred for 5 hrs. 8N
Aqueous sodium hydroxide solution (5 mL) and water (10 mL) were
added, and the mixture was extracted with dichloromethane. The
extract was dried over magnesium sulfate and concentrated. The
residue was added to the reaction system, wherein
1,1'-carbonylbis(1H-imidazole) (48.5 mg) and 2-methylpropan-2-amine
(22.0 mg) were dissolved in tetrahydrofuran (5.0 mL), and the
mixture was stirred for 1 hr. Triethylamine (1.0 mL) was further
added dropwise and the mixture was stirred for 1 hr. Under
ice-cooling, saturated aqueous sodium hydrogen carbonate was added,
and the mixture was extracted with dichloromethane. The extract was
dried over magnesium sulfate and concentrated, and the residue was
separated and purified by silica gel column chromatography (eluent,
ethyl acetate:methanol=100:0.fwdarw.ethyl acetate:methanol=80:20).
Crystallization from diethyl ether/ethyl acetate gave the title
compound (17.9 mg) as crystals.
[1543] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.26 (9H, s), 1.50-1.70
(2H, m), 1.81-1.95 (2H, m), 3.10 (3H, s), 3.11-3.65 (6H, m), 4.05
(2H, s), 4.45-4.65 (3H, m), 5.82 (1H, s), 6.47 (1H, d, J=3 Hz),
7.22 (1H, d, J=9 Hz), 7.55-7.58 (2H, m), 7.75 (1H, d, J=3 Hz), 8.27
(1H, s), 8.48 (1H, s), 8.66 (1H, m).
Example 273
##STR00321##
[1544] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N'-methoxyurea
[1545] To a solution of N,N'-carbonyldiimidazole (187 mg) in
N,N-dimethylformamide (2 mL) were added O-methylhydroxylamine
hydrochloride (96 mg) and triethylamine (0.27 mL) under
ice-cooling, and the mixture was stirred at room temperature for 30
min. A solution of
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg) in
N,N-dimethylformamide (5 mL) was added. The reaction mixture was
stirred at room temperature for 22 hrs, aqueous sodium hydrogen
carbonate and brine were added under ice-cooling, and the mixture
was extracted twice with ethyl acetate. The organic layers were
collected, dried over anhydrous magnesium sulfate and concentrated.
The residue was purified by silica gel column chromatography
(eluent, ethyl acetate:methanol=100:0.fwdarw.80:20) and further
recrystallized from ethyl acetate/diisopropyl ether to give the
title compound (116 mg) as crystals.
[1546] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.6-3.7 (2H, m), 3.70 (3H,
s), 4.5-4.6 (2H, m), 6.14 (1H, br s), 6.63 (1H, d, J=3.0 Hz), 7.05
(1H, d, J=9.0 Hz), 7.1-7.5 (5H, m), 7.65-7.75 (1H, m), 8.02 (1H, d,
J=2.7 Hz), 8.46 (1H, s), 8.52 (1H, s).
Example 274
##STR00322##
[1547] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N'-(2-methoxyethyl)urea
[1548] The title compound (147 mg) was obtained as a powder by the
reaction in the same manner as in Example 273 using
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg),
2-methoxyethylamine (87 mg) and N,N-dimethylformamide (3 mL).
[1549] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.05-3.15 (2H, m), 3.12
(3H, s), 3.2-3.5 (4H, m), 4.55-4.65 (2H, m), 6.42 (1H, br s), 6.56
(1H, br s), 6.68 (1H, d, J=1.8 Hz), 7.25-7.35 (2H, m), 7.36 (1H, d,
J=8.7 Hz), 7.52 (1H, d, J=8.1 Hz), 7.64 (1H, d, J=9.0 Hz), 7.76
(1H, d, J=9.0 Hz), 7.95-8.05 (2H, m), 8.75 (1H, s), 9.12 (1H,
s).
Example 275
##STR00323##
[1550] Production of
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]propanenitrile
[1551] The title compound (2.02 g) was obtained as a powder by the
reaction in the same manner as in Example 171 using
4-chloro-5H-pyrrolo[3,2-d]pyrimidine (3.07 g),
N,N-dimethylformamide (30 mL), potassium carbonate (4.15 g),
3-bromopropionitrile (3.48 g),
3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (2.26 g) and
isopropyl alcohol (20 mL).
[1552] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.01 (2H, t, J=6.4 Hz),
4.83 (2H, t, J=6.4 Hz), 6.58 (1H, s), 7.2-7.3 (2H, m), 7.31 (1H, d,
J=8.4 Hz), 7.47 (1H, d, J=7.5 Hz), 7.55-7.7 (2H, m), 7.7-7.8 (1H,
m), 7.87 (1H, s), 8.37 (1H, s), 8.76 (1H, s).
Example 276
##STR00324##
[1553] Production of
6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-8,9-dihydro-3,5,6,9a-te-
traazabenzo[cd]azulen-7(6H)-imine dihydrochloride
[1554] 12N Hydrogen chloride/ethanol (3 mL) was added to
3-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,-
2-d]pyrimidin-5-yl]propanenitrile (200 mg) under ice-cooling, and
the mixture was stirred at 0.degree. C. for 2 hrs. The reaction
mixture was concentrated and the residue was washed with ethyl
acetate and diisopropyl ether to give the title compound (161 mg)
as a powder.
[1555] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.55-3.65 (2H, m),
4.7-4.8 (2H, m), 6.75-6.8 (1H, m), 7.4-7.5 (2H, m), 7.5-7.6 (2H,
m), 7.65-7.75 (1H, m), 7.94 (1H, s), 8.05-8.1 (1H, m), 8.59 (1H,
s), 9.37 (1H, s), 11.29 (1H, s).
Example 277
##STR00325##
[1556] Production of
N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo-
[3,2-d]pyrimidin-5-yl]ethyl}-N'-methylguanidine dihydrochloride
[1557] To a solution of N-methyl-N,N'-bis(tert-butoxy
carbonyl)-1H-pyrazole-1-carboxamidine (138 mg) and
ethyldiisopropylamine (0.16 mL) in acetonitrile (4 mL) was added
5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg), and the
mixture was stirred at room temperature for 4 days. Under
ice-cooling, water was added, and the mixture was extracted with
ethyl acetate. The extract was washed with brine, dried over
anhydrous magnesium sulfate and concentrated. The residue was
purified by silica gel column chromatography (eluent, ethyl
acetate:hexane=80:20.fwdarw.100:0). The obtained product was
dissolved in ethyl acetate, 4N hydrochloric acid/ethyl acetate was
added, and the mixture was stirred at room temperature for 22 hrs.
The precipitate was collected by filtration, and washed with ethyl
acetate and diisopropyl ether to give the title compound (98 mg) as
a powder.
[1558] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.57 (3H, d, J=3.3 Hz),
3.5-3.7 (2H, m), 4.8-4.9 (2H, m), 6.72 (1H, s), 7.25-7.3 (2H, m),
7.38 (1H, d, J=9.0 Hz), 7.4-7.6 (3H, m), 7.6-7.75 (3H, m), 8.01
(2H, d, J=8.1 Hz), 8.75 (1H, s), 10.15 (1H, s).
Example 278
##STR00326##
[1559] Production of
2-(2-{4-[(3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}phenyl)amino]-
-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol dihydrochloride
(i) Production of
3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}nitrobenzene
[1560] To a solution of 4-[3-(1H-imidazol-1-yl)propyl]phenol (405
mg) and 3-chloro-4-fluoronitrobenzene (370 mg) in
N,N-dimethylformamide (4 mL) was added potassium carbonate (415
mg), and the mixture was stirred at room temperature for 16 hrs.
Under ice-cooling, water was added and the mixture was extracted
with ethyl acetate. The extract was washed with brine, dried over
anhydrous magnesium sulfate and concentrated. The residue was
purified by basic silica gel column chromatography (eluent, ethyl
acetate:hexane=80:20.fwdarw.100:0) to give the title compound (669
mg) as an oil.
[1561] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.1-2.25 (2H, m), 2.65
(2H, t, J=7.6 Hz), 3.98 (2H, t, J=6.9 Hz), 6.86 (1H, d, J=9.0 Hz),
6.93 (1H, s), 7.02 (1H, d, J=8.6 Hz), 7.09 (1H, s), 7.21 (1H, d,
J=8.6 Hz), 7.47 (1H, s), 8.04 (1H, dd, J=9.0, 2.7 Hz), 8.38 (1H, d,
J=2.7 Hz).
(ii) Production of
3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}aniline
[1562] To a solution of
3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}nitrobenzene (669
mg) in methanol (7 mL) was added 5% Pt/C (140 mg), and the mixture
was stirred under hydrogen atmosphere at room temperature for 16
hrs. 5% Pt/C was filtered off and the filtrate was concentrated.
The residue was purified by basic silica gel column chromatography
(eluent, ethyl acetate:hexane=80:20.fwdarw.100:0) and further
washed with diethyl ether and hexane to give the title compound
(277 mg) as a powder.
[1563] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.09 (2H, quintet, J=7.2
Hz), 2.56 (2H, t, J=7.2 Hz), 3.67 (2H, br s), 3.93 (2H, t, J=7.2
Hz), 6.56 (1H, dd, J=8.4, 2.7 Hz), 6.75-6.95 (5H, m), 7.0-7.1 (3H,
m), 7.45 (1H, s).
(iii) Production of
2-(2-{4-[(3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}phenyl)amino]-
-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol dihydrochloride
[1564] The title compound (99 mg) was obtained as a powder by the
reaction in the same manner as in Example 138 (ii) and (iii) using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (207 mg),
3-chloro-4-{4-[3-(1H-imidazol-1-yl)propyl]phenoxy}aniline (197 mg)
and tetrahydrofuran (4 mL).
[1565] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.1-2.3 (2H, m), 2.5-2.7
(2H, m), 3.4-3.6 (2H, m), 3.8-3.9 (2H, m), 4.23 (2H, t, J=6.8 Hz),
4.87 (2H, s), 6.71 (1H, d, J=2.4 Hz), 6.92 (2H, d, J=8.1 Hz), 7.14
(1H, d, J=8.1 Hz), 7.25 (2H, d, J=8.4 Hz), 7.6-7.7 (1H, m), 7.70
(1H, s), 7.83 (1H, s), 7.94 (1H, s), 8.04 (1H, d, J=3.0 Hz), 8.73
(1H, s), 9.22 (1H, s).
Example 279
##STR00327##
[1566] Production of
2-(2-{4-[(3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}phenyl)am-
ino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol
(i) Production of
3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}nitrobenzene
[1567] The title compound (721 mg) was obtained as an oil by the
reaction in the same manner as in Example 278 (i) using
4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (435 mg),
3-chloro-4-fluoronitrobenzene (370 mg) and N,N-dimethylformamide (4
mL).
[1568] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.6-1.75 (2H, m), 1.9-2.05
(2H, m), 2.68 (2H, t, J=7.4 Hz), 4.43 (2H, t, J=7.2 Hz), 6.85 (1H,
d, J=9.2 Hz), 7.00 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz), 7.53
(1H, s), 7.72 (1H, s), 8.04 (1H, dd, J=2.6, 9.2 Hz), 8.37 (1H, d,
J=2.6 Hz).
(ii) Production of
3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}aniline
[1569] The title compound (626 mg) was obtained as an oil by the
reaction in the same manner as in Example 278 (ii) using
3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}nitrobenzene
(711 mg) and ethyl acetate (10 mL).
[1570] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.55-1.7 (2H, m), 1.8-2.0
(2H, m), 2.60 (2H, t, J=7.5 Hz), 3.65 (2H, br s), 4.39 (2H, t,
J=7.2 Hz), 6.55 (1H, dd, J=8.7, 2.7 Hz), 6.75-6.85 (3H, m), 6.87
(1H, d, J=8.4 Hz), 7.04 (2H, d, J=8.4 Hz), 7.49 (1H, d, J=1.0 Hz),
7.69 (1H, d, J=1.0 Hz).
(iii) Production of
2-(2-{4-[(3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}phenyl)am-
ino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl}ethoxy)ethanol
[1571] The title compound (293 mg) was obtained as a powder by the
reaction in the same manner as in Example 139 (ii) and (iii) using
2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl
benzoate (346 mg),
3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenoxy}aniline (405
mg) and isopropyl alcohol (5 mL).
[1572] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.55-1.7 (2H, m),
1.85-2.0 (2H, m), 2.62 (2H, t, J=7.2 Hz), 3.7-3.75 (2H, m),
3.75-3.8 (2H, m), 4.02 (2H, t, J=4.2 Hz), 4.39 (2H, t, J=6.9 Hz),
4.56 (2H, t, J=4.2 Hz), 6.63 (1H, d, J=3.0 Hz), 6.88 (2H, d, J=8.7
Hz), 6.98 (1H, d, J=8.4 Hz), 7.08 (2H, d, J=8.7 Hz), 7.21 (1H, d,
J=3.3 Hz), 7.50 (1H, s), 7.54 (1H, dd, J=8.7, 2.7 Hz), 7.87 (1H, d,
J=2.7 Hz), 7.69 (1H, s), 8.51 (1H, s), 8.73 (1H, s).
Example 280
##STR00328##
[1573] Production of
2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phen-
yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide
methanesulfonate
[1574] The title compound (1.0 g) was obtained as colorless
crystals by the reaction in the same manner as in Example 256 using
2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phen-
yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-y]ethyl}acetamide (900 mg),
ethyl acetate (4.5 mL) and methanesulfonic acid (0.114 mL).
[1575] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.19 (3H, s), 2.32 (3H,
s), 3.05 (3H, s), 3.55 (2H, q, J=6 Hz), 4.06 (2H, s), 4.68 (2H, t,
J=6 Hz), 6.65 (1H, d, J=3 Hz), 6.93 (2H, m), 7.12 (2H, m), 7.4-7.6
(3H, m), 7.92 (1H, d, J=3 Hz), 8.70 (2H, m), 9.84 (1H, br s).
Formulation Example 1
Amount Per Tablet
TABLE-US-00001 [1576] (1) Compound obtained in Example 39 10.0 mg
(2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5)
Magnesium stearate 2.0 mg
[1577] A mixture of 10.0 mg of the compound obtained in Example 39,
60.0 mg of lactose and 35.0 mg of corn starch is granulated through
a 1 mm-mesh sieve using 0.03 ml of a 10% by weight aqueous solution
of gelatin (3.0 mg of gelatin), after which the granules are dried
at 40.degree. C. and filtered again. The granules obtained are
mixed with 2.0 mg of magnesium stearate and compressed. The core
tablets obtained are coated with a sugar coat comprising a
suspension of sucrose, titanium dioxide, talc and gum arabic and
polished with beeswax to yield sugar-coated tablets.
Formulation Example 2
Dose Per Tablet
TABLE-US-00002 [1578] (1) Compound obtained in Example 39 10.0 mg
(2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0
mg (5) Magnesium stearate 3.0 mg
[1579] 10.0 mg of the compound obtained in Example 39 and 3.0 mg of
magnesium stearate are granulated using 0.07 ml of an aqueous
solution of soluble starch (7.0 mg of soluble starch), after which
these granules are dried and mixed with 70.0 mg of lactose and 50.0
mg of corn starch. This mixture is compressed to yield tablets.
[1580] Experimental Example 1A Cloning of human HER2 gene and
preparation of recombinant baculovirus Human HER2 gene was cloned
by RT-PCR using total RNA prepared from MCF7 cells as a template.
The primer used for RT-PCR was prepared from nucleotide sequence
(Genbank Accession M11730) information of HER2 gene by adding a
nucleotide sequence encoding flag peptide and a restriction enzyme
recognition sequence to a nucleotide sequence (2176-3918 of Genbank
Accession M11730) encoding the HER2 intracellular domain region, so
that the protein contains an N-terminal Flag tag. The primer
nucleotide sequence is shown below.
TABLE-US-00003 HER2-U: (SEQ ID NO:1)
5'-AATTAAGTCGACATGGACTACAAAGACGATGACGACAAGCGACGGCA
GCAGAAGATCCGGAAGTAC-3' and HER2-L: (SEQ ID NO:2)
5'-AATTAAGCATGCTCACACTGGCACGTCCAGACCCAGGTACTC-3'
[1581] The RT reaction was conducted using SuperScript First-Strand
Synthesis System for RT-PCR (Invitrogen) and the PCR reaction was
conducted using a KOD-plus kit (TOYOBO). The obtained PCR product
was electrophoresed on agarose gel (1%), the DNA fragment amplified
by PCR was recovered from the gel, and then digested with
restriction enzymes Sal I and Sph I. The DNA treated with the
restriction enzymes was electrophoresed on agarose gel (1%), and
the obtained DNA fragment was recovered and ligated to plasmid
pFASTBAC1 (Invitrogen) digested with restriction enzymes Sal I and
Sph I to give expression plasmid pFB-HER2. The nucleotide sequence
of the insertion fragment was confirmed and found to be identical
with the nucleotide sequence (2176-3918 of Genbank Accession
M11730) of HER2 intracellular domain. Furthermore, using BAC-TO-BAC
Baculovirus Expression System (Invitrogen), recombinant baculovirus
BAC-HER2 was prepared.
Experimental Example 1B
Preparation of HER2 Intracellular Domain Protein
[1582] SF-21 cells were sown at 1.times.10.sup.6 cells/mL to
Sf-900II SFM medium (1 L, Invitrogen) containing 10% fetal bovine
serum (trace), 50 mg/L gentamicin (Invitrogen) and 0.1% Pluronic
F-68 (Invitrogen), and shaking culture was performed using a 2 L
volume Erlenmeyer flask at 27.degree. C., 100 rpm. After culturing
for 24 hrs, recombinant baculovirus BAC-HER2 (13.4 mL) was added,
and the mixture was further cultured for 3 days. The culture medium
was centrifuged at 2,000 rpm for 5 min. to give virus-infected
cells. The infected cells were washed with a phosphate buffered
saline (Invitrogen), centrifuged under the same conditions, and the
cells were preserved at -80.degree. C. The cryopreserved cells were
thawed in ice, suspended in buffer A (50 mM Tris buffer (30 mL, pH
7.4) containing 20% glycerol, 0.15 M NaCl) supplemented with
Complete Protease Inhibitor (Boehringer), and ruptured 3 times with
a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 sec. The
rupture medium was clarified by centrifugation at 40,000 rpm for 30
min. and filtered with a 0.45 .mu.m filter. The filtrate was passed
through a column packed with Anti-FLAG M2 Affinity Gel (4 mL,
Sigma) at a flow rate of about 0.5 mL/min. The column was washed
with buffer A, and eluted with buffer A containing 100 .mu.g/mL of
FLAG peptide. The eluate was concentrated with Vivaspin 20
(Vivascience) having a molecular weight cut off of 30K. The
concentrate was purified by gel filtration using Hi Load Superdex
200 .mu.g 16/60 (Amersham Bioscience) equilibrated with buffer A.
The fractions containing HER2 intracellular domain were collected,
glycerol was added to the final concentration of 50% and
cryopreserved at -80.degree. C.
Experimental Example 1C
Determination of HER2 Kinase Inhibitory Activity
[1583] A test compound dissolved in dimethyl sulfoxide (DMSO) was
diluted with a buffer for kinase reaction (50 mM Tris-HCl (pH7.5),
5 mM MgCl.sub.2, 5 mM MnCl.sub.2, 2 mM dithiothreitol, 0.01%
Tween-20). To this compound solution (10 .mu.L) was added a buffer
for kinase reaction (20 .mu.L) containing 5 .mu.g/mL of HER2
intracellular domain obtained in Experimental Example 1B and 12.5
.mu.g/mL of polypeptide substrate poly-Glu:Tyr (4:1) (Sigma). To
the obtained mixture was added 20 .mu.L of ATP solution (1.25 .mu.M
ATP, 0.05 .mu.Ci [.gamma.-.sup.32P]ATP), the mixture was allowed to
react at 25.degree. C. for 10 min. and the reaction was quenched
with 50 .mu.L of 20% TCA solution. The reaction solution was
allowed to stand at 4.degree. C. for 20 min., and the acid
insoluble fraction was transferred to GF/C filter (PerkinElmer)
using cell harvester (PerkinElmer) and washed with 250 mM
phosphoric acid solution. After washing, the plate was dried at
45.degree. C. for 60 min., and 35 .mu.L of MicroScinti 0
(PerkinElmer) was added. The radioactivity was measured using
TopCount (PerkinElmer). HER2 kinase inhibitory rate (%) of the test
compound was calculated by the following formula:
Inhibitory rate (%)=(1-(count of test
compound-blank)/(control-blank)).times.100
[1584] The count of the solution reacted without addition of the
compound was used as a "control", and the count of the solution
without the compound and HER2 intracellular domain was used as a
"blank". The results of the inhibitory rate of the compounds are
shown in Table 1.
[1585] From the foregoing, it was shown that the compounds of the
present invention strongly inhibited the activity of HER2
kinase.
TABLE-US-00004 TABLE 1 Example No. (compound No.) Inhibitory rate
(%) at 1.0 .mu.M 13 94.9 38 95.9 39 96.1 158 87.0 190 95.9 191
100
[1586] Experimental Example 2A Cloning of human EGF receptor gene
and preparation of recombinant baculovirus Human EGF receptor gene
was cloned by RT-PCR using total RNA prepared from A431 cells as a
template. The primer for RT-PCR was prepared from nucleotide
sequence (Genbank Accession XM.sub.--167493) information of EGF
receptor gene by adding a nucleotide sequence encoding flag peptide
and a restriction enzyme recognition sequence to a nucleotide
sequence (2182-3810 of Genbank Accession XM.sub.--167493) encoding
EGF receptor intracellular domain region, so that the protein
contains an N-terminal Flag tag. The primer nucleotide sequence is
shown below.
TABLE-US-00005 EGFR-U: (SEQ ID NO:3)
5'-AATTAAGTCGACATGGACTACAAAGACGATGACGACCGAAGGCGCCA
CATCGTTCGGAAGCGCACG-3' and EGFR-L: (SEQ ID NO:4)
5'-AATTAAGCATGCTCATGCTCCAATAAATTCACTGCTTTGTGG-3'
[1587] The RT reaction was conducted using SuperScript First-Strand
Synthesis System for RT-PCR (Invitrogen) and the PCR reaction was
conducted using a KOD-plus kit (TOYOBO). The obtained PCR product
was electrophoresed on agarose gel (1%), the DNA fragment amplified
by PCR was recovered from the gel, and then digested with
restriction enzymes Sal I and Sph I. The DNA treated with the
restriction enzymes was electrophoresed on agarose gel (1%), and
the obtained DNA fragment was recovered and ligated to plasmid
pFASTBAC1 (Invitrogen) digested with restriction enzymes Sal I and
Sph I to give expression plasmid pFB-EGFR. The nucleotide sequence
of insertion fragment was confirmed and found to be identical with
the nucleotide sequence (2182-3810 of Genbank Accession
XM.sub.--167493) of EGFR intracellular domain. Furthermore, using
BAC-TO-BAC Baculovirus Expression System (Invitrogen), virus stock
BAC-EGFR of recombinant baculovirus was prepared.
Experimental Example 2B
Preparation of EGF Receptor Intracellular Domain Protein
[1588] SF-21 cells were sown at 1.times.10.sup.6 cells/mL to
Sf-900II SFM medium (1 L, Invitrogen) containing 10% fetal bovine
serum (trace), 50 mg/L gentamicin (Invitrogen) and 0.1% Pluronic
F-68 (Invitrogen), and shaking culture was performed using a 2 L
volume Erlenmeyer flask at 27.degree. C., 100 rpm. After culturing
for 24 hrs, recombinant baculovirus BAC-EGFR (13.4 mL) was added,
and the mixture was further cultured for 3 days. The culture medium
was centrifuged at 2,000 rpm for 5 min. to give virus-infected
cells. The infected cells were washed with a phosphate buffered
saline (Invitrogen), centrifuged under the same conditions, and the
cells were preserved at -80.degree. C. The cryopreserved cells were
thawed in ice, suspended in buffer A (50 mM Tris buffer (30 mL,
pH7.4) containing 20% glycerol, 0.15 M NaCl) supplemented with
Complete Protease Inhibitor (Boehringer), and ruptured 3 times with
a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 sec. The
ruptured medium was clarified by centrifugation at 40,000 rpm for
30 min. and filtered with a 0.45 .mu.m filter. The filtrate was
passed through a column packed with Anti-FLAG M2 Affinity Gel (4
mL, Sigma) at a flow rate of about 0.5 mL/min. The column was
washed with buffer A, and eluted with buffer A containing 100
.mu.g/mL of FLAG peptide. The eluate was concentrated with Vivaspin
20 (Vivascience) having a molecular weight cut off of 30K. The
buffer of this concentrate was exchanged using NAPE column
(Amersham Bioscience) equilibrated with buffer A. The fractions
containing EGF receptor intracellular domain protein were
collected, glycerol was added to the final concentration of 50% and
cryopreserved at -80.degree. C.
Experimental Example 2C
Determination of EGF Receptor Kinase Inhibitory Activity
[1589] A test compound dissolved in dimethyl sulfoxide (DMSO) was
diluted with a buffer (50 mM Tris-HCl (pH 7.5), 5 mM MgCl.sub.2, 5
mM MnCl.sub.2, 2 mM dithiothreitol, 0.01% Tween-20). To this
compound solution (5 .mu.L) was added a buffer (10 .mu.L)
containing 250 ng/mL of EGF receptor intracellular domain protein
and 250 ng/mL of biotin labeled polypeptide biotinyl-poly-Glu:Tyr
(4:1) (CIS bio International). To the obtained mixture was added a
buffer (10 .mu.L) containing ATP (5 .mu.M), the mixture was allowed
to react at 25.degree. C. for 10 min. and the reaction was quenched
with 25 .mu.L of a stop solution (100 mM EDTA disodium salt, 62.5
mM HEPES buffer (pH 7.4), 250 mM NaCl, 0.1% bovine serum albumin,
10 .mu.g/mL AlphaScreen assay streptavidin donor beads
(Streptavidin Donor beads: PerkinElmer), 10 .mu.g/mL AlphaScreen
assay anti-phosphotyrosine recognition antibody PY-100 binding
acceptor beads (Anti-phosphotyrosine (P-Tyr-100) Acceptor beads:
PerkinElmer)). The reaction solution was allowed to stand at
25.degree. C. for 16 hrs, and the cells were counted using a plate
reader Fusions (PerkinElmer). The kinase inhibitory rate (%) of the
test compound was calculated by the following formula:
Inhibitory rate (%)=(1-(count of test
compound-blank)/(control-blank)).times.100
[1590] The count of the solution reacted without addition of the
compound was used as a "control", and the count of the solution
without the compound and ATP was used as a "blank". The results of
the inhibitory rate of the compounds are shown in Table 2.
[1591] From the foregoing, it was shown that the compounds of the
present invention strongly inhibited the activity of EGF receptor
kinase.
TABLE-US-00006 TABLE 2 Example No. (compound No.) Inhibitory rate
(%) at 1.0 .mu.M 22 98.5 41 98.9 92 98.0 138 99.0 147 96.0 160
97.0
Experimental Example 3
Inhibitory Action on Breast Cancer Cell BT-474 Proliferation In
Vitro
[1592] A suspension of human breast cancer cell BT-474 (100 .mu.l
(6,000 cells)) were sown to a 96-well microplate and cultured in an
incubator (37.degree. C., 5% carbon dioxide). On the following day,
100 .mu.l of a solution of each test compound, which was previously
diluted 2-fold, was added, and the cells were cultured for 5 days.
After the culture medium containing the test compound was removed,
the cells were washed and fixed with 50% trichloroacetic acid,
after which a 0.4% (w/v) SRB solution (dissolved in 1% acetic acid)
was added to fix and stain the cell protein (Skehan et al., Journal
of the National Cancer Institute, Vol. 82, pp. 1107-1112, 1990).
After washing with a 1% acetic acid solution, 100 .mu.l of an
extract (10 mM Tris solution) was added to extract the pigment, and
absorbance was measured at an absorption wavelength of 550 nm to
quantify the amount of cells as protein content. Taking as 100% the
protein content for the control group, which received no test
compound solution, the ratio of the residual protein content for
each treatment group was determined, and the compound concentration
required to achieve 50% suppression of the residual cell content
relative to the control (IC.sub.50 value) was calculated. The
results are shown in Table 3.
TABLE-US-00007 TABLE 3 Example No. (compound No.) IC.sub.50 (nM) 82
<100 92 <100 169 <100 176 <100
INDUSTRIAL APPLICABILITY
[1593] According to the present invention, pyrrolo[3,2-d]pyrimidine
and pyrazolo[4,3-d]pyrimidine compounds, a production method
thereof and use thereof are provided. These fused pyrimidine
compounds have a superior tyrosine kinase inhibitory action, are
low toxic, and are sufficiently satisfactory as pharmaceutical
products.
[1594] This application is based on patent application Nos.
165050/2004 and 58231/2005 filed in Japan, the contents of which
are hereby incorporated by reference.
Sequence CWU 1
1
4166DNAArtificialprimer for cloning human HER2 gene 1aattaagtcg
acatggacta caaagacgat gacgacaagc gacggcagca gaagatccgg 60aagtac
66242DNAArtificialprimer for cloning human HER2 gene 2aattaagcat
gctcacactg gcacgtccag acccaggtac tc 42366DNAArtificialprimer for
cloning human EGFR gene 3aattaagtcg acatggacta caaagacgat
gacgaccgaa ggcgccacat cgttcggaag 60cgcacg 66442DNAArtificialprimer
for cloning human EGFR gene 4aattaagcat gctcatgctc caataaattc
actgctttgt gg 42
* * * * *