U.S. patent application number 12/240004 was filed with the patent office on 2009-02-26 for pyrazolopyrimidine derivatives or pharmaceutically acceptable salts thereof.
This patent application is currently assigned to TEIJIN PHARMA LIMITED. Invention is credited to Kenichiro KATAOKA, Tomomi KOSUGI, Hiroaki MAKINO, Mika TAKAKUWA, Gen UNOKI, Yuko YAMAKOSHI.
Application Number | 20090054472 12/240004 |
Document ID | / |
Family ID | 38286331 |
Filed Date | 2009-02-26 |
United States Patent
Application |
20090054472 |
Kind Code |
A1 |
UNOKI; Gen ; et al. |
February 26, 2009 |
Pyrazolopyrimidine Derivatives or Pharmaceutically Acceptable Salts
Thereof
Abstract
A pyrazolopyrimidine derivative represented by formula (1) and
pharmaceutically acceptable salt thereof exhibit excellent
inhibitory activity against MAPKAP-K2. Accordingly, medicines
containing this compound as an active ingredient are expected to be
effective for treating diseases mediated by MAPKAP-K2 such as, for
example, inflammatory disorder, autoimmune diseases, destructive
osteopathy, cancer and/or tumor growth. ##STR00001##
Inventors: |
UNOKI; Gen; (Tokyo, JP)
; KOSUGI; Tomomi; (Tokyo, JP) ; TAKAKUWA;
Mika; (Tokyo, JP) ; MAKINO; Hiroaki;
(Yamaguchi, JP) ; KATAOKA; Kenichiro; (Tokyo,
JP) ; YAMAKOSHI; Yuko; (Tokyo, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W., SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
TEIJIN PHARMA LIMITED
Tokyo
JP
|
Family ID: |
38286331 |
Appl. No.: |
12/240004 |
Filed: |
September 29, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11377363 |
Mar 17, 2006 |
|
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12240004 |
|
|
|
|
60663205 |
Mar 21, 2005 |
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Current U.S.
Class: |
514/267 ;
540/578; 544/251 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 487/14 20130101; A61P 25/00 20180101; A61P 37/00 20180101;
A61P 35/00 20180101; A61P 3/10 20180101; C07D 471/14 20130101 |
Class at
Publication: |
514/267 ;
544/251; 540/578 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 487/14 20060101 C07D487/14; A61P 25/00 20060101
A61P025/00; A61P 37/00 20060101 A61P037/00; A61P 29/00 20060101
A61P029/00; A61P 3/10 20060101 A61P003/10; A61P 35/00 20060101
A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 17, 2005 |
JP |
2005-077509 |
Claims
1. A pyrazolopyrimidine derivative or medically acceptable salt
thereof represented by formula (1): ##STR01350## [wherein, R.sup.1
represents a hydrogen atom or a halogen; R.sup.2 represents a
hydrogen atom or a halogen; R.sup.3 represents a hydrogen atom, an
optionally substituted C1-C8 alkyl group, an optionally substituted
C3-C8 cycloalkyl group, an optionally substituted heterocyclic
group, an optionally substituted C6-C14 aryl group or --OR.sup.5;
R.sup.5 represents a hydrogen atom, an optionally substituted C1-C8
alkyl group or --(C.dbd.O)R.sup.6; R.sup.6 represents an optionally
substituted C1-C8 alkyl group; n represents 0 or 1, or n represents
0 when R.sup.3 is --OR.sup.5; R.sup.4 represents a hydrogen atom,
an optionally substituted C1-C8 alkyl group, an optionally
substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl,
an optionally substituted C3-C8 cycloalkyl group, an optionally
substituted C6-C14 aryl group, an optionally substituted
heterocyclic group, an optionally substituted heterocyclylalkyl
group or an optionally substituted C7-C16 aralkyl group; the
substituents in the optionally substituted C6-C14 aryl group as
R.sup.4 are one or more substituents selected from the group
consisting of halogen, --CN, --NO.sub.2, --CHO, --OH, --COOH,
optionally substituted C1-C8 alkyl group, optionally substituted
C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally
substituted C3-C8 cycloalkyl group, --O--(CH.sub.2).sub.m--W,
optionally substituted C6-C14 aryl group, optionally substituted
heterocyclic group, --C(.dbd.O)--R.sup.133, --O--C(.dbd.O)R.sup.26,
--C(.dbd.O)OR.sup.27, --NR.sup.28C(.dbd.O)R.sup.29,
--NR.sup.30R.sup.31, --C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.34C(.dbd.X.sup.1)OR.sup.35,
--NR.sup.36C(.dbd.X.sup.2)NR.sup.37R.sup.38,
--NR.sup.39--SO.sub.2R.sup.40, --S(O).sub.r--R.sup.41 and
--SO.sub.2NR.sup.42R.sup.43, wherein X.sup.1 or X.sup.2 represents
O, S, N--CN or NH and r represents 0 to 2; W represents a hydrogen
atom, an optionally substituted C1-C8 alkyl group, an optionally
substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl,
an optionally substituted C3-C8 cycloalkyl group, an optionally
substituted C6-C14 aryl group or an optionally substituted
heterocyclic group, and in this case m represents 0 to 4; or W
represents an optionally substituted C1-C8 alkoxy group,
--NR.sup.150R.sup.151 or an optionally substituted phenoxy group
and in this case m represents 1 to 4; R.sup.26 to R.sup.43,
R.sup.133, R.sup.150 and R.sup.151 may be identical or different
and each represents a hydrogen atom, an optionally substituted
C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an
optionally substituted C2-C8 alkynyl, an optionally substituted
C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl
group, an optionally substituted heterocyclic group, an optionally
substituted aralkyl group or an optionally substituted
heterocyclylalkyl group, or, when R.sup.30 and R.sup.31R.sup.32 and
R.sup.33R.sup.37 and R.sup.38, R.sup.42 and R.sup.43 or R.sup.150
and R.sup.151 are optionally substituted alkyl groups, the
substituents in each combination may form a saturated or
unsaturated 5- to 7-membered ring together with the nitrogen atom
to which they bond, and this ring may contain 1 or 2 heteroatoms
selected from the group consisting of oxygen atom, nitrogen atom
and sulfur atom besides the nitrogen atom to which these
substituents bond; -A-B- represents --CH.sub.2--CH(-Z.sup.1)-,
--(CH.sub.2).sub.p--, --CH.sub.2--CH.dbd.CH--CH.sub.2--,
--CH.dbd.C(-Z.sup.2)-- or --(CH.sub.2).sub.q--C(.dbd.O)--; p
represents 3 or 4 and q represents 1 or 2; Z.sup.1 and Z.sup.2 may
be identical or different and each represents a hydrogen atom or
--CH.sub.2--OR.sup.11; and R.sup.11 represents a hydrogen atom, an
optionally substituted C1-C8 alkyl group or a substituted silyl
group.]
2. A pyrazolopyrimidine derivative or medically acceptable salt
thereof represented by formula (1): ##STR01351## [wherein, R.sup.1
represents a hydrogen atom or a halogen; R.sup.2 represents a
hydrogen atom or a halogen; R.sup.3 represents a hydrogen atom, an
optionally substituted C1-C8 alkyl group, an optionally substituted
C3-C8 cycloalkyl group, an optionally substituted heterocyclic
group, an optionally substituted C6-C14 aryl group or --OR.sup.5;
R.sup.5 represents a hydrogen atom, an optionally substituted C1-C8
alkyl group or --(C.dbd.O)R.sup.6; R.sup.6 represents an optionally
substituted C1-C8 alkyl group; n represents 0 or 1 or n represents
0 and when R.sup.3 is --OR.sup.5; R.sup.4 represents an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group, an optionally substituted C6-C14 aryl group, an
optionally substituted heterocyclic group or an optionally
substituted C7-C16 aralkyl group; the substituents in the
optionally substituted C6-C14 aryl group as R.sup.4 are one or more
substituents selected from the group consisting of halogen, --CN,
--NO.sub.2, optionally substituted C1-C8 alkyl group,
--O--(CH.sub.2).sub.m--W, optionally substituted C6-C14 aryl group,
optionally substituted heterocyclic group, --C(.dbd.O)OR.sup.7,
--NR.sup.8C(.dbd.O)R.sup.9, --NR.sup.10R.sup.127,
--C(.dbd.O)NR.sup.128R.sup.129 and --SO.sub.2NR.sup.130R.sup.131; W
represents a hydrogen atom, an optionally substituted C1-C8 alkyl
group, an optionally substituted C3-C8 cycloalkyl group, an
optionally substituted C6-C14 aryl group or an optionally
substituted heterocyclic group and in this case m represents 0 to
4; or W represents an optionally substituted C1-C8 alkoxy group or
an optionally substituted phenoxy group and in this case m
represents 1 to 4; R.sup.7 to R.sup.10 and R.sup.127 to R.sup.131
may be identical or different and each represents a hydrogen atom,
an optionally substituted C1-C8 alkyl group, an optionally
substituted C3-C8 cycloalkyl group or an optionally substituted
C6-C14 aryl group, or, when R.sup.10 and R.sup.127, R.sup.128 and
R.sup.129 or R.sup.130 and R.sup.131 are optionally substituted
alkyl groups, they may form a saturated or unsaturated 5- to
7-membered ring together with the nitrogen atom to which they bond,
and this ring may contain 1 or 2 heteroatoms selected from the
group consisting of oxygen atom, nitrogen atom and sulfur atom
besides the nitrogen atom to which these substituents bond; -A-B-
represents --CH.sub.2--CH(-Z.sup.3)-, --(CH.sub.2).sub.p--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--, --CH.dbd.C(-Z.sup.4)-- or
--(CH.sub.2).sub.q--C(.dbd.O)--; p represents 3 or 4 and q
represents 1 or 2; Z.sup.3 and Z.sup.4 may be identical or
different and each represents a hydrogen atom or
--CH.sub.2--OR.sup.11; and R.sup.11 represents a hydrogen atom or
an optionally substituted C1-C8 alkyl group.]
3. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.1 is a hydrogen
atom.
4. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.2 is a hydrogen
atom.
5. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.2 is a
halogen.
6. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.3 is an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group or an optionally substituted heterocyclic
group.
7. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.3 is an
unsubstituted C1-C4 alkyl group, a substituted C1-C4 alkyl group
(wherein the substituents are 1 to 3 substituents selected from the
group consisting of halogen, phenyl group, C1-C4 alkyl group
substituted with 1 to 9 halogens, C1-C4 alkoxy group, C1-C4 alkoxy
group substituted with 1 to 9 halogens, --CN, --CHO, --OH,
--(C.dbd.O)OH, --(C.dbd.O)OR.sup.86--(C.dbd.O)NR.sup.87R.sup.88 and
--NR.sup.89R.sup.90; R.sup.86 represents a C1-C4 alkyl group, a
C3-C8 cycloalkyl group or a phenyl group; R.sup.87 and R.sup.88 may
be identical or different and each represents a hydrogen atom, a
C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or an
aralkyl group; R.sup.89 represents a hydrogen atom, a C1-C4 alkyl
group, a phenyl group or a benzyl group; R.sup.90 represents a
hydrogen atom, a C1-C4 alkyl group, a benzyl group, an acetyl
group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group,
or, when R.sup.89 and R.sup.90 are alkyl groups, they may form a
saturated or unsaturated 5- to 7-membered ring together with the
nitrogen atom to which they bond; further this ring may contain 1
or 2 heteroatoms selected from the group consisting of oxygen atom,
nitrogen atom and sulfur atom besides the nitrogen atom to which
R.sup.89 and R.sup.90 bond), an unsubstituted C3-C8 cycloalkyl
group, a substituted C3-C8 cycloalkyl group (wherein the
substituents are 1 to 3 substituents selected from the group
consisting of halogen, --OH, --(C.dbd.O)OH, C1-C4 alkyl group,
C1-C4 alkoxy group and --NR.sup.91R.sup.92, wherein R.sup.91
represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or
a benzyl group and R.sup.92 represents a hydrogen atom, a C1-C8
alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl
group or a benzyloxycarbonyl group), an unsubstituted heterocyclic
group or a substituted heterocyclic group (wherein, when carbon
atom(s) in the substituted heterocyclic group are substituted, the
substituent(s) are 1 to 3 substituents selected from the group
consisting of halogen, --(C.dbd.O)OH, C1-C4 alkyl group, C1-C4
alkyl group substituted with 1 to 9 halogens, phenyl group, benzyl
group, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with 1 to
9 halogens and --NR.sup.93R.sup.94, wherein R.sup.93 represents a
hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl
group and R.sup.94 represents a hydrogen atom, a C1-C8 alkyl group,
a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group, wherein, when nitrogen atom(s) in the
heterocycle are substituted, the substituents are one or more
substituents selected from the group consisting of C1-C4 alkyl
group, benzyl group, acetyl group, tert-butoxycarbonyl group and
benzyloxycarbonyl group).
8. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.3 is an
unsubstituted heterocyclic group (wherein the heterocyclic group
represents a monocyclic 5- to 8-membered heterocyclic group
containing 1 or 2 heteroatoms selected from the group consisting of
N, O and S), a substituted saturated heterocyclic group (wherein
the heterocyclic group represents a monocyclic 5- to 8-membered
heterocyclic group containing 1 or 2 heteroatoms selected from the
group consisting of N, O and S, and the substituent bonds to a
nitrogen atom in the heterocycle and the substituents represent one
or more substituents selected from the group consisting of C1-C4
alkyl group, benzyl group and tert-butoxycarbonyl group), a C1-C4
alkyl group substituted with one amino group or a C3-C8 cycloalkyl
group substituted with one amino group.
9. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.3 is a piperidyl
group, a pyrrolidinyl group or a cyclohexyl group substituted with
an amino group.
10. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein n is 0.
11. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted C6-C14 aryl group.
12. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted C6-C14 aryl group and the substituents are one or more
substituents selected from the group consisting of halogen, --CN,
optionally substituted C1-C8 alkyl group, --O--(CH.sub.2).sub.m--W,
optionally substituted C6-C14 aryl group, optionally substituted
heterocyclic group, --C(.dbd.O)OR.sup.7 and
--C(.dbd.O)NR.sup.9R.sup.10.
13. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted C6-C14 aryl group and the substituents are one or more
substituents selected from the group consisting of halogen, --CN,
optionally substituted C1-C8 alkyl group and
--O--(CH.sub.2).sub.m--W.
14. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted C6-C14 aryl group and the substituents are one or more
--O--(CH.sub.2).sub.m--W, wherein W is a hydrogen atom, an
optionally substituted C1-C8 alkyl group, an optionally substituted
heterocyclic group or an optionally substituted C1-C8 alkoxy
group.
15. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted C6-C14 aryl group and the substituents are one or more
substituents selected from the group consisting of halogen, --CN,
optionally substituted C1-C8 alkyl group, optionally substituted
C6-C14 aryl group and optionally substituted heterocyclic
group.
16. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted C6-C14 aryl group and the substituents are one or more
substituents selected from the group consisting of halogen, --CN,
optionally substituted C1-C8 alkyl group, --C(.dbd.O)OR.sup.7 and
--C(.dbd.O)NR.sup.9R.sup.10.
17. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted C6-C14 aryl group (wherein the substituents are 1 to 3
substituents selected from the group consisting of halogen, --CN,
optionally substituted C1-C8 alkyl group, --O--(CH.sub.2).sub.m--W
and --C(.dbd.O)OR.sup.113, wherein W represents a hydrogen atom, an
optionally substituted C1-C4 alkyl group, an optionally substituted
C3-C8 cycloalkyl group, an optionally substituted phenyl group or
an optionally substituted monocyclic or bicyclic heterocyclic group
and m represents 0 to 4; or W represents an optionally substituted
C1-C4 alkoxy group and m represents 1 to 4, and R.sup.113
represents an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group or an optionally
substituted phenyl group).
18. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted phenyl group (wherein the substituent is one
--O--(CH.sub.2).sub.m--W, wherein W represents a hydrogen atom or
an optionally substituted C1-C4 alkyl group and m represents 0 to
4; or W represents an optionally substituted C1-C4 alkoxy group and
m represents 1 to 4).
19. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted C6-C14 aryl group (wherein the substituents are one or
more substituents selected from the group consisting of halogen,
--CN, optionally substituted C1-C4 alkyl group, optionally
substituted phenyl group and optionally substituted monocyclic or
bicyclic heterocyclic group).
20. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted C6-C14 aryl group (wherein the substituents are one or
more substituents selected from the group consisting of halogen,
--CN, optionally substituted C1-C4 alkyl group,
--C(.dbd.O)OR.sup.113 and --C(.dbd.O)NR.sup.118R.sup.119, wherein
R.sup.113, R.sup.118 and R.sup.119 may be identical or different
and each represents a hydrogen atom, an optionally substituted
C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group
or an optionally substituted C6-C14 aryl group; and when R.sup.118
and R.sup.119 are alkyl groups, they may form a saturated or
unsaturated 5- to 7-membered ring together with the nitrogen atom
to which they bond, and this ring may contain 1 or 2 heteroatoms
selected from the group consisting of oxygen atom, nitrogen atom
and sulfur atom besides the nitrogen atom to which they bond).
21. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted heterocyclic group.
22. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted bicyclic heteroaryl group (wherein, when carbon atom(s)
in the bicyclic heteroaryl group are substituted, the substituents
are 1 to 3 substituents selected from the group consisting of
halogen, --CN, C1-C8 alkyl group, C1-C4 alkyl group substituted
with 1 to 9 halogens, C1-C8 alkoxy group, C1-C4 alkoxy group
substituted with 1 to 9 halogens, phenyl group, monocyclic or
bicyclic heterocyclic group, --C(.dbd.O)OR.sup.122,
--NR.sup.123R.sup.124 and --C(.dbd.O)NR.sup.125R.sup.126, wherein
R.sup.123 represents a hydrogen atom, a C1-C8 alkyl group, a phenyl
group or a benzyl group, R.sup.124 represents a hydrogen atom, a
C1-C8 alkyl group, a benzyl group, an acetyl group, a
tert-butoxycarbonyl group or a benzyloxycarbonyl group, R.sup.122
represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a
phenyl group, and R.sup.125 and R.sup.126 may be identical or
different and each represents a hydrogen atom, a C1-C8 alkyl group,
a C3-C8 cycloalkyl group, a phenyl group or a benzyl group; when
nitrogen atom(s) in the heterocycle are substituted, the
substituents are one or more substituents selected from the group
consisting of C1-C4 alkyl group, benzyl group, acetyl group,
tert-butoxycarbonyl group and benzyloxycarbonyl group).
23. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted bicyclic heteroaryl group (wherein the bicyclic
heteroaryl group means a bicyclic heteroaryl group wherein a phenyl
group is fused with an aromatic heterocycle containing 1 or 2
heteroatoms selected from the group consisting of N, O and S; when
carbon atom(s) in the bicyclic heteroaryl group are substituted,
the substituents are 1 to 3 substituents selected from the group
consisting of halogen, C1-C4 alkyl group and C1-C4 alkyl group
substituted with 1 to 9 halogens; when nitrogen atom(s) in the
heterocycle are substituted, the substituent represents one or more
C1-C4 alkyl group).
24. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is a hydrogen
atom, an optionally substituted C1-C8 alkyl group, an optionally
substituted C3-C8 cycloalkyl group, an optionally substituted
C7-C16 aralkyl group or an optionally substituted heterocyclylalkyl
group.
25. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein R.sup.4 is an optionally
substituted heterocyclylalkyl group.
26. The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to claim 1 or 2, wherein -A-B- is
--CH.sub.2--CH.sub.2--, --(CH.sub.2).sub.p--,
--CH.sub.2--CH.dbd.CH--CH.sub.2-- or --CH.dbd.CH--.
27. A pyrazolopyrimidine derivative represented by formula (2):
##STR01352## [wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, n and
-A-B- are as defined in either claim 1 or 2, and Boc represents
tert-butoxycarbonyl].
28. The pyrazolopyrimidine derivative according to claim 27,
wherein R.sup.1 and R.sup.2 are a hydrogen atom.
29. The pyrazolopyrimidine derivative according to claim 27,
wherein R.sup.1 is a hydrogen atom and R.sup.2 is a halogen.
30. The pyrazolopyrimidine derivative according to claim 27,
wherein R.sup.3 is an optionally substituted C1-C8 alkyl group, an
optionally substituted cyclohexyl group or an optionally
substituted heterocyclic group (wherein the heterocyclic group
means a 3- to 10-membered monocyclic or bicyclic heterocyclic group
containing 1 to 4 heteroatoms selected from the group consisting of
N, O and S).
31. The pyrazolopyrimidine derivative according to claim 27,
wherein R.sup.3 is an unsubstituted heterocyclic group (wherein the
heterocyclic group means a 5- to 8-membered monocyclic heterocyclic
group containing 1 or 2 heteroatoms selected from the group
consisting of N, O and S), a substituted heterocyclic group
(wherein the heterocyclic group means a 5- to 8-membered monocyclic
heterocyclic group containing 1 or 2 heteroatoms selected from the
group consisting of N, O and S, and the substituent bonds to a
nitrogen atom in a saturated heterocyclic group and the
substituents represent one or more substituents selected from the
group consisting of C1-C4 alkyl group, benzyl group, acetyl group,
tert-butoxycarbonyl group and benzyloxycarbonyl group), a C1-C4
alkyl group substituted with an amino group or a C3-C8 alkyl group
substituted with an amino group.
32. The pyrazolopyrimidine derivative according to claim 27,
wherein R.sup.4 is an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group, an optionally
substituted C6-C14 aryl group, an optionally substituted
heterocyclic group or an optionally substituted heterocyclylalkyl
group.
33. The pyrazolopyrimidine derivative according to claim 27,
wherein R.sup.4 is an optionally substituted phenyl group or an
optionally substituted bicyclic heteroaryl group.
34. The pyrazolopyrimidine derivative according to claim 27,
wherein R.sup.4 is an optionally substituted phenyl group (wherein
the substituents are one or more --O--(CH.sub.2).sub.m--W, wherein
W represents a hydrogen atom or an optionally substituted C1-C4
alkyl group and m is 0 to 4, or W represents an optionally
substituted C1-C4 alkoxy group and m is 2 to 4).
35. The pyrazolopyrimidine derivative according to claim 27,
wherein R.sup.4 is an optionally substituted bicyclic heteroaryl
group (wherein the substituents are 1 to 3 substituents selected
from the group consisting of halogen, C1-C4 alkyl group and C1-C4
alkyl group substituted with 1 to 9 halogens.).
36. The pyrazolopyrimidine derivative according to claim 27,
wherein -A-B- is --CH.sub.2--CH.sub.2--, --(CH.sub.2).sub.p--,
--CH.sub.2--CH.dbd.CH--CH.sub.2-- or --CH.dbd.CH--.
37. The pyrazolopyrimidine derivative according to claim 27,
wherein n is 0.
38. A pharmaceutical composition comprising the pyrazolopyrimidine
derivative or medically acceptable salt thereof according to claim
1 or 2 and a pharmaceutically acceptable carrier.
39. A MAPKAP-K2 inhibitor comprising the pyrazolopyrimidine
derivative or medically acceptable salt thereof according to claim
1 or 2 as an active ingredient.
40. A therapeutic agent comprising the pyrazolopyrimidine
derivative or medically acceptable salt thereof according to claim
1 or 2 as an active ingredient for neurodegenerative and/or
neurological disorders (including dementia), sepsis, autoimmune
diseases, destructive osteopathy, inflammatory bowel disease,
psoriasis, diabetes mellitus, cancer, ischemic reperfusion injury,
angiodysplasia, cachexia, obesity, angiogenesis, asthma or chronic
obstructive pulmonary disease (COPD).
41. The therapeutic agent according to claim 40, wherein the
autoimmune disease is rheumatoid arthritis, ankylosing spondylitis,
juvenile rheumatoid arthritis, psoriatic arthritis,
graft-versus-host disease, diabetes mellitus or Crohn's disease.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of application Ser. No. 11/377,363
filed Mar. 17, 2006, which claims benefit of Provisional
Application No. 60/663,205 filed Mar. 21, 2005. The entire
disclosures of the prior applications, application Ser. Nos.
11/377,363 and 60/663,205 are considered part of the disclosure of
the accompanying divisional application and are hereby incorporated
by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a novel pyrazolopyrimidine
derivative or a medically acceptable salt thereof, a pharmaceutical
composition comprising them as an active ingredient, a MAPKAP-K2
(mitogen-activating protein kinase activating protein kinase 2)
inhibitor comprising them as an active ingredient and a novel
intermediate thereof. The present invention also relates to a
therapeutic agent comprising these compounds as an active
ingredient for neurodegenerative/neurological disorders (including
dementia), sepsis, autoimmune diseases, destructive osteopathy,
inflammatory bowel disease, psoriasis, diabetes mellitus, cancer,
ischemic reperfusion injury, angiodysplasia, cachexia, obesity,
angiogenesis, asthma and/or chronic obstructive pulmonary disease
(COPD).
BACKGROUND ART
[0003] MAPKAP-K2 (mitogen-activating protein kinase activating
protein kinase 2) is a serine/threonine kinase and operates at
immediate downstream of p38 kinase in a stress-induced MAPK pathway
(FIG. 1).
[0004] This p38 kinase pathway is activated by various
stress-related extracellular stimuli such as heat, ultraviolet ray,
bacterial lipopolysaccharide or inflammatory cytokines. The
activation of this pathway causes phosphorylation of transcription
and initiation factors and affects cell division, apoptosis, cell
differentiation, inflammatory response and infiltration of cancer
cells (Martin-Blanco, Bioessays 22, 637-645).
[0005] p38 Kinase itself activates many protein kinases other than
MAPKAP kinase, for example, Mnk1/2, PRAK and MSK1 (FIG. 1). This
pathway is particularly important for discovery of novel
anti-inflammatory drugs. A p38 kinase-selective inhibitor is
effective for suppressing inflammatory cytokines in both cell base
model and model animals of chronic inflammation (Lee et al.,
Immunopharmacology 47, 185-201 (2000)). However, a p38
kinase-knockout mouse is embryonic lethal. Moreover, it has been
proved that cells derived from such an embryo exhibit a lot of
anomaly in fundamental cellular responses. As another strategy for
developing anti-inflammatory drugs, there may be mentioned a drug
inhibiting this pathway in the level of MAPKAP-K2. MAPKAP-K2 exists
in the nucleus in an unstimulated cell, and is transferred to
cytosol when the cell is stimulated. It is known that this kinase
phosphorylates many nuclear transcription factors and cytosolic
proteins such as heat-shock protein involved in cell protection and
5-lipoxygenase involved in bioprotection and inflammation (Stokoe
et al., FEBS Lett. 313, 307-313 (1992); Werz et al., Proc. Natl.
Acad. Sci. USA 97, 5261-5266 (2000); Heindenreich et al., J. Biol.
Chem. 274, 14434-14443 (1999); Tan et al., EMBO J. 15, 4629-4642
(1996); Neufeld, J. Biol. Chem. 275, 20239-20242 (2000)). All of
these substrates contain a unique amino acid motif (XX-Hyd-XRXXSXX
where Hyd represents a bulky hydrophobic residue) which is required
for effective phosphorylation by MAPKAP-K2 (Stokoe et al., Biochem.
J. 296, 843-849 (1993)).
[0006] MAPKAP-K2 is the only substrate of p38 kinase whose special
function is currently identified. The special roll of MAPKAP-K2 in
mediation of inflammatory response is remarkably demonstrated in a
phenotype of MAPKAP-K2 knockout mouse (MAPKAP-K2.sup.-/-)
(Kotlyarov et al., Nature Cell Biol. 1, 94-97 (1999)). This mouse
is not lethal and normal except for particularly reduced
inflammatory response. Recently, it has been proved that lack of
MAPKAP-K2 causes particular protection of neurons from ischemic
brain injury (Wang et al., J. Biol. Chem. 277, 43968-43972
(29002)). It is considered that MAPKAP-K2 regulates translation
and/or stabilization of mRNA of important inflammatory cytokines.
This is likely because MAPKAP-K2 phosphorylates proteins which bind
to AU-rich elements found in untranslated regions of these
cytokines. Identification of these proteins is now under
investigation.
[0007] Furthermore, it is reported that MAPKAP-K2 has activity of
repairing anomaly in DNA induced by ultraviolet ray (Isaac A. Manke
et al., Molecular Cell 17, 37-48 (2005)). Inhibition of MAPKAP-K2
activity may disable repairing damaged DNA and cause death in some
types of cancer cell.
[0008] From the above, a MAPKAP-K2 inhibitor is effective for
neurodegenerative/neurological disorders (including dementia),
sepsis, autoimmune diseases, destructive osteopathy, inflammatory
bowel disease, psoriasis, diabetes mellitus, cancer, ischemic
reperfusion injury, angiodysplasia, cachexia, obesity,
angiogenesis, asthma and/or chronic obstructive pulmonary disease
(COPD).
[0009] As MAPKAP-K2 inhibitors there have been disclosed in
WO2004/054504, WO2004/054505, WO2004/055015, WO2004/055019,
WO2004/058176, WO2004/058762, WO2004/099127, WO2005/009370,
WO2005/007092, WO2004/076458 and WO2004/081013, but these compounds
are different in the structure from the compound of the present
invention.
DISCLOSURE OF THE INVENTION
[0010] An object of the present invention is to provide a novel
compound useful as a MAPKAP-K2 inhibitor.
[0011] Another object of the present invention is to provide a
novel MAPKAP-K2 inhibitor or a novel therapeutic agent for
neurodegenerative and/or neurological disorders (including
dementia), sepsis, autoimmune diseases, destructive osteopathy,
inflammatory bowel disease, psoriasis, diabetes mellitus, cancer,
ischemic reperfusion injury, angiodysplasia, cachexia, obesity,
angiogenesis, asthma and/or chronic obstructive pulmonary disease
(COPD). A still other object of the present invention is to provide
a novel intermediate of the novel MAPKAP-K2 inhibitor.
[0012] The present inventors pursued zealous study, found that
novel pyrazolopyrimidine derivatives and pharmaceutically
acceptable salts thereof represented by the following formula (1)
exhibit excellent MAPKAP-K1 inhibitory activity, and accomplished
the present invention.
[0013] Namely, the present invention is
<1> A pyrazolopyrimidine derivative or medically acceptable
salt thereof represented by formula (1):
##STR00002##
[wherein, R.sup.1 represents a hydrogen atom or a halogen; R.sup.2
represents a hydrogen atom or a halogen; R.sup.3 represents a
hydrogen atom, an optionally substituted C1-C1 alkyl group, an
optionally substituted C1-C1 cycloalkyl group, an optionally
substituted heterocyclic group, an optionally substituted C6-C14
aryl group or --OR.sup.5; R.sup.5 represents a hydrogen atom, an
optionally substituted C1-C8 alkyl group or --(C.dbd.O)R.sup.6;
R.sup.6 represents an optionally substituted C1-C8 alkyl group; n
represents 0 or 1, or n represents 0 when R.sup.3 is --OR.sup.5;
R.sup.4 represents a hydrogen atom, an optionally substituted C1-C8
alkyl group, an optionally substituted C2-C8 alkenyl, an optionally
substituted C2-C8 alkynyl, an optionally substituted C3-C8
cycloalkyl group, an optionally substituted C6-C14 aryl group, an
optionally substituted heterocyclic group, an optionally
substituted heterocyclylalkyl group or an optionally substituted
C7-C16 aralkyl group; the substituents in the optionally
substituted C6-C14 aryl group as R.sup.4 are one or more
substituents selected from the group consisting of halogen, --CN,
--NO.sub.2, --CHO, --OH, --COOH, optionally substituted C1-C8 alkyl
group, optionally substituted C2-C8 alkenyl, optionally substituted
C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl group,
--O--(CH.sub.2).sub.m--W, optionally substituted C6-C14 aryl group,
optionally substituted heterocyclic group, --C(.dbd.O)--R.sup.133,
--O--C(.dbd.O)R.sup.26, --C(.dbd.O)OR.sup.27,
--NR.sup.28C(.dbd.O)R.sup.29, --NR.sup.30R.sup.31,
--C(.dbd.O)NR.sup.32R.sup.33, --NR.sup.34C(.dbd.X.sup.1)OR.sup.35,
--NR.sup.36C(.dbd.X.sup.2)NR.sup.37R.sup.38,
--NR.sup.39--SO.sub.2R.sup.40, --S(O).sub.r--R.sup.41 and
--SO.sub.2NR.sup.42R.sup.43, wherein X.sup.1 or X.sup.2 represents
O, S, N--CN or NH and r represents 0 to 2; W represents a hydrogen
atom, an optionally substituted C1-C8 alkyl group, an optionally
substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl,
an optionally substituted C3-C8 cycloalkyl group, an optionally
substituted C6-C14 aryl group or an optionally substituted
heterocyclic group, and in this case m represents 0 to 4; or W
represents an optionally substituted C1-C8 alkoxy group,
--NR.sup.150R.sup.151 or an optionally substituted phenoxy group
and in this case m represents 1 to 4; R.sup.26 to R.sup.43,
R.sup.33, R.sup.150 and R.sup.151 may be identical or different and
each represents a hydrogen atom, an optionally substituted C1-C8
alkyl group, an optionally substituted C2-C8 alkenyl, an optionally
substituted C2-C8 alkynyl, an optionally substituted C3-C8
cycloalkyl group, an optionally substituted C6-C14 aryl group, an
optionally substituted heterocyclic group, an optionally
substituted aralkyl group or an optionally substituted
heterocyclylalkyl group, or, when R.sup.30 and R.sup.31, R.sup.32
and R.sup.33, R.sup.37 and R.sup.38, R.sup.42 and R.sup.43 or
R.sup.150 and R.sup.151 are optionally substituted alkyl groups,
the substituents in each combination may form a saturated or
unsaturated 5- to 7-membered ring together with the nitrogen atom
to which they bond, and this ring may contain 1 or 2 heteroatoms
selected from the group consisting of oxygen atom, nitrogen atom
and sulfur atom besides the nitrogen atom to which these
substituents bond; -A-B- represents --CH.sub.2--CH(-Z.sup.1)-,
--(CH.sub.2).sub.p--, --CH.sub.2--CH.dbd.CH--CH.sub.2--,
--CH.dbd.C(-Z.sup.2)-- or --(CH.sub.2).sub.q--C(.dbd.O)--; p
represents 3 or 4 and q represents 1 or 2; Z.sup.1 and Z.sup.2 may
be identical or different and each represents a hydrogen atom or
--CH.sub.2--OR.sup.11; and R.sup.11 represents a hydrogen atom, an
optionally substituted C1-C8 alkyl group or a substituted silyl
group.] <2> A pyrazolopyrimidine derivative or medically
acceptable salt thereof represented by formula (1):
##STR00003##
[wherein, R.sup.1 represents a hydrogen atom or a halogen; R.sup.2
represents a hydrogen atom or a halogen; R.sup.3 represents a
hydrogen atom, an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group, an optionally
substituted heterocyclic group, an optionally substituted C6-C14
aryl group or --OR.sup.5; R.sup.5 represents a hydrogen atom, an
optionally substituted C1-C8 alkyl group or --(C.dbd.O)R.sup.6;
R.sup.6 represents an optionally substituted C1-C8 alkyl group; n
represents 0 or 1 or n represents 0 and when R.sup.3 is --OR.sup.5;
R.sup.4 represents an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group, an optionally
substituted C6-C14 aryl group, an optionally substituted
heterocyclic group or an optionally substituted C7-C16 aralkyl
group; the substituents in the optionally substituted C6-C14 aryl
group as R.sup.4 are one or more substituents selected from the
group consisting of halogen, --CN, --NO.sub.2, optionally
substituted C1-C8 alkyl group, --O--(CH.sub.2).sub.m--W, optionally
substituted C6-C14 aryl group, optionally substituted heterocyclic
group, --C(.dbd.O)OR.sup.7, --NR.sup.8C(.dbd.O)R.sup.9,
--NR.sup.10R.sup.127, --C(.dbd.O)NR.sup.128R.sup.129 and
--SO.sub.2NR.sup.130R.sup.131; W represents a hydrogen atom, an
optionally substituted C1-C8 alkyl group, an optionally substituted
C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group
or an optionally substituted heterocyclic group and in this case m
represents 0 to 4; or W represents an optionally substituted C1-C8
alkoxy group or an optionally substituted phenoxy group and in this
case m represents 1 to 4; R.sup.7 to R.sup.10 and R.sup.127 to
R.sup.131 may be identical or different and each represents a
hydrogen atom, an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group or an optionally
substituted C6-C14 aryl group, or, when R.sup.10 and R.sup.127,
R.sup.128 and R.sup.129 or R.sup.130 and R.sup.131 are optionally
substituted alkyl groups, they may form a saturated or unsaturated
5- to 7-membered ring together with the nitrogen atom to which they
bond, and this ring may contain 1 or 2 heteroatoms selected from
the group consisting of oxygen atom, nitrogen atom and sulfur atom
besides the nitrogen atom to which these substituents bond; -A-B-
represents --CH.sub.2--CH(-Z.sup.3)-, --(CH.sub.2).sub.p--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--, --CH.dbd.C(-Z.sup.4)-- or
--(CH.sub.2).sub.q--C(.dbd.O)--; p represents 3 or 4 and q
represents 1 or 2; Z.sup.3 and Z.sup.4 may be identical or
different and each represents a hydrogen atom or
--CH.sub.2--OR.sup.11; and R.sup.11 represents a hydrogen atom or
an optionally substituted C1-C8 alkyl group.] <3> The
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to either <1> or <2>, wherein R.sup.1 is a
hydrogen atom. <4> The pyrazolopyrimidine derivative or
medically acceptable salt thereof according to any of <1> to
<3>, wherein R.sup.2 is a hydrogen atom. <5> The
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <3>, wherein R.sup.2 is a
halogen. <6> The pyrazolopyrimidine derivative or medically
acceptable salt thereof according to any of <1> to <5>,
wherein R.sup.3 is an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group or an optionally
substituted heterocyclic group. <7> The pyrazolopyrimidine
derivative or medically acceptable salt thereof according to any of
<1> to <5>, wherein R.sup.3 is an unsubstituted C1-C4
alkyl group, a substituted C1-C4 alkyl group (wherein the
substituents are 1 to 3 substituents selected from the group
consisting of halogen, phenyl group, C1-C4 alkyl group substituted
with 1 to 9 halogens, C1-C4 alkoxy group, C1-C4 alkoxy group
substituted with 1 to 9 halogens, --CN, --CHO, --OH, --(C.dbd.O)OH,
--(C.dbd.O)OR.sup.86, --(C.dbd.O)NR.sup.87R.sup.88 and
--NR.sup.89R.sup.90; R.sup.86 represents a C1-C4 alkyl group, a
C3-C8 cycloalkyl group or a phenyl group; R.sup.87 and R.sup.88 may
be identical or different and each represents a hydrogen atom, a
C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or an
aralkyl group; R.sup.89 represents a hydrogen atom, a C1-C4 alkyl
group, a phenyl group or a benzyl group; R.sup.90 represents a
hydrogen atom, a C1-C4 alkyl group, a benzyl group, an acetyl
group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group,
or, when R.sup.89 and R.sup.90 are alkyl groups, they may form a
saturated or unsaturated 5- to 7-membered ring together with the
nitrogen atom to which they bond; further this ring may contain 1
or 2 heteroatoms selected from the group consisting of oxygen atom,
nitrogen atom and sulfur atom besides the nitrogen atom to which
R.sup.89 and R.sup.90 bond), an unsubstituted C3-C8 cycloalkyl
group, a substituted C3-C8 cycloalkyl group (wherein the
substituents are 1 to 3 substituents selected from the group
consisting of halogen, --OH, --(C.dbd.O)OH, C1-C4 alkyl group,
C1-C4 alkoxy group and --NR.sup.91R.sup.92, wherein R.sup.91
represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or
a benzyl group and R.sup.92 represents a hydrogen atom, a C1-C8
alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl
group or a benzyloxycarbonyl group), an unsubstituted heterocyclic
group or a substituted heterocyclic group (wherein, when carbon
atom(s) in the substituted heterocyclic group are substituted, the
substituent(s) are 1 to 3 substituents selected from the group
consisting of halogen, --(C.dbd.O)OH, C1-C4 alkyl group, C1-C4
alkyl group substituted with 1 to 9 halogens, phenyl group, benzyl
group, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with 1 to
9 halogens and --NR.sup.93R.sup.94, wherein R.sup.93 represents a
hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl
group and R.sup.94 represents a hydrogen atom, a C1-C8 alkyl group,
a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group, wherein, when nitrogen atom(s) in the
heterocycle are substituted, the substituents are one or more
substituents selected from the group consisting of C1-C4 alkyl
group, benzyl group, acetyl group, tert-butoxycarbonyl group and
benzyloxycarbonyl group). <8> The pyrazolopyrimidine
derivative or medically acceptable salt thereof according to any of
<1> to <5>, wherein R.sup.3 is an unsubstituted
heterocyclic group (wherein the heterocyclic group represents a
monocyclic 5- to 8-membered heterocyclic group containing 1 or 2
heteroatoms selected from the group consisting of N, O and S), a
substituted saturated heterocyclic group (wherein the heterocyclic
group represents a monocyclic 5- to 8-membered heterocyclic group
containing 1 or 2 heteroatoms selected from the group consisting of
N, O and S, and the substituent bonds to a nitrogen atom in the
heterocycle and the substituents represent one or more substituents
selected from the group consisting of C1-C4 alkyl group, benzyl
group and tert-butoxycarbonyl group), a C1-C4 alkyl group
substituted with one amino group or a C3-C8 cycloalkyl group
substituted with one amino group. <9> The pyrazolopyrimidine
derivative or medically acceptable salt thereof according to any of
<1> to <5>, wherein R.sup.3 is a piperidyl group, a
pyrrolidinyl group or a cyclohexyl group substituted with an amino
group. <10> The pyrazolopyrimidine derivative or medically
acceptable salt thereof according to any of <1> to <9>,
wherein n is 0. <11> The pyrazolopyrimidine derivative or
medically acceptable salt thereof according to any of <1> to
<10>, wherein R.sup.4 is an optionally substituted C6-C14
aryl group. <12> The pyrazolopyrimidine derivative or
medically acceptable salt thereof according to any of <1> to
<10>, wherein R.sup.4 is an optionally substituted C6-C14
aryl group and the substituents are one or more substituents
selected from the group consisting of halogen, --CN, optionally
substituted C1-C8 alkyl group, --O--(CH.sub.2).sub.m--W, optionally
substituted C6-C14 aryl group, optionally substituted heterocyclic
group, --C(.dbd.O)OR.sup.7 and --C(.dbd.O)NR.sup.9R.sup.10.
<13> The pyrazolopyrimidine derivative or medically
acceptable salt thereof according to any of <1> to
<10>, wherein R.sup.4 is an optionally substituted C6-C14
aryl group and the substituents are one or more substituents
selected from the group consisting of halogen, --CN, optionally
substituted C1-C8 alkyl group and --O--(CH.sub.2).sub.m--W.
<14> The pyrazolopyrimidine derivative or medically
acceptable salt thereof according to any of <1> to
<10>, wherein R.sup.4 is an optionally substituted C6-C14
aryl group and the substituents are one or more
--O--(CH.sub.2).sub.m--W, wherein W is a hydrogen atom, an
optionally substituted C1-C8 alkyl group, an optionally substituted
heterocyclic group or an optionally substituted C1-C8 alkoxy group.
<15> The pyrazolopyrimidine derivative or medically
acceptable salt thereof according to any of <1> to <8>,
wherein R.sup.4 is an optionally substituted C6-C14 aryl group and
the substituents are one or more substituents selected from the
group consisting of halogen, --CN, optionally substituted C1-C8
alkyl group, optionally substituted C6-C14 aryl group and
optionally substituted heterocyclic group. <16> The
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <10>, wherein R.sup.4 is an
optionally substituted C6-C14 aryl group and the substituents are
one or more substituents selected from the group consisting of
halogen, --CN, optionally substituted C1-C8 alkyl group,
--C(.dbd.O)OR.sup.7 and --C(.dbd.O)NR.sup.9R.sup.10. <17> The
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <10>, wherein R.sup.4 is an
optionally substituted C6-C14 aryl group (wherein the substituents
are 1 to 3 substituents selected from the group consisting of
halogen, --CN, optionally substituted C1-C8 alkyl group,
--O--(CH.sub.2).sub.m--W and --C(.dbd.O)OR.sup.113, wherein W
represents a hydrogen atom, an optionally substituted C1-C4 alkyl
group, an optionally substituted C3-C8 cycloalkyl group, an
optionally substituted phenyl group or an optionally substituted
monocyclic or bicyclic heterocyclic group and m represents 0 to 4;
or W represents an optionally substituted C1-C4 alkoxy group and m
represents 1 to 4, and R.sup.113 represents an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group or an optionally substituted phenyl group).
<18> The pyrazolopyrimidine derivative or medically
acceptable salt thereof according to any of <1> to
<10>, wherein R.sup.4 is an optionally substituted phenyl
group (wherein the substituent is one --O--(CH.sub.2).sub.m--W,
wherein W represents a hydrogen atom or an optionally substituted
C1-C4 alkyl group and m represents 0 to 4; or W represents an
optionally substituted C1-C4 alkoxy group and m represents 1 to 4).
<19> The pyrazolopyrimidine derivative or medically
acceptable salt thereof according to any of <1> to
<10>, wherein R.sup.4 is an optionally substituted C6-C14
aryl group (wherein the substituents are one or more substituents
selected from the group consisting of halogen, --CN, optionally
substituted C1-C4 alkyl group, optionally substituted phenyl group
and optionally substituted monocyclic or bicyclic heterocyclic
group). <20> The pyrazolopyrimidine derivative or medically
acceptable salt thereof according to any of <1> to
<10>, wherein R.sup.4 is an optionally substituted C6-C14
aryl group (wherein the substituents are one or more substituents
selected from the group consisting of halogen, --CN, optionally
substituted C1-C4 alkyl group, --C(.dbd.O)OR.sup.113 and
--C(.dbd.O)NR.sup.118R.sup.119, wherein R.sup.113, R.sup.118 and
R.sup.119 may be identical or different and each represents a
hydrogen atom, an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group or an optionally
substituted C6-C14 aryl group; and when R.sup.118 and R.sup.119 are
alkyl groups, they may form a saturated or unsaturated 5- to
7-membered ring together with the nitrogen atom to which they bond,
and this ring may contain 1 or 2 heteroatoms selected from the
group consisting of oxygen atom, nitrogen atom and sulfur atom
besides the nitrogen atom to which they bond). <21> The
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <10>, wherein R.sup.4 is an
optionally substituted heterocyclic group. <22> The
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <10>, wherein R.sup.4 is an
optionally substituted bicyclic heteroaryl group (wherein, when
carbon atom(s) in the bicyclic heteroaryl group are substituted,
the substituents are 1 to 3 substituents selected from the group
consisting of halogen, --CN, C1-C8 alkyl group, C1-C4 alkyl group
substituted with 1 to 9 halogens, C1-C8 alkoxy group, C1-C4 alkoxy
group substituted with 1 to 9 halogens, phenyl group, monocyclic or
bicyclic heterocyclic group, --C(.dbd.O)OR.sup.122,
--NR.sup.123R.sup.124 and --C(.dbd.O)NR.sup.125R.sup.126 wherein
R.sup.123 represents a hydrogen atom, a C1-C8 alkyl group, a phenyl
group or a benzyl group, R.sup.124 represents a hydrogen atom, a
C1-C8 alkyl group, a benzyl group, an acetyl group, a
tert-butoxycarbonyl group or a benzyloxycarbonyl group, R.sup.122
represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a
phenyl group, and R.sup.125 and R.sup.126 may be identical or
different and each represents a hydrogen atom, a C1-C8 alkyl group,
a C3-C8 cycloalkyl group, a phenyl group or a benzyl group; when
nitrogen atom(s) in the heterocycle are substituted, the
substituents are one or more substituents selected from the group
consisting of C1-C4 alkyl group, benzyl group, acetyl group,
tert-butoxycarbonyl group and benzyloxycarbonyl group). <23>
The pyrazolopyrimidine derivative or medically acceptable salt
thereof according to any of <1> to <10>, wherein
R.sup.4 is an optionally substituted bicyclic heteroaryl group
(wherein the bicyclic heteroaryl group means a bicyclic heteroaryl
group wherein a phenyl group is fused with an aromatic heterocycle
containing 1 or 2 heteroatoms selected from the group consisting of
N, O and S; when carbon atom(s) in the bicyclic heteroaryl group
are substituted, the substituents are 1 to 3 substituents selected
from the group consisting of halogen, C1-C4 alkyl group and C1-C4
alkyl group substituted with 1 to 9 halogens; when nitrogen atom(s)
in the heterocycle are substituted, the substituent represents one
or more C1-C4 alkyl group).
<24> The pyrazolopyrimidine derivative or medically
acceptable salt thereof according to any of <1> to
<10>, wherein R.sup.4 is a hydrogen atom, an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group, an optionally substituted C7-C16 aralkyl group or
an optionally substituted heterocyclylalkyl group. <25> The
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <10>, wherein R.sup.4 is an
optionally substituted heterocyclylalkyl group. <26> The
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <25>, wherein -A-B- is
--CH.sub.2--CH.sub.2--, --(CH.sub.2).sub.p--,
--CH.sub.2--CH.dbd.CH--CH.sub.2-- or --CH.dbd.CH--. <27> The
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <25>, wherein -A-B- is
--CH.sub.2--CH.sub.2. <28> A pyrazolopyrimidine derivative
represented by formula (2):
##STR00004##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, n and -A-B- are as
defined in either claim 1 or 2, and Boc represents
tert-butoxycarbonyl]. <29> The pyrazolopyrimidine derivative
according to <28>, wherein R.sup.1 and R.sup.2 are a hydrogen
atom. <30> The pyrazolopyrimidine derivative according to
<28>, wherein R.sup.1 is a hydrogen atom and R.sup.2 is a
halogen. <31> The pyrazolopyrimidine derivative according to
any of <28> to <30>, wherein R.sup.3 is an optionally
substituted C1-C8 alkyl group, an optionally substituted cyclohexyl
group or an optionally substituted heterocyclic group (wherein the
heterocyclic group means a 3- to 10-membered monocyclic or bicyclic
heterocyclic group containing 1 to 4 heteroatoms selected from the
group consisting of N, O and S). <32> The pyrazolopyrimidine
derivative according to any of <28> to <30>, wherein
R.sup.3 is an unsubstituted heterocyclic group (wherein the
heterocyclic group means a 5- to 8-membered monocyclic heterocyclic
group containing 1 or 2 heteroatoms selected from the group
consisting of N, O and S), a substituted heterocyclic group
(wherein the heterocyclic group means a 5- to 8-membered monocyclic
heterocyclic group containing 1 or 2 heteroatoms selected from the
group consisting of N, O and S, and the substituent bonds to a
nitrogen atom in a saturated heterocyclic group and the
substituents represent one or more substituents selected from the
group consisting of C1-C4 alkyl group, benzyl group, acetyl group,
tert-butoxycarbonyl group and benzyloxycarbonyl group), a C1-C4
alkyl group substituted with an amino group or a C3-C8 alkyl group
substituted with an amino group. <33> The pyrazolopyrimidine
derivative according to any of <28> to <32>, wherein
R.sup.4 is an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group, an optionally
substituted C6-C14 aryl group, an optionally substituted
heterocyclic group or an optionally substituted heterocyclylalkyl
group. <34> The pyrazolopyrimidine derivative according to
any of <28> to <32>, wherein R.sup.4 is an optionally
substituted phenyl group or an optionally substituted bicyclic
heteroaryl group. <35> The pyrazolopyrimidine derivative
according to any of <28> to <32>, wherein R.sup.4 is an
optionally substituted phenyl group (wherein the substituents are
one or more --O--(CH.sub.2).sub.m--W, wherein W represents a
hydrogen atom or an optionally substituted C1-C4 alkyl group and m
is 0 to 4, or W represents an optionally substituted C1-C4 alkoxy
group and m is 2 to 4). <36> The pyrazolopyrimidine
derivative according to any of <28> to <32>, wherein
R.sup.4 is an optionally substituted bicyclic heteroaryl group
(wherein the substituents are 1 to 3 substituents selected from the
group consisting of halogen, C1-C4 alkyl group and C1-C4 alkyl
group substituted with 1 to 9 halogens.). <37> The
pyrazolopyrimidine derivative according to any of <28> to
<36>, wherein -A-B- is --CH.sub.2--CH.sub.2--,
--(CH.sub.2).sub.p--, --CH.sub.2--CH.dbd.CH--CH.sub.2-- or
--CH.dbd.CH--. <38> The pyrazolopyrimidine derivative
according to any of <28> to <36>, wherein -A-B- is
--CH.sub.2--CH.sub.2. <39> The pyrazolopyrimidine derivative
according to any of <28> to <38>, wherein n is 0.
<40> A pharmaceutical composition comprising the
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <27> and a pharmaceutically
acceptable carrier. <41> A MAPKAP-K2 inhibitor comprising the
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <27> as an active
ingredient. <42> A therapeutic agent comprising the
pyrazolopyrimidine derivative or medically acceptable salt thereof
according to any of <1> to <27> as an active ingredient
for neurodegenerative and/or neurological disorders (including
dementia), sepsis, autoimmune diseases, destructive osteopathy,
inflammatory bowel disease, psoriasis, diabetes mellitus, cancer,
ischemic reperfusion injury, angiodysplasia, cachexia, obesity,
angiogenesis, asthma or chronic obstructive pulmonary disease
(COPD). <43> The therapeutic agent according to <42>,
wherein the autoimmune disease is rheumatoid arthritis, ankylosing
spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis,
graft-versus-host disease, diabetes mellitus or Crohn's
disease.
BRIEF DESCRIPTION OF DRAWINGS
[0014] FIG. 1 is a FIGURE illustrating p38MAPK cascade.
BEST MODE FOR CARRYING OUT THE INVENTION
[0015] The compounds represented by formula (1) in the present
invention are defined as follows.
[0016] "Alkyl group" in the present specification represents either
a linear or branched alkyl group. Preferably it is an alkyl group
having 1 to 8 carbon atoms. For example, although not limited
thereto, there may be mentioned methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,
neopentyl, tert-pentyl, 2-methylpentyl, 4-methylpentyl, 3-hexyl,
n-hexyl, n-heptyl, 2-methylhexyl, 5-methylhexyl, 2-methyl-2-hexyl,
6-methylheptyl and n-octyl. More preferably, it is an alkyl group
having 1 to 6 carbon atoms, and still more preferably it is an
alkyl group having 1 to 4 carbon atoms. For example, although not
limited thereto, there may be mentioned methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.
[0017] "Alkenyl group" in the present specification represents a
linear, branched or cyclic alkenyl group having one or more C--C
double bonds. When the group exists as either trans or cis form, it
includes both isomers. Preferably it is an alkenyl group having 2
to 8 carbon atoms. For example, although not limited thereto, there
may be mentioned vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl,
1-butenyl, 2-methyl-1-propenyl, 2-methyl-3-pentenyl, 1-pentenyl,
2-pentenyl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl,
2-cyclopentenyl, 2-cyclohexenyl, 2-heptenyl, 2-octenyl,
3-cyclopentenyl, 1,3-butadienyl and 1,5-hexadienyl. More
preferably, it is an alkenyl group having 2 to 6 carbon atoms, and
still more preferably it is an alkenyl group having 2 to 4 carbon
atoms. For example, although not limited thereto, there may be
mentioned vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl,
1-butenyl and 2-methyl-1-propenyl.
[0018] "Alkynyl group" in the present specification represents
either a linear or a branched alkynyl group having one or more C--C
triple bonds. Preferably it is an alkynyl group having 2 to 8
carbon atoms. For example, although not limited thereto, there may
be mentioned ethynyl, 2-propynyl, 1-propynyl, 1-butynyl, 2-butynyl,
3-hexynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 3-pentynyl,
2-petynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 1-methyl-3-pentynyl,
1-methyl-3-hexynyl, 2-heptynyl and 2-octynyl. More preferably, it
is an alkynyl group having 2 to 6 carbon atoms, and still more
preferably it is an alkynyl group having 2 to 4 carbon atoms. For
example, although not limited thereto, there may be mentioned
ethynyl, 2-propynyl, 1-propynyl and 1-butynyl.
[0019] "Cycloalkyl group" in the present specification represents a
cyclic alkyl group. Preferably it is a cycloalkyl group having 3 to
8 carbon atoms. For example, although not limited thereto, there
may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl and cyclooctyl.
[0020] "Aryl group" in the present specification represents a
monocyclic, bicyclic or tricyclic aromatic hydrocarbon group having
6 or 14 carbon atoms; or an aromatic hydrocarbon group having
totally 6 to 14 carbon atoms wherein such an aromatic hydrocarbon
group is fused with one or more saturated or partially saturated
carbocycles. For example, although not limited thereto, there may
be mentioned phenyl, naphthyl, anthracenyl, 5-indanyl and
5,6,7,8-tetrahydro-2-naphthyl. Preferably it is an aryl group
having 6 to 10 carbon atoms. For example, although not limited
thereto, there may be mentioned phenyl, naphthyl, 5-indanyl and
5,6,7,8-tetrahydro-2-naphthyl. More preferably it is phenyl.
[0021] "Heterocyclic group" in the present specification means a
monovalent group derived from a 3- to 14-membered monocyclic,
bicyclic or tricyclic heterocycle containing 1 to 4 heteroatoms
selected from the group consisting of N, O and S. The heterocyclic
group may be completely saturated, partially saturated or
aromatized. The heterocyclic group may contain one or two
--C(.dbd.O) or --C(.dbd.S)--. As example of the heterocyclic group,
although not limited thereto, there may be mentioned a monovalent
group derived from furan, thiophene, pyrrole, pyrroline,
pyrrolidine, oxazole, oxazolidine, isoxazolidine, thiazole,
thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline,
imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole,
thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran,
thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine,
pyridazine, benzofuran, dibenzofuran, benzothiophene, indole,
benzimidazole, benzothiazole, benzoxazole, chroman, isochroman,
quinoline, decahydroquinoline, isoquinoline, quinazoline,
quinoxaline, purine, pteridine, azetidine, morpholine,
thiomorpholine, piperidine, homopiperidine, piperazine,
homopiperazine, indoline, isoindoline, phenoxazine, phenazine,
phenothiazne, quinuclidine, acridine, carbazole, cinnoline,
dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane,
indolizine, indazole, isoindole, isoxazole, isobenzofuan,
naphthyridine, oxathiazole, oxathiazolidine, oxazine, oxadiazine,
phthalazine, quinolizine, tetrahydrofuran, tetrazine, thiadiazine,
thiatriazole, thiazine, thianaphthalene, triazine, 1,3-dioxane,
2,5-dihydrofuran, oxazoline, trithiane, piperidin-2-one,
3H-isobenzofuran-1-one, 8-caprolactam, 2-furanone, 2-pyrrolidone,
tetrahydro-3H-pyrazol-3-one, piperazin-2-one, coumarin,
tetrahydro-2-pyrimidinone, glutarimide or morpholine-3,5-dione.
Preferably it means a 3- to 10-membered monocyclic or bicyclic
heterocyclic group containing 1 to 4 heteroatoms selected from the
group consisting of N, O and S.
[0022] "Heteroaryl group" in the present specification means, among
the above "heterocyclic group", a monocyclic, bicyclic or tricyclic
heterocyclic group wherein the ring forming a monovalent group is
aromatized. In the case of a bicyclic or tricyclic group, rings
other than the ring forming a monovalent group may be completely
saturated, partially saturated or aromatized. The heteroaryl group
may contain one or two --C(.dbd.O)-- or --C(.dbd.S)--. For example,
although not limited thereto, there may be mentioned a monovalent
group derived from furan, thiophene, pyrrole, oxazole, thiazole,
isothiazole, isoxazole, imidazole, pyrazole, pyridine, pyrazine,
pyrimidine, pyridazine, benzofuran, benzothiophene, indole,
benzimidazole, benzothiazole, benzoxazole, indazole, isobenzofuran,
quinoline, isoquinoline, quinazoline, purine or acridine,
7-chromanyl, 6-isochromanyl and 5-indolinyl. Preferably it means a
bicyclic heteroaryl group wherein a phenyl group is fused with a
heterocycle containing 1 to 4 heteroatoms selected from the group
consisting of N, O and S. As examples of such a group, although not
limited thereto, there may be mentioned 4-benzothiazolyl,
5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl,
5-benzoxazolyl, 6-benzoxazolyl, 5-benzothienyl, 6-benzofuranyl,
6-indazolyl, 5-quinolyl, 7-phthalazinyl, 6-quinoxalinyl,
6-quinazolinyl, 6-cinnolinyl, 7-chromanyl, 5-indolinyl and
6-isoindolinyl. More preferably, it means a bicyclic heteroaryl
group wherein a phenyl group is fused with a heteroaryl containing
1 or 2 heteroatoms selected from the group consisting of N, O and
S. As examples of such a group, although not limited thereto, there
may be mentioned 4-benzothiazolyl, 5-benzothiazolyl,
6-benzothiazolyl, 7-benzothiazolyl, 5-benzoxazolyl, 6-benzoxazolyl,
5-benzothienyl, 6-benzofuranyl, 6-indazolyl, 5-quinolyl,
7-phthalazinyl, 6-quinoxalinyl, 6-quinazolinyl and
6-cinnolinyl.
[0023] "Saturated heterocyclic group" in the present specification
represents, among the above "heterocyclic group", a monocyclic,
bicyclic or tricyclic heterocyclic group wherein the ring forming a
monovalent group is completely or partially saturated. In the case
of a bicyclic or tricyclic group, rings other than the ring forming
a monovalent group may be completely saturated, partially saturated
or aromatized. The saturated heterocyclic group may contain one or
two --C(.dbd.O)-- or --C(.dbd.S)--. For example, although not
limited thereto, there may be mentioned a monovalent group derived
from pyrrolidine, imidazolidine, pyrazolidine, morpholine,
thiomorpholine, piperidine, homopiperidine, piperazine,
homopiperazine or tetrahydrofuran, 3-chromanyl and 3-indolyl.
Preferably it represents a 5- to 8-membered monocyclic saturated
heterocyclic group containing 1 or 2 heteroatoms selected from the
group consisting of N, O and S. For example, although not limited
thereto, there may be mentioned a monovalent group derived from
pyrrolidine, imidazolidine, pyrazolidine, morpholine,
thiomorpholine, piperidine, homopiperidine, piperazine,
homopiperazine or tetrahydrofuran.
[0024] "Heterocyclylalkyl group" in the present specification
represents a group composed of a heterocyclic group and an alkyl
group. Here, the heterocyclic group and the alkyl group correspond
to "heterocyclic group" and "alkyl group" defined above,
respectively. As preferred examples of the heterocyclylalkyl group,
there may be mentioned a group composed of a group included in the
above definition and one of the preferred groups or a combination
of one of the referred groups for each moiety. Preferably, it is a
group composed of a 3- to 10-membered monocyclic or bicyclic
"heterocyclic group" containing 1 to 4 heteroatoms selected from
the group consisting of N, O and S and an "alkyl group" having 1 to
8 carbon atoms. More preferably, it is a group containing a
combination of a 3- to 10-membered monocyclic or bicyclic
"heterocyclic group" containing 1 to 4 heteroatoms selected from
the group consisting of N, O and S and an "alkyl group" having 1 to
4 carbon atoms. As examples, although not limited thereto, there
may be mentioned (2-furyl)methyl, (3-thienyl)methyl,
(5-isobenzofuranyl)methyl, (5-benzothienyl)methyl,
(6-benzoxazolyl)methyl, 2-(4-morpholyl)ethyl, 2-(3-thienyl)ethyl,
2-(1-pyrazinyl)ethyl, 3-(2-pyridyl)propyl and
3-(4-piperidyl)propyl.
[0025] "Aralkyl group" in the present specification represents a
group composed of an aryl group and an alkyl group. Here, the aryl
group and the alkyl group correspond to "aryl group" and "alkyl
group" defined above, respectively. Preferably it is a group
composed of an "aryl group" having 6 to 10 carbon atoms and an
"alkyl group" having 1 to 8 carbon atoms. As examples, although not
limited thereto, there may be mentioned benzyl, phenethyl,
(2-naphthyl)methyl, 3-phenylpropyl, 4-phenylbutyl and
5-(1-naphthyl)pentyl. More preferably, it is a group composed of a
phenyl group and an alkyl group having 1 to 4 carbon atoms. As
examples of such a group, although not limited thereto, there may
be mentioned benzyl, phenethyl, (2-naphthyl)methyl, 3-phenylpropyl
and 4-phenylbutyl.
[0026] "Alkoxy group" in the present specification represents a
linear, branched or cyclic alkoxy group. Preferably it is an alkoxy
group having 1 to 8 carbon atoms. As examples, although not limited
thereto, there may be mentioned methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy and
n-heptyloxy. More preferably, it is an alkoxy group having 1 to 6
carbon atoms, and still more preferably it is an alkoxy group
having 1 to 4 carbon atoms. As examples of such a group, although
not limited thereto, there may be mentioned methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
[0027] "Halogen" in the present specification represents F, Cl, Br
or I. Preferably it is F, Cl or Br. In the present specification,
the FIGURE following "C" in, for example, "C1" represents the
number of carbon atoms, and "C1-C6" represents the range of number
of carbon atoms of 1 to 6. Needless to say, in the present
invention, each group different in number of carbon atoms means the
same type of group having each number of carbon atoms. For example,
"C1-C6 alkyl group" means an alkyl group, which is defined for
"C1-C8 alkyl group", having 1 to 6 carbon atoms. Numbers of carbon
atoms in other groups are interpreted in the same way.
[0028] "Substituted silyl group" in the present specification
represents a silyl group that can be used as a protecting group for
a hydroxyl group. Preferably it is trimethylsilyl,
tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triethylsilyl,
and more preferably it is tert-butyldimethylsilyl.
[0029] The substituents in the "optionally substituted alkyl group"
in the present invention are one or more substituent(s) selected
from the group consisting of a halogen, --CN, --CHO,
--(C.dbd.O)--R.sup.10, --NO.sub.2, --OH, --(C.dbd.O)OH,
--(C.dbd.O)OR.sup.51, --(C.dbd.O)NR.sup.52R.sup.53, a C1-C8 alkyl
group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a
C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group,
a C1-C4 alkoxy group substituted with 1 to 9 halogens and
--NR.sup.12R.sup.13. Preferably, they are one or more substituents
selected from the group consisting of a halogen, --OH,
--(C.dbd.O)OH, a phenyl group, a C1-C4 alkoxy group, a C1-C4 alkoxy
group substituted with 1 to 9 halogens and --NR.sup.12R.sup.13. The
preferred number of substituents is 1 to 3. Here, R.sup.12
represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or
a benzyl group, and preferably it is a hydrogen atom or a C1-C4
alkyl group. R.sup.13 represents a hydrogen atom, a C1-C8 alkyl
group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group
or a benzyloxycarbonyl group, and preferably it is a hydrogen atom
or a C1-C4 alkyl group. When R.sup.12 and R.sup.13 are alkyl
groups, they may form a saturated or unsaturated 5- to 7-membered
ring together with the nitrogen atom to which they bond. Further,
this ring may contain 1 or 2 heteroatoms selected from the group
consisting of an oxygen atom, a nitrogen atom and a sulfur atom
besides the nitrogen atom to which R.sup.12 and R.sup.13 bond.
R.sup.50 represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group
or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or
a phenyl group. R.sup.51 represents a C1-C8 alkyl group, a C3-C8
cycloalkyl group or a C6-C14 aryl group, and preferably it is a
C1-C4 alkyl group. R.sup.52 and R.sup.53 may be identical or
different and each represents a hydrogen atom, a C1-C8 alkyl group,
a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group.
When R.sup.52 and R.sup.53 are alkyl groups, they may form a
saturated or unsaturated 5- to 7-membered ring together with the
nitrogen atom to which they bond. Further, this ring may contain 1
or 2 heteroatoms selected from the group consisting of an oxygen
atom, a nitrogen atom and a sulfur atom besides the nitrogen atom
to which R.sup.52 and R.sup.53 bond. Preferably each of R.sup.52
and R.sup.53, which may be identical or different, is a hydrogen
atom or a C1-C4 alkyl group.
[0030] The substituents in "optionally substituted alkenyl" in the
present invention are one or more substituents selected from the
group consisting of a halogen, --CN, --CHO, --(C.dbd.O)--R.sup.54,
--NO.sub.2, --OH, --(C.dbd.O)OH, --(C.dbd.O)OR.sup.55,
--(C.dbd.O)NR.sup.56R.sup.57, a C1-C8 alkyl group, a C1-C4 alkyl
group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a
C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group
substituted with 1 to 9 halogens and --NR.sup.44R.sup.45.
Preferably, they are one or more substituents selected from the
group consisting of a halogen, a C1-C4 alkyl group, a phenyl group
and an amino group. The preferred number of substituents is 1 to 3.
Here, R.sup.44 represents a hydrogen atom, a C1-C8 alkyl group or a
benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl
group. R.sup.45 represents a hydrogen atom, a C1-C8 alkyl group, a
benzyl group, an acetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group, and preferably it is a hydrogen atom or a
C1-C4 alkyl group. R.sup.54 represents a C1-C8 alkyl group, a C3-C8
cycloalkyl group or a C6-C14 aryl group, and preferably it is a
C1-C4 alkyl group or a phenyl group. R.sup.55 represents a C1-C8
alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and
preferably it is a C1-C4 alkyl group. R.sup.56 and R.sup.57 may be
identical or different and each represents a hydrogen atom, a C1-C8
alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an
aralkyl group. Preferably they are a hydrogen atom or a C1-C4 alkyl
group. The substituents in "optionally substituted alkynyl" in the
present invention are one or more substituents selected from the
group consisting of a halogen, --CN, --CHO, --(C.dbd.O)--R.sup.58,
--NO.sub.2, --OH, --(C.dbd.O)OH, --(C.dbd.O)OR.sup.59,
--(C.dbd.O)NR.sup.60R.sup.61, a C1-C8 alkyl group, a C1-C4 alkyl
group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a
C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group
substituted with 1 to 9 halogens and --NR.sup.46R.sup.47.
Preferably, they are one or more substituents selected from the
group consisting of a halogen, a C1-C4 alkyl group, a phenyl group
and an amino group. Preferably the number of substituents is 1 to
3. Here, R.sup.46 represents a hydrogen atom, a C1-C8 alkyl group
or a benzyl group, and preferably it is a hydrogen atom or a C1-C4
alkyl group. R.sup.47 represents a hydrogen atom, a C1-C8 alkyl
group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group
or a benzyloxycarbonyl group, and preferably it is a hydrogen atom
or a C1-C4 alkyl group. R.sup.58 represents a C1-C8 alkyl group, a
C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is
a C1-C4 alkyl group or a phenyl group. R.sup.59 represents a C1-C8
alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and
preferably it is a C1-C4 alkyl group. R.sup.60 and R.sup.61 may be
identical or different and each represents a hydrogen atom, a C1-C8
alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an
aralkyl group, and preferably they are a hydrogen atom or a C1-C4
alkyl group.
[0031] The substituents in "optionally substituted cycloalkyl
group" in the present invention are one or more substituents
selected from the group consisting of a halogen, --CN, --CHO,
--NO.sub.2, --OH, --(C.dbd.O)OH, --(C.dbd.O)OR.sup.6,
--(C.dbd.O)NR.sup.64R.sup.65, a C1-C8 alkyl group, a C3-C8
cycloalkyl group or a C6-C14 aryl group, a C1-C8 alkoxy group and
--NR.sup.14R.sup.15. Preferably they are one or more substituents
selected from the group consisting of a halogen, --OH,
--(C.dbd.O)OH, a C1-C4 alkyl group, a phenyl group and
--NR.sup.14R.sup.15. More preferably they are one or more
substituents selected from the group consisting of --OH, a C1-C4
alkoxy group and --NR.sup.14R.sup.15. Preferably the number of
substituents is 1 to 3. Here, R.sup.14 represents a hydrogen atom,
a C1-C8 alkyl group, a phenyl group or a benzyl group, and
preferably it is a hydrogen atom or a C1-C4 alkyl group. R.sup.15
represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an
acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl
group, and preferably it is a hydrogen atom or a C1-C4 alkyl group.
R.sup.62 represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group
or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or
a phenyl group. R.sup.63 represents a C1-C8 alkyl group, a C3-C8
cycloalkyl group or a C6-C14 aryl group, and preferably it is a
C1-C4 alkyl group. R.sup.64 and R.sup.65 may be identical or
different and each represents a hydrogen atom, a C1-C8 alkyl group,
a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group.
When R.sup.64 and R.sup.65 are alkyl groups, they may form a
saturated or unsaturated 5- to 7-membered ring together with the
nitrogen atom to which they bond. Further, this ring may contain 1
or 2 heteroatoms selected from the group consisting of an oxygen
atom, a nitrogen atom and a sulfur atom besides the nitrogen atom
to which R.sup.64 and R.sup.65 bond. Preferably, R.sup.64 and
R.sup.65, which may be identical or different, are a hydrogen atom
or a C1-C4 alkyl group.
[0032] The substituents in "optionally substituted aralkyl group"
in the present invention are one or more substituents selected from
the group consisting of a halogen, --CN, --CHO,
--(C.dbd.O)--R.sup.66, --NO.sub.2, --OH, --(C.dbd.O)OH,
--(C.dbd.O)OR.sup.67, --(C.dbd.O)NR.sup.68R.sup.69, a C1-C8 alkyl
group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a
C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group,
a C1-C4 alkoxy group substituted with 1 to 9 halogen atoms and
--NR.sup.16R.sup.17. Preferably, they are one or more substituents
selected from the group consisting of a halogen, a C1-C4 alkyl
group, a C1-C8 alkoxy group, a phenyl group and an amino group.
Preferably the number of substituents is 1 to 3. Here, R.sup.16
represents a hydrogen atom, a C1-C8 alkyl group or a benzyl group,
and preferably it is a hydrogen atom or a C1-C4 alkyl group.
R.sup.17 represents a hydrogen atom, a C1-C8 alkyl group, a benzyl
group, an acetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group, and preferably it is a hydrogen atom or a
C1-C4 alkyl group. R.sup.66 represents a C1-C8 alkyl group, a C3-C8
cycloalkyl group or a C6-C14 aryl group, and preferably it is a
C1-C4 alkyl group or a phenyl group. R.sup.67 represents a C1-C8
alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and
preferably it is a C1-C4 alkyl group. R.sup.68 and R.sup.69 may be
identical or different and each represents a hydrogen atom, a C1-C8
alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an
aralkyl group, and preferably they are a hydrogen atom or a C1-C4
alkyl group.
[0033] The substituents in "optionally substituted alkoxy group" in
the present invention are one or more substituents selected from
the group consisting of a halogen, --CN, --CHO,
--(C.dbd.O)--R.sup.70, --NO.sub.2, --OH, --(C.dbd.O)OH,
--(C.dbd.O)OR.sup.71, --(C.dbd.O)NR.sup.72R.sup.73, a C1-C8 alkyl
group, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8
alkoxy group and --NR.sup.18R.sup.19. Preferably they are one or
more substituents selected from the group consisting of a halogen,
a C1-C4 alkyl group, a phenyl group and an amino group. Preferably
the number of substituents is 1 to 3. Here, R.sup.18 represents a
hydrogen atom, a C1-C8 alkyl group or a benzyl group, and
preferably it is a hydrogen atom or a C1-C4 alkyl group. R.sup.19
represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an
acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl
group, and preferably it is a hydrogen atom or a C1-C4 alkyl group.
R.sup.70 represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group
or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or
a phenyl group. R.sup.71 represents a C1-C8 alkyl group, a C3-C8
cycloalkyl group or a C6-C14 aryl group, and preferably it is a
C1-C4 alkyl group. R.sup.72 and R.sup.73 may be identical or
different and each represents a hydrogen atom, a C1-C8 alkyl group,
a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group,
and preferably each of them is a hydrogen atom or a C1-C4 alkyl
group.
[0034] The substituents in "optionally substituted phenoxy group"
in the present invention are one or more substituents selected from
the group consisting of a halogen, --CN, --CHO,
--(C.dbd.O)--R.sup.74, --NO.sub.2, --OH, --(C.dbd.O)OH,
--(C.dbd.O)OR.sup.75, --(C.dbd.O)NR.sup.76R.sup.77, a C1-C8 alkyl
group, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8
alkoxy group and --NR.sup.20R.sup.21. Preferably, they are one or
more substituents selected from the group consisting of a halogen,
a C1-C4 alkyl group, a C1-C4 alkoxy group, a phenyl group and an
amino group. Preferably the number of substituents is 1 to 3. Here,
R.sup.20 represents a hydrogen atom, a C1-C8 alkyl group or a
benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl
group. R.sup.21 represents a hydrogen atom, a C1-C8 alkyl group, a
benzyl group, an acetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group, and preferably it is a hydrogen atom or a
C1-C4 alkyl group. R.sup.74 represents a C1-C8 alkyl group, a C3-C8
cycloalkyl group or a C6-C14 aryl group, and preferably it is a
C1-C4 alkyl group or a phenyl group. R.sup.75 represents a C1-C8
alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and
preferably it is a C1-C4 alkyl group. R.sup.76 and R.sup.77 may be
identical or different and each represents a hydrogen atom, a C1-C8
alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an
aralkyl group, and preferably they are a hydrogen atom or a C1-C4
alkyl group.
[0035] The substituents on carbon atom(s) in "optionally
substituted heterocyclic group" in the present invention are one or
more substituents selected from the group consisting of a halogen,
--(C.dbd.O)--R.sup.78, --CN, --NO.sub.2, --OH, --(C.dbd.O)OH,
--(C.dbd.O)OR.sup.79, --(C.dbd.O)NR.sup.80R.sup.81, a C1-C8 alkyl
group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a
C2-C8 alkenyl, a C2-C8 alkynyl, a C3-C8 cycloalkyl group, a C6-C14
aryl group, a heterocyclic group, a C7-C16 aralkyl group, a C1-C8
alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens
and --NR.sup.22R.sup.23. Preferably they are one or more
substituents selected from the group consisting of a halogen, --CN,
--NO.sub.2, --OH, --(C.dbd.O)OH, a C1-C8 alkyl group, a C1-C4 alkyl
group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a
C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group
substituted with 1 to 9 halogens and --NR.sup.22R.sup.23Still more
preferably they are one or more substituents selected from the
group consisting of a halogen, --(C.dbd.O)OH, a C1-C4 alkyl group,
a C1-C4 alkyl group substituted with 1 to 9 halogens, a phenyl
group, a C1-C4 alkoxy group and an amino group. Preferably the
number of substituents is 1 to 3. Here, R.sup.22 represents a
hydrogen atom, a C1-C8 alkyl group, a phenyl group and a benzyl
group, and preferably it is a hydrogen atom or a C1-C4 alkyl group.
R.sup.23 represents a hydrogen atom, a C1-C8 alkyl group, a benzyl
group, an acetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group, and preferably it is a hydrogen atom or a
C1-C4 alkyl group. R.sup.78 represents a hydrogen atom, a C1-C8
alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and
preferably it is a C1-C4 alkyl group or a phenyl group. R.sup.79
represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a
C6-C14 aryl group, and preferably it is a C1-C4 alkyl group.
R.sup.80 and R.sup.81 may be identical or different and each
represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl
group, a C6-C14 aryl group or an aralkyl group, and preferably they
are a hydrogen atom or a C1-C4 alkyl group. When nitrogen atom(s)
in the heterocyclic group are substituted, the substituents are one
or more substituents selected from the group consisting of a C1-C4
alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl
group and a benzyloxycarbonyl group.
[0036] When R.sup.4 is an "optionally substituted aryl group" in
the present invention, the substituents are one or more
substituents selected from the group consisting of a halogen, --CN,
--NO.sub.2, --CHO, --OH, --COOH, an optionally substituted C1-C8
alkyl group, an optionally substituted C2-C8 alkenyl, an optionally
substituted C2-C8 alkynyl, an optionally substituted C3-C8
cycloalkyl group, --O--(CH.sub.2).sub.m--W, an optionally
substituted C6-C14 aryl group, an optionally substituted
heterocyclic group, --C(.dbd.O)--R.sup.133, --O--C(.dbd.O)R.sup.26,
--C(.dbd.O)OR.sup.27, --NR.sup.28C(.dbd.O)R.sup.29,
--NR.sup.30R.sup.31, --C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.34--C(.dbd.X)OR.sup.35,
--NR.sup.36--C(.dbd.X)NR.sup.37R.sup.38,
--NR.sup.39--SO.sub.2R.sup.40, --S(O).sub.r--R.sup.41 and
--SO.sub.2NR.sup.42R.sup.43. Preferably they are one or more
substituents selected from the group consisting of a halogen, --CN,
--NO.sub.2, an optionally substituted C1-C8 alkyl group,
--O--(CH.sub.2).sub.m--W, an optionally substituted phenyl group,
an optionally substituted heterocyclic group, --(C.dbd.O)OR.sup.7,
--NR.sup.7(C.dbd.O)R.sup.8, --NR.sup.9R.sup.10,
--(C.dbd.O)NR.sup.9R.sup.10 and --SO.sub.2NR.sup.9R.sup.10. More
preferably they are one or more substituents selected from the
group consisting of a halogen, an optionally substituted C1-C4
alkyl group, --O--(CH.sub.2).sub.m--W and --C(.dbd.O)OR.sup.27, and
--O--(CH.sub.2).sub.m--W is still more preferred. The number of
substituents is 1 to 3, and preferably 1.
[0037] W represents a hydrogen atom, an optionally substituted
C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an
optionally substituted C2-C8 alkynyl, an optionally substituted
C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group
or an optionally substituted heterocyclic group and m is 0 to 4; or
W represents an optionally substituted C1-C8 alkoxy group or an
optionally substituted phenoxy group and m is 1 to 4.
Preferably,
[0038] W is a hydrogen atom, an optionally substituted C1-C4 alkyl
group, an optionally substituted C3-C8 cycloalkyl group, an
optionally substituted phenyl group or an optionally substituted
monocyclic or bicyclic heterocyclic group and m is 0 to 4; or W is
an optionally substituted C1-C4 alkoxy group and m is 1 to 4. More
preferably, W is a hydrogen atom or an optionally substituted C1-C4
alkyl group and m is 0 to 4; or W is an optionally substituted
C1-C4 alkoxy group and m is 1 to 4. Still more preferably, W is a
C1-C4 alkyl group and m is 0; or W is a C1-C4 alkoxy group and m is
2.
[0039] R.sup.7, R.sup.8, R.sup.9 and R.sup.10 may be identical or
different and each represents a hydrogen atom, an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group or an optionally substituted C6-C14 aryl group.
When R.sup.9 and R.sup.10 are alkyl groups, they may form a
saturated or unsaturated 5- to 7-membered ring together with the
nitrogen atom to which they bond. Further, this ring may contain 1
or 2 heteroatoms selected from the group consisting of an oxygen
atom, a nitrogen atom and a sulfur atom besides the nitrogen atom
to which R.sup.9 and R.sup.10 bond. Preferably R.sup.7, R.sup.8,
R.sup.9 and R.sup.10, which may be identical or different, are a
hydrogen atom or an optionally substituted C1-C4 alkyl group.
[0040] R.sup.26--R.sup.43, R.sup.33, R.sup.150 and R.sup.151 may be
identical or different and each represents is a hydrogen atom, an
optionally substituted C1-C8 alkyl group, an optionally substituted
C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an
optionally substituted C3-C8 cycloalkyl group, an optionally
substituted C6-C14 aryl group, an optionally substituted
heterocyclic group, an optionally substituted aralkyl group or an
optionally substituted heterocyclylalkyl group. When R.sup.30 and
R.sup.31R.sup.32 and R.sup.33R.sup.37 and R.sup.38, R.sup.42 and
R.sup.43, or R.sup.150 and R.sup.151 are alkyl groups, the
substituents in each combination may form a saturated or
unsaturated 5- to 7-membered ring together with the nitrogen atom
to which they bond. Further, this ring may contain 1 or 2
heteroatoms selected from the group consisting of an oxygen atom, a
nitrogen atom and a sulfur atom besides the nitrogen atom to which
the substituents bond. Preferably R.sup.26--R.sup.43, R.sup.133,
R.sup.150 and R.sup.151, which may be identical or different, are a
hydrogen atom, an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group or an optionally
substituted C6-C14 aryl group. More preferably they are a hydrogen
atom or an optionally substituted C1-C4 alkyl group. Each of
X.sup.1 and X.sup.2 represents O, S, N--CN or NH, and preferably O.
r represents an integer ranging from 0 to 2, and preferably it is 0
or 2.
[0041] The substituents in "optionally substituted aryl group"
other than "optionally substituted aryl group as R.sup.4" in the
present invention are one or more substituents selected from the
group consisting of a halogen, --CN, --CHO, --(C.dbd.O)--R.sup.82,
--NO.sub.2, --OH, --(C.dbd.O)OH, --(C.dbd.O)OR.sup.83,
--(C.dbd.O)NR.sup.84R.sup.85, a C1-C8 alkyl group, a C1-C4 alkyl
group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a
C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group
substituted with 1 to 9 halogens and --NR.sup.24R.sup.25.
Preferably they are one or more substituents selected from the
group consisting of a halogen, --CN, --OH, --(C.dbd.O)OH, a C1-C6
alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens,
a C1-C6 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9
halogens and --NR.sup.24R.sup.25. A halogen is further preferred.
The number of substituents is 1 to 3 and preferably 1. Here,
R.sup.24 represents a hydrogen atom, a C1-C8 alkyl group or a
benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl
group. R.sup.25 represents a hydrogen atom, a C1-C8 alkyl group or
a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group, and preferably it is a hydrogen atom or a
C1-C4 alkyl group. R.sup.82 represents a C1-C8 alkyl group, a C3-C8
cycloalkyl group or a C6-C14 aryl group, and preferably it is a
C1-C4 alkyl group or a phenyl group. R.sup.83 represents a C1-C8
alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and
preferably it is a C1-C4 alkyl group. R.sup.84 and R.sup.85 may be
identical or different and each represents is a hydrogen atom, a
C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or
an aralkyl group. Preferably they are a hydrogen atom or a C1-C4
alkyl group.
[0042] The substituents on carbon atom(s) in "optionally
substituted heterocyclylalkyl group" in the present invention are
one or more substituents selected from the group consisting of a
halogen, --(C.dbd.O)--R.sup.127, --CN, --NO.sub.2, --OH,
--(C.dbd.O)OH, --(C.dbd.O)OR.sup.128,
--(C.dbd.O)NR.sup.129R.sup.130, a C1-C8 alkyl group, a C1-C4 alkyl
group substituted with 1 to 9 halogens, a C6-C14 aryl group, a
C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9
halogens and --NR.sup.131R.sup.132. Preferably the alkyl moiety in
the heterocyclylalkyl group is unsubstituted and substituents on
carbon atom(s) in the heterocycle moiety are one or more
substituents selected from the group consisting of a halogen,
--(C.dbd.O)OH, a C1-C4 alkyl group, a C1-C4 alkyl group substituted
with 1 to 9 halogens, a C1-C4 alkoxy group, a C1-C4 alkoxy group
substituted with 1 to 9 halogens and --NR.sup.131R.sup.132, further
preferably, one or more substituents selected from the group
consisting of a halogen, a C1-C4 alkyl group and a C1-C4 alkyl
group substituted with 1 to 9 halogens. Preferably the number of
substituents is 1 to 3. Here, R.sup.131 represents a hydrogen atom,
a C1-C8 alkyl group, a phenyl group or a benzyl group, and
preferably it is a hydrogen atom or a C1-C4 alkyl group. R.sup.132
represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an
acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl
group, and preferably it is a hydrogen atom or a C1-C4 alkyl group.
R.sup.127 represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8
cycloalkyl group or a C6-C14 aryl group, and preferably it is a
C1-C4 alkyl group or a phenyl group. R.sup.128 represents a C1-C8
alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and
preferably it is a C1-C4 alkyl group. R.sup.129 and R.sup.130 may
be identical or different and each represents a hydrogen atom, a
C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or
an aralkyl group. Preferably they are a hydrogen atom or a C1-4
alkyl group. When nitrogen atom(s) in the heterocycle are
substituted, the substituents are one or more substituents selected
from the group consisting of a C1-4 alkyl group, a benzyl group, an
acetyl group, a tert-butoxycarbonyl group and a benzyloxycarbonyl
group.
[0043] R.sup.1 is preferably hydrogen.
[0044] R.sup.2 is preferably hydrogen.
[0045] R.sup.3 is preferably an optionally substituted C1-8 alkyl
group, an optionally substituted C3-8 cycloalkyl group or an
optionally substituted heterocyclic group.
[0046] Among the optionally substituted C1-C8 alkyl groups, which
are preferred groups as R.sup.3, as more preferred example, there
may be mentioned unsubstituted C1-C6 alkyl groups and substituted
C1-C6 alkyl groups. (Here, the substituents are 1 to 3 substituents
selected from the group consisting of a halogen, a phenyl group, a
C1-C4 alkyl group substituted with 1 to 9 halogens, a C1-C4 alkoxy
group, a C1-C4 alkoxy group substituted with 1 to 9 halogens, --CN,
--CHO, --OH, --(C.dbd.O)OH, --(C.dbd.O)OR.sup.86,
--(C.dbd.O)NR.sup.87R.sup.88 and --NR.sup.89R.sup.90. Further
preferably they are 1 to 3 substituents selected from the group
consisting of a phenyl group, a C1-C4 alkoxy group, --CHO and
--NR.sup.89R.sup.90. More preferably the substituent is one
--NR.sup.89R.sup.90. Preferably the number of substituents is 1 to
3 for halogen or 1 for the others. R.sup.86 represents a C1-C4
alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and
preferably it is a C1-C4 alkyl group. R.sup.87 and R.sup.88 may be
identical or different, and each represents a hydrogen atom, a
C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or an
aralkyl group, and preferably they are a hydrogen atom or a C1-C4
alkyl group. R.sup.89 represents a hydrogen atom, a C1-C4 alkyl
group, a phenyl group or a benzyl group, and preferably it is a
hydrogen atom or a C1-C4 alkyl group. R.sup.90 represent a hydrogen
atom, a C1-C4 alkyl group, a benzyl group, an acetyl group, a
tert-butoxycarbonyl group or a benzyloxycarbonyl group, and
preferably it is a hydrogen atom or a C1-C4 alkyl group. When
R.sup.89 and R.sup.90 are alkyl groups, they may form a saturated
or unsaturated 5- to 7-membered ring together with the nitrogen
atom to which they bond. Further, this ring may contain 1 or 2
heteroatoms selected from the group consisting of an oxygen atom, a
nitrogen atom and a sulfur atom besides the nitrogen atom to which
R.sup.89 and R.sup.90 bond.)
[0047] Among the optionally substituted C3-C8 cycloalkyl groups,
which are preferred groups as R.sup.3, as more preferred examples,
there may be mentioned unsubstituted C3-C8 cycloalkyl groups and
substituted C3-C8 cycloalkyl groups. (Here, the substituents are 1
to 3 substituents selected from the group consisting of a halogen,
--OH, --(C.dbd.O)OH, a C1-C4 alkyl group, a phenyl group, a C1-C4
alkoxy group and --NR.sup.91R.sup.92. Preferably they are 1 to 3
substituents selected from the group consisting of --OH,
--(C.dbd.O)OH and --NR.sup.91R.sup.92. More preferably it is one
--NR.sup.91R.sup.92. Preferably the number of substituents is 1 to
3 for halogens or 1 for the others. Here, R.sup.91 represents a
hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl
group, and preferably it is a hydrogen atom or a C1-C4 alkyl group.
R.sup.92 represents a hydrogen atom, a C1-C8 alkyl group, a benzyl
group, an acetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group, and preferably it is a hydrogen atom or a
C1-C4 alkyl group.)
[0048] Among the optionally substituted heterocyclic groups, which
are preferred groups as R.sup.3, as more preferred examples, there
may be mentioned an unsubstituted monocyclic heterocyclic group, an
unsubstituted bicyclic heterocyclic group, a substituted monocyclic
heterocyclic group and a substituted bicyclic heterocyclic group,
and more preferably there may be mentioned an unsubstituted
monocyclic heterocyclic group and a substituted monocyclic
heterocyclic group. Here, when carbon atom(s) in the substituted
monocyclic heterocyclic group or substituted bicyclic heterocyclic
group are substituted, the substituent(s) are 1 to 3 substituents
selected from the group consisting of a halogen, --(C.dbd.O)OH, a
C1-C4 alkyl group, a C1-C4 alkyl group substituted with 1 to 9
halogens, a phenyl group, a benzyl group, a C1-C4 alkoxy group, a
C1-C4 alkoxy group substituted with 1 to 9 halogens and
--NR.sup.93R.sup.94. Preferably they are 1 to 3 substituents
selected from the group consisting of a C1-C4 alkyl group and an
amino group. Preferably the number of substituents is 1 to 3 for
halogens or 1 for the others. Here, R.sup.93 represents a hydrogen
atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, and
preferably it is a hydrogen atom or a C1-C4 alkyl group. R.sup.94
represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an
acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl
group, and preferably it is a hydrogen atom or a C1-C4 alkyl group.
When nitrogen atom(s) in the heterocyclic group are substituted,
the substituents are one or more substituents selected from the
group consisting of a C1-C4 alkyl group, a benzyl group, an acetyl
group, a tert-butoxycarbonyl group and a benzyloxycarbonyl group.
Preferably the substituent is a C1-C4 alkyl group, a benzyl group
or a tert-butoxycarbonyl group and more preferably a C1-C4 alkyl
group or a tert-butoxycarbonyl group.
[0049] Preferably, R.sup.3 is an unsubstituted 5- to 8-membered
monocyclic heterocyclic group containing 1 or 2 heteroatoms
selected from the group consisting of N, O and S, a C1-C4 alkyl
group substituted with one amino group or a C3-C8 cycloalkyl group
substituted with one amino group.
[0050] More preferably, R.sup.3 is an unsubstituted 5- to
8-membered monocyclic saturated heterocyclic group containing one
nitrogen atom, a C1-C4 alkyl group substituted with one amino group
or a C3-C8 cycloalkyl group substituted with one amino group.
[0051] Still more preferably, R.sup.3 is a piperidyl group, a
pyrrolidinyl group or a cyclohexyl group substituted with one amino
group.
[0052] Furthermore preferably R.sup.3 is a piperidyl group or a
pyrrolidinyl group.
[0053] Preferably R.sup.4 is a hydrogen atom, an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group, an optionally substituted aralkyl group, an
optionally substituted heterocyclylalkyl group, an optionally
substituted C6-C14 aryl group or an optionally substituted
heterocyclic group.
[0054] Among the optionally substituted C1-C8 alkyl groups, which
are preferred groups as R.sup.4, as more preferred examples, there
may be mentioned unsubstituted C1-C8 alkyl groups and substituted
C1-C8 alkyl groups. (Here, the substituents are 1 to 3 substituents
selected from the group consisting of a halogen,
--(C.dbd.O)--R.sup.95, --OH, --(C.dbd.O)OH, --(C.dbd.O)OR.sup.96,
--(C.dbd.O)NR.sup.97R.sup.98, a C1-C4 alkyl group, a C1-C4 alkyl
group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a
C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group
substituted with 1 to 9 halogens and --NR.sup.99R.sup.100. More
preferably, they are 1 to 3 substituents selected from the group
consisting of a halogen, a C3-C8 cycloalkyl group, a phenyl group,
a C1-C8 alkoxy group and a C1-C4 alkoxy group substituted with 1 to
9 halogens. Preferably the number of the substituents is 1 to 3 for
halogens or 1 for the others. R.sup.95 represents a C1-C8 alkyl
group, a C3-C8 cycloalkyl group or a phenyl group, and preferably
it is a C1-C4 alkyl group or a phenyl group. R.sup.96 represents a
C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and
preferably it is a C1-C4 alkyl group. R.sup.97 and R.sup.98 may be
identical or different and each represents a hydrogen atom, a C1-C8
alkyl group, a C3-C8 cycloalkyl group, a phenyl group or an aralkyl
group. When R.sup.97 and R.sup.98 are alkyl groups, they may form a
saturated or unsaturated 5- to 7-membered ring together with the
nitrogen atom to which they bond. Further this ring may contain 1
or 2 heteroatoms selected from the group consisting of an oxygen
atom, a nitrogen atom and a sulfur atom besides the nitrogen atom
to which R.sup.97 and R.sup.98 bond. Preferably R.sup.97 and
R.sup.98, which may be identical or different, are a hydrogen atom
or a C1-C4 alkyl group. R.sup.99 represents a hydrogen atom, a
C1-C4 alkyl group, a phenyl group or a benzyl group, and preferably
it is a hydrogen atom or a C1-C4 alkyl group. R.sup.100 represents
a hydrogen atom, a C1-C4 alkyl group, a benzyl group, an acetyl
group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group,
and preferably it is a hydrogen atom or a C1-C4 alkyl group.)
[0055] Among the optionally substituted C3-C8 cycloalkyl groups,
which are preferred groups as R.sup.4, as more preferred examples,
there may be mentioned unsubstituted C3-C8 cycloalkyl groups and
substituted C3-C8 cycloalkyl groups. (Here, the substituents are 1
to 3 substituents selected from the group consisting of a halogen,
--(C.dbd.O)--R.sup.101, --OH, --(C.dbd.O)OH, --(C.dbd.O)OR.sup.102,
--(C.dbd.O)NR.sup.103R.sup.104, a C1-C8 alkyl group, a C6-C14 aryl
group, a C1-C8 alkoxy group and --NR.sup.105R.sup.106. More
preferably they are 1 to 3 substituents selected from the group
consisting of a halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group
and a phenyl group. Preferably the number of the substituents is 1
to 3 for halogens or 1 for the others. Here, R.sup.105 represents a
hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl
group, and preferably it is a hydrogen atom or a C1-C4 alkyl group.
R.sup.106 represents a hydrogen atom, a C1-C8 alkyl group, a benzyl
group, an acetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group, and preferably it is a hydrogen atom or a
C1-C4 alkyl group. R.sup.101 represents a C1-C8 alkyl group, a
C3-C8 cycloalkyl group or a phenyl group, and preferably it is a
C1-C4 alkyl group or a phenyl group. R.sup.102 represents a C1-C8
alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and
preferably it is a C1-C4 alkyl group. R.sup.103 and R.sup.104 may
be identical or different and each represents a hydrogen atom, a
C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or a
benzyl group. When R.sup.103 and R.sup.104 are alkyl groups, they
may form a saturated or unsaturated 5- to 7-membered ring together
with the nitrogen atom to which they bond. Further this ring may
contain 1 or 2 heteroatoms selected from the group consisting of an
oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen
atom to which R.sup.103 and R.sup.104 bond. Preferably each of
R.sup.103 and R.sup.104, which may be identical or different, is a
hydrogen atom or a C1-C4 alkyl group.)
[0056] Among the optionally substituted aralkyl groups, which are
preferred groups as R.sup.4, as more preferred examples, there may
be mentioned an aralkyl group composed of an unsubstituted C1-C4
alkyl group and an unsubstituted phenyl group or an aralkyl group
composed of an unsubstituted C1-C4 alkyl group and a substituted
phenyl group. Here, the substituents in the substituted phenyl
group are one or more substituents selected from the group
consisting of a halogen, --CN, --CHO, --(C.dbd.O)--R.sup.107,
--NO.sub.2, --OH, --(C.dbd.O)OH, --(C.dbd.O)OR.sup.108,
--(C.dbd.O)NR.sup.109R.sup.110, a C1-C8 alkyl group, a C1-C4 alkyl
group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a
phenyl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group
substituted with 1 to 9 halogens and --NR.sup.111R.sup.112.
Preferably they are 1 to 3 substituents selected from the group
consisting of a halogen, a C1-C4 alkyl group, a C1-C8 alkoxy group,
--(C.dbd.O)OR.sup.108 and --(C.dbd.O)NR.sup.109R.sup.110.
Preferably the number of the substituents is 1 to 3 for halogens or
1 for the others. R.sup.111 represents a hydrogen atom, a C1-C8
alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl
group or a benzyloxycarbonyl group, and preferably it is a hydrogen
atom or a C1-C4 alkyl group. R.sup.112 represents a C1-C8 alkyl
group, a C3-C8 cycloalkyl group or a phenyl group, and preferably
it is a C1-C4 alkyl group or a phenyl group. R.sup.107 represents a
C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and
preferably it is a C1-C4 alkyl group. R.sup.108 represents a C1-C8
alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and
preferably it is a C1-C4 alkyl group. R.sup.109 and R.sup.110 may
be identical or different and each represents a hydrogen atom, a
C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or a
benzyl group, and preferably they are a hydrogen atom or a C1-C4
alkyl group.
[0057] Among the optionally substituted heterocyclylalkyl groups,
which are preferred groups as R.sup.4, as more preferred examples,
there may be mentioned unsubstituted heterocyclylalkyl groups and
substituted heterocyclylalkyl groups. More preferably there may be
mentioned a heterocyclylalkyl group composed of an unsubstituted
C1-C4 alkyl group and an unsubstituted heteroaryl group and a
heterocyclylalkyl group composed of an unsubstituted C1-C4 alkyl
group and a substituted heteroaryl group. Furthermore preferably
there may be mentioned a heterocyclylalkyl group composed of an
unsubstituted C1-C4 alkyl group and an unsubstituted monocyclic or
bicyclic heteroaryl group and a heterocyclylalkyl group composed of
an unsubstituted C1-C4 alkyl group and a substituted monocyclic or
bicyclic heteroaryl group. Here, in the substituted heterocyclic
group, the heterocyclylalkyl group composed of an unsubstituted
C1-C4 alkyl group and a substituted heteroaryl group or the
heterocyclylalkyl group composed of an unsubstituted C1-C4 alkyl
group and a substituted monocyclic or bicyclic heteroaryl group,
the substituents on carbon atom(s) are one or more substituents
selected from the group consisting of a halogen, --(C.dbd.O)OH, a
C1-C4 alkyl group, a C1-C4 alkyl group substituted with 1 to 9
halogens, a C1-C4 alkoxy group and a C1-C4 alkoxy group substituted
with 1 to 9 halogens. Preferably, the alkyl moiety in the
heterocyclylalkyl group is unsubstituted and the substituents on
carbon atom(s) in the heterocyclic group are one or more
substituents selected form the group consisting of a halogen, a
C1-C4 alkyl group and a C1-C4 alkyl group substituted with 1 to 9
halogens. Preferably the number of the substituents is 1 to 3. When
nitrogen atom(s) in the heterocyclic group are substituted, the
substituents are one or more substituents selected from the group
consisting of a C1-C4 alkyl group, a benzyl group, an acetyl group,
a tert-butoxycarbonyl group and a benzyloxycarbonyl group. More
preferably, the substituent is a C1-C4 alkyl group or a
tert-butoxycarbonyl group.
[0058] Among the optionally substituted C6-C14 aryl groups, which
are preferred groups as R.sup.4, as more preferred examples, there
may be mentioned unsubstituted C6-C10 aryl groups and substituted
C6-C10 aryl groups, and more preferably there may be mentioned an
unsubstituted phenyl group and a substituted phenyl group. Here,
the substituents in the substituted C6-C10 aryl group or the
substituted phenyl group are 1 to 3 substituents selected from the
group consisting of a halogen, --CN, --NO.sub.2, an optionally
substituted C1-C8 alkyl group, --O--(CH.sub.2).sub.m--W, an
optionally substituted phenyl group, an optionally substituted
heterocyclic group, --(C.dbd.O)OR.sup.113,
--NR.sup.114(C.dbd.O)R.sup.115, --NR.sup.116R.sup.117,
--(C.dbd.O)NR.sup.118R.sup.119 and --SO.sub.2NR.sup.120R.sup.121.
More preferably they are 1 to 3 substituents selected from the
group consisting of a halogen, an optionally substituted C1-C4
alkyl group, --O--(CH.sub.2).sub.m W and --(C.dbd.O)OR.sup.113.
Still more preferably the substituent is one
--O--(CH.sub.2).sub.m--W. Preferably the number of the substituents
is 1.
[0059] W represents a hydrogen atom, an optionally substituted
C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an
optionally substituted C2-C8 alkynyl, an optionally substituted
C3-C8 cycloalkyl group, an optionally substituted C6-C10 aryl group
or an optionally substituted heterocyclic group and in this case m
is 0 to 4; or W represents an optionally substituted C1-C8 alkoxy
group, --NR.sup.150R.sup.151 or an optionally substituted phenoxy
group and in this case m is 1 to 4. Preferably W is a hydrogen
atom, an optionally substituted C1-C4 alkyl group, an optionally
substituted C3-C8 cycloalkyl group, an optionally substituted
phenyl group or an optionally substituted monocyclic or bicyclic
heterocyclic group and m is 0 to 4; or W is an optionally
substituted C1-C4 alkoxy group and m is 1 to 4. More preferably, W
is a hydrogen atom or an optionally substituted C1-C4 alkyl group
and m is 0 to 4; or W is an optionally substituted C1-C4 alkoxy
group and m is 1 to 4. Furthermore preferably W is a C1-C4 alkyl
group and m is 0; or W is a C1-C4 alkoxy group and m is 2.
[0060] R.sup.113-R.sup.121 may be identical or different and each
represents a hydrogen atom, an optionally substituted C1-C8 alkyl
group, an optionally substituted C2-C8 alkenyl, an optionally
substituted C2-C8 alkynyl, an optionally substituted C3-C8
cycloalkyl group, an optionally substituted C6-C14 aryl group, an
optionally substituted heterocyclic group, an optionally
substituted aralkyl group or an optionally substituted
heterocyclylalkyl group; or when R.sup.116 and R.sup.117, R.sup.118
and R.sup.119, or R.sup.120 and R.sup.121 are alkyl groups, they
may form a saturated or unsaturated 5- to 7-membered ring together
with the nitrogen atom to which they bond. Further this ring may
contain 1 or 2 heteroatoms selected from the group consisting of an
oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen
atom to which these substituents bond. Preferably
R.sup.113-R.sup.121, which may be identical or different, are a
hydrogen atom, an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group or an optionally
substituted C6-C14 aryl group. More preferably R.sup.113-R.sup.121
which may be identical or different, are a hydrogen atom or an
optionally substituted C1-C4 alkyl group, and still more preferably
R.sup.113-R.sup.121, which may be identical or different, are a
hydrogen atom or a C1-C4 alkyl group.
[0061] Among the optionally substituted heterocyclic groups, which
are preferred groups as R.sup.4, as more preferred examples, there
may be mentioned unsubstituted monocyclic heterocyclic groups,
unsubstituted bicyclic heterocyclic groups, substituted monocyclic
heterocyclic groups and substituted bicyclic heterocyclic groups.
Unsubstituted bicyclic heteroaryl groups and substituted bicyclic
heteroaryl groups are more preferred. Here, in the substituted
monocyclic heterocyclic group, the substituted bicyclic
heterocyclic group or the substituted bicyclic heteroaryl group,
when carbon atom(s) are substituted, the substituent(s) are 1 to 3
substituents selected from the group consisting of a halogen, --CN,
--NO.sub.2, a C1-C8 alkyl group, a C1-C4 alkyl group substituted
with 1 to 9 halogens, a C1-C8 alkoxy group, a C1-C4 alkoxy group
substituted with 1 to 9 halogens, a phenyl group, a monocyclic or
bicyclic heterocyclic group, --(C.dbd.O)OR.sup.122,
--NR.sup.123R.sup.124 and --(C.dbd.O)NR.sup.125R.sup.126.
Preferably they are 1 to 3 substituents selected from the group
consisting of a halogen, a C1-C4 alkyl group and a C1-C4 alkyl
group substituted with 1 to 9 halogens. More preferably the
substituent is one C1-C4 alkyl group. Preferably the number of
substituents is 1. Here, R.sup.123 represents a hydrogen atom, a
C1-C8 alkyl group, a phenyl group or a benzyl group, and preferably
it is a hydrogen atom or a C1-C4 alkyl group. R.sup.124 represents
a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl
group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group,
and preferably it is a hydrogen atom or a C1-C4 alkyl group.
R.sup.122 represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group
or a phenyl group, and preferably it is a C1-C4 alkyl group.
R.sup.125 and R.sup.126 may be identical or different and each
represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl
group, a phenyl group or a benzyl group, and preferably they are a
hydrogen atom or a C1-C4 alkyl group. When nitrogen atom(s) in the
heterocycle are substituted, the substituents are one or more
substituents selected from the group consisting of a C1-C4 alkyl
group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group
or a benzyloxycarbonyl group. Preferably the substituent is a C1-C4
alkyl group or a tert-butoxycarbonyl group.
[0062] More preferably R.sup.4 is an unsubstituted phenyl group, a
phenyl group substituted with one --O--(CH.sub.2).sub.m--W, an
unsubstituted bicyclic heteroaryl group, a bicyclic heteroaryl
group substituted with C1-C4 alkyl group(s) or a bicyclic
heteroaryl group substituted with C1-C4 alkyl group(s) substituted
with 1 to 9 halogens. (Here, W represents a C1-C4 alkyl group (in
this case m is 0) or a C1-C4 alkoxy group (in this case m is 2).
The bicyclic heteroaryl group means a bicyclic heteroaryl group
wherein a phenyl group is fused with a heterocycle containing 1 to
4 heteroatoms selected from the group consisting of N, O and S, and
preferably it is a bicyclic heteroaryl group wherein a phenyl group
is fused with a heterocycle containing 1 or 2 heteroatoms selected
from the group consisting of N, O and S.).
[0063] Still more preferably R.sup.4 is an unsubstituted phenyl
group, a phenyl group substituted with one
--O--(CH.sub.2).sub.m--W, an unsubstituted bicyclic heteroaryl
group, a bicyclic heteroaryl group substituted with one C1-C4 alkyl
group or a bicyclic heteroaryl group substituted with one C1-C4
alkyl group substituted with 1 to 9 halogens (Here, W represents a
C1-C4 alkyl group (in this case m is 0) or a C1-C4 alkoxy group (in
this case m is 2). As the bicyclic heteroaryl group, there may be
mentioned 5-benzothiazolyl, 6-benzothiazolyl, 5-benzoxazolyl,
6-benzoxazolyl, 5-benzothienyl, 6-benzothienyl, 5-benzofuranyl,
6-benzofuranyl, 5-indazolyl, 6-indazolyl, 5-benzimidazolyl,
6-benzimidazolyl, 5-indolyl and 6-indolyl.)
[0064] Furthermore preferably R.sup.4 is an unsubstituted phenyl
group, a phenyl group substituted with one --O--(CH.sub.2).sub.m--W
(Wherein W is an ethyl group (in this case m is 0) or a methoxy
group (in this case m is 2)), 6-indazolyl,
2-methyl-6-benzothiazolyl, 5-benzothienyl or
2-trifluoromethyl-5-benzimidazolyl.
[0065] Preferably n is 0.
[0066] Preferably -A-B- is --CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--CH.sub.2-- or --CH.dbd.CH--, and further
preferably --CH.sub.2--CH.sub.2--.
[0067] Preferably R.sup.5 is a hydrogen atom or
--(C.dbd.O)R.sup.6.
[0068] Preferably R.sup.6 is a methyl group.
[0069] Preferably X.sup.1 or X.sup.2 is O.
[0070] Preferably r is 0 or 2.
[0071] Preferably each of Z.sup.1-Z.sup.4 is a hydrogen atom.
[0072] Preferably R.sup.11 is a hydrogen atom.
[0073] For R.sup.1-R.sup.4, n and -A-B- in formula (2) in the
present invention, groups like the corresponding groups in formula
(1) described above are preferred.
[0074] As preferred combinations of R.sup.1-R.sup.4, n and -A-B- in
formula (1) in the present invention, in addition to combinations
of group(s) included in the above definition for the individual
group(s) and group(s) mentioned as preferred example for the
individual group(s) and combinations of groups mentioned above as
preferred example for the individual groups, there may be mentioned
the following 1) to 23).
1) In formula (1), R.sup.1 is hydrogen; R.sup.2 is hydrogen;
R.sup.3 is an optionally substituted C1-C8 alkyl group, an
optionally substituted C3-C8 cycloalkyl group or an optionally
substituted heterocyclic group; R.sup.4 is an optionally
substituted phenyl group (wherein the substituent in the optionally
substituted phenyl group is a halogen, --CN, an optionally
substituted C1-C8 alkyl group or --O--(CH.sub.2).sub.m--W, wherein
W represents a hydrogen atom, an optionally substituted C1-C8 alkyl
group or an optionally substituted heterocyclic group and m is 0 to
4 or W represents an optionally substituted C1-C8 alkoxy group and
m is 2 to 4); n is 0; and -A-B- is --CH.sub.2--CH.sub.2--. 2) In
formula (1), R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is
an optionally substituted C1-C8 alkyl group, an optionally
substituted C3-C8 cycloalkyl group or an optionally substituted
heterocyclic group; R.sup.4 is an optionally substituted
heterocyclic group; n is 0; and -A-B- is --CH.sub.2--CH.sub.2--. 3)
In formula (1), R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3
is an optionally substituted C1-C8 alkyl group, an optionally
substituted C3-C8 cycloalkyl group or an optionally substituted
heterocyclic group; R.sup.4 is an optionally substituted phenyl
group (wherein, the substituent in the optionally substituted
phenyl group is a halogen, --CN, an optionally substituted C1-C8
alkyl group or --O--(CH.sub.2).sub.m--W, wherein W represents a
hydrogen atom, an optionally substituted C1-C8 alkyl group or an
optionally substituted heterocyclic group and m is 0 to 4 or W
represents an optionally substituted C1-C8 alkoxy group and m is 2
to 4); n is 0; and -A-B- is --CH.sub.2--CH.sub.2--CH.sub.2-- or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--. 4) In formula (1),
R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group or an optionally substituted heterocyclic group;
R.sup.4 is an optionally substituted heterocyclic group; n is 0;
and -A-B- is --CH.sub.2--CH.sub.2--CH.sub.2-- or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--. 5) In formula (1),
R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group or an optionally substituted heterocyclic group;
R.sup.4 is an optionally substituted phenyl group (wherein, the
substituent in the optionally substituted phenyl group is a
halogen, --CN, an optionally substituted C1-C8 alkyl group or
--O--(CH.sub.2).sub.m--W, wherein W represents a hydrogen atom, an
optionally substituted C1-C8 alkyl group or an optionally
substituted heterocyclic group and m is 0 to 4 or W represents an
optionally substituted C1-C8 alkoxy group and m is 2 to 4); n is 0;
and -A-B- is --CH.sub.2--CH.dbd.CH--CH.sub.2-- or --CH.dbd.CH--. 6)
In formula (1), R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3
is an optionally substituted C1-C8 alkyl group, an optionally
substituted C3-C8 cycloalkyl group or an optionally substituted
heterocyclic group; R.sup.4 is an optionally substituted
heterocyclic group; n is 0; and -A-B- is
--CH.sub.2--CH.dbd.CH--CH.sub.2-- or --CH.dbd.CH--. 7) In formula
(1), R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is an
optionally substituted C1-C8 alkyl group, an optionally substituted
C3-C8 cycloalkyl group or an optionally substituted heterocyclic
group; R.sup.4 is a hydrogen atom, an optionally substituted C1-C8
alkyl group or an optionally substituted C3-C8 cycloalkyl group; n
is 0; and -A-B- is --CH.sub.2--CH.sub.2--. 8) In formula (1),
R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group or an optionally substituted heterocyclic group;
R.sup.4 is a hydrogen atom, an optionally substituted C1-C8 alkyl
group or an optionally substituted C3-C8 cycloalkyl group; n is 0;
and -A-B- is --CH.sub.2--CH.sub.2--CH.sub.2-- or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--. 9) In formula (1),
R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is an optionally
substituted C1-C8 alkyl group, an optionally substituted C3-C8
cycloalkyl group or an optionally substituted heterocyclic group;
R.sup.4 is a hydrogen atom, an optionally substituted C1-C8 alkyl
group or an optionally substituted C3-C8 cycloalkyl group; n is 0;
and -A-B- is --CH.sub.2--CH.dbd.CH--CH.sub.2-- or --CH.dbd.CH--.
10) In formula (1), R.sup.1 is hydrogen; R.sup.2 is hydrogen;
R.sup.3 is an optionally substituted C3-C8 cycloalkyl group;
R.sup.4 is an optionally substituted phenyl group (wherein the
substituent in the optionally substituted phenyl group is a halogen
or an optionally substituted C1-C4 alkyl group); n is 0; and -A-B-
is --CH.sub.2--CH.sub.2--. 11) In formula (1), R.sup.1 is hydrogen;
R.sup.2 is hydrogen; R.sup.3 is an optionally substituted C3-C8
cycloalkyl group; R.sup.4 is an optionally substituted phenyl group
(wherein the substituent of the optionally substituted phenyl group
is --O--(CH.sub.2).sub.m--W, wherein W represents a hydrogen atom
or an optionally substituted C1-C4 alkyl group and m is 0 to 4 or W
represents an optionally substituted C1-C4 alkoxy group and m is 2
to 4); n is 0; and -A-B- is --CH.sub.2--CH.sub.2--. 12) In formula
(1), R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is an
optionally substituted C3-C8 cycloalkyl group; R.sup.4 is an
optionally substituted heteroaryl group; n is 0; and -A-B- is
--CH.sub.2--CH.sub.2--. 13) In formula (1), R.sup.1 is hydrogen;
R.sup.2 is hydrogen; R.sup.3 is an optionally substituted saturated
heterocyclic group; R.sup.4 is an optionally substituted phenyl
group (wherein the substituent in the optionally substituted phenyl
group is a halogen or an optionally substituted C1-C4 alkyl group);
n is 0; and -A-B- is --CH.sub.2--CH.sub.2--. 14) In formula (1),
R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is an optionally
substituted saturated heterocyclic group; R.sup.4 is an optionally
substituted phenyl group (wherein the substituent of the optionally
substituted phenyl group is --O--(CH.sub.2).sub.m--W, wherein W
represents a hydrogen atom or an optionally substituted C1-C4 alkyl
group and m is 0 to 4 or W represents an optionally substituted
C1-C4 alkoxy group and m is 2 to 4); n is 0; and -A-B- is
--CH.sub.2--CH.sub.2--. 15) In formula (1), R.sup.1 is hydrogen;
R.sup.2 is hydrogen; R.sup.3 is an optionally substituted saturated
heterocyclic group; R.sup.4 is an optionally substituted heteroaryl
group; n is 0; and -A-B- is --CH.sub.2--CH.sub.2--. 16) In formula
(1), R.sup.1 is hydrogen; R.sup.2 is halogen; R.sup.3 is an
optionally substituted saturated heterocyclic group; R.sup.4 is an
optionally substituted phenyl group (wherein the substituent in the
optionally substituted phenyl group is a halogen or an optionally
substituted C1-C4 alkyl group); n is 0; and -A-B- is
--CH.sub.2--CH.sub.2--. 17) In formula (1), R.sup.1 is hydrogen;
R.sup.2 is halogen; R.sup.3 is an optionally substituted saturated
heterocyclic group; R.sup.4 is an optionally substituted phenyl
group (wherein the substituent of the optionally substituted phenyl
group is --O--(CH.sub.2).sub.m--W, wherein W represents a hydrogen
atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4
or W represents an optionally substituted C1-C4 alkoxy group and m
is 2 to 4); n is 0; and -A-B- is --CH.sub.2--CH.sub.2--. 18) In
formula (1), R.sup.1 is hydrogen; R.sup.2 is halogen; R.sup.3 is an
optionally substituted saturated heterocyclic group; R.sup.4 is an
optionally substituted heteroaryl group; n is 0; and -A-B- is
--CH.sub.2--CH.sub.2--. 19) In formula (1), R.sup.1 is hydrogen;
R.sup.2 is hydrogen; R.sup.3 is an optionally substituted piperidyl
group or a pyrrolidyl group; R.sup.4 is an optionally substituted
phenyl group (wherein the substituent of the optionally substituted
phenyl group is --O--(CH.sub.2).sub.m--W, wherein W represents a
hydrogen atom or an optionally substituted C1-C4 alkyl group and m
is 0 to 4 or W represents an optionally substituted C1-C4 alkoxy
group and m is 2 to 4.) or an optionally substituted bicyclic
heteroaryl group; n is 0; and -A-B- is --CH.sub.2--CH.sub.2--. 20)
In formula (1), R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3
is an optionally substituted piperidyl group or a pyrrolidyl group;
R.sup.4 is an optionally substituted heteroaryl group; n is 0; and
-A-B- is --CH.sub.2--CH.sub.2--. 21) In formula (1), R.sup.1 is
hydrogen; R.sup.2 is hydrogen; R.sup.3 is an unsubstituted
piperidyl group or a pyrrolidyl group; R.sup.4 is an optionally
substituted phenyl group (wherein the substituent of the optionally
substituted phenyl group is --O--(CH.sub.2).sub.m--W, wherein W
represents a hydrogen atom or an optionally substituted C1-C4 alkyl
group and m is 0 to 4 or W represents an optionally substituted
C1-C4 alkoxy group and m is 2 to 4.); n is 0; and -A-B- is
--CH.sub.2--CH.sub.2--. 22) In formula (1), R.sup.1 is hydrogen;
R.sup.2 is hydrogen; R.sup.3 is a cyclohexyl group substituted with
an amino group; R.sup.4 is an optionally substituted phenyl group
(wherein the substituent of the optionally substituted phenyl group
is --O--(CH.sub.2).sub.m--W, wherein W represents a hydrogen atom
or an optionally substituted C1-C4 alkyl group and m is 0 to 4 or W
represents an optionally substituted C1-C4 alkoxy group and m is 2
to 4.); n is 0; and -A-B- is --CH.sub.2--CH.sub.2--. 23) In formula
(1), R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is a
cyclohexyl group substituted with an amino group; R.sup.4 is an
optionally substituted heteroaryl group; n is 0; and -A-B- is
--CH.sub.2--CH.sub.2--.
[0075] As preferred combinations of R.sup.1-R.sup.4, n and -A-B- in
formula (2) in the present invention, in addition to combinations
of group(s) included in the above definition for R.sup.1-R.sup.4, n
and -A-B- in formula (1) and group(s) mentioned above as preferred
example for the individual groups and combinations of groups
mentioned as preferred example for the individual groups, there may
be mentioned the above 1) to 23).
[0076] The compound of the present invention may contain a basic
group in the molecule. In this case it may be converted to a
medically acceptable acid-addition salt if necessary. As such
acids, for example, there may be mentioned inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid
and carbonic acid; and organic acids such as acetic acid, citric
acid, malic acid, oxalic acid, tartaric acid, lactic acid, maleic
acid, fumaric acid and methanesulfonic acid.
[0077] The compound of the present invention may contain an acidic
group in the molecule. In this case it may be converted to a
medically acceptable salt if necessary. As such salts, there may be
mentioned salts with non-toxic cations. Specifically, there may be
mentioned salts with alkali metal ions such as Na.sup.+ and
K.sup.+, alkaline earth metal ions such as Mg.sup.2+ and Ca.sup.2+,
metal ions such as Al.sup.3+ and Zn.sup.2+, ammonium ion, and
organic bases such as triethylamine, ethylenediamine,
propanediamine, pyrrolidine, piperidine, piperazine, pyridine,
lysine, choline, ethanolamine, N,N-dimethylethanolamine,
4-hydroxypiperidine, glucosamine and N-methylglucamine.
[0078] When the compound of the present invention exists
enantiomer, the present invention includes racemic and optically
active forms. When the compound of the present invention contains
two or more chiral carbon atoms, the present invention includes all
diastereomers. When the compound of the present invention exists
trans- cis geometrical isomer, the present invention includes
either the trans form or the cis form.
[0079] As examples of compound represented by formula (1) in the
present invention, there may be mentioned compounds listed in
Tables A to G.
TABLE-US-00001 TABLE A ##STR00005## Compound No. R.sup.1 R.sup.2
R.sup.3 R.sup.4 n Z A-001 H H ##STR00006## ##STR00007## 0 H A-002 H
H ##STR00008## ##STR00009## 0 H A-003 H H ##STR00010## ##STR00011##
0 H A-004 H H ##STR00012## ##STR00013## 0 H A-005 H H ##STR00014##
##STR00015## 0 H A-006 H H ##STR00016## ##STR00017## 1 H A-007 H H
##STR00018## ##STR00019## 0 H A-008 H H ##STR00020## ##STR00021## 0
H A-009 H H ##STR00022## ##STR00023## 0 H A-010 H H ##STR00024##
##STR00025## 0 H A-011 H H ##STR00026## ##STR00027## 0 H A-012 H H
##STR00028## ##STR00029## 0 H A-013 H H ##STR00030## ##STR00031## 0
H A-014 H H ##STR00032## ##STR00033## 1 H A-015 H H ##STR00034##
##STR00035## 1 H A-016 H H ##STR00036## ##STR00037## 1 H A-017 H H
##STR00038## ##STR00039## 1 H A-018 H F ##STR00040## ##STR00041## 0
H A-019 F F ##STR00042## ##STR00043## 0 H A-020 H H OH ##STR00044##
0 H A-021 H H ##STR00045## ##STR00046## 0 H A-022 H H ##STR00047##
##STR00048## 0 H A-023 H H ##STR00049## ##STR00050## 0 H A-024 H H
##STR00051## ##STR00052## 0 ##STR00053## A-025 H H ##STR00054##
##STR00055## 0 H A-026 H H ##STR00056## ##STR00057## 0 H A-027 H H
##STR00058## ##STR00059## 0 H A-028 H H ##STR00060## ##STR00061## 0
H A-029 H H ##STR00062## ##STR00063## 0 H A-030 H H ##STR00064##
##STR00065## 0 H A-031 H H ##STR00066## ##STR00067## 0 H A-032 H H
##STR00068## ##STR00069## 0 H A-033 H H ##STR00070## ##STR00071## 0
H A-034 H H ##STR00072## ##STR00073## 0 H A-035 H H ##STR00074##
##STR00075## 0 H A-036 H H ##STR00076## ##STR00077## 0 H A-037 H H
##STR00078## ##STR00079## 0 H A-038 H H ##STR00080## ##STR00081## 0
H A-039 H H ##STR00082## ##STR00083## 0 H A-040 H H ##STR00084##
##STR00085## 0 H A-041 H H ##STR00086## ##STR00087## 0 H A-042 H H
##STR00088## ##STR00089## 0 H A-043 H H ##STR00090## ##STR00091## 0
H A-044 H H ##STR00092## ##STR00093## 0 H A-045 H H ##STR00094##
##STR00095## 0 H A-046 H H ##STR00096## ##STR00097## 0 H A-047 H H
##STR00098## ##STR00099## 0 H A-048 H H ##STR00100## ##STR00101## 0
H A-049 H H ##STR00102## ##STR00103## 0 H A-050 H H ##STR00104##
##STR00105## 0 H A-051 H H ##STR00106## ##STR00107## 0 H A-052 H H
##STR00108## ##STR00109## 0 H A-053 H H ##STR00110## ##STR00111## 0
H A-054 H H ##STR00112## ##STR00113## 0 H A-055 H H ##STR00114##
##STR00115## 0 H A-056 H H ##STR00116## ##STR00117## 0 H A-057 H H
##STR00118## ##STR00119## 0 H A-058 H H ##STR00120## ##STR00121## 0
H A-059 H H ##STR00122## ##STR00123## 0 H A-060 H H ##STR00124##
##STR00125## 0 H A-061 H H ##STR00126## ##STR00127## 0 H A-062 H H
##STR00128## ##STR00129## 0 H A-063 H H ##STR00130## ##STR00131## 0
H A-064 H H ##STR00132## ##STR00133## 0 H A-065 H H ##STR00134##
##STR00135## 0 H A-066 H H ##STR00136## ##STR00137## 0 H A-067 H H
##STR00138## ##STR00139## 0 H A-068 H H ##STR00140## ##STR00141## 0
H A-069 H H ##STR00142## ##STR00143## 0 H A-070 H H ##STR00144##
##STR00145## 0 H A-071 H H ##STR00146## ##STR00147## 0 H A-072 H H
##STR00148## ##STR00149## 0 H A-073 H H ##STR00150## ##STR00151## 0
H A-074 H H ##STR00152## ##STR00153## 0 H A-075 H H ##STR00154##
##STR00155## 0 H A-076 H H ##STR00156## ##STR00157## 0 H A-077 H H
##STR00158## ##STR00159## 0 H A-078 H H ##STR00160## ##STR00161## 0
H A-079 H H ##STR00162## ##STR00163## 0 H A-080 H H ##STR00164##
##STR00165## 0 H A-081 H H ##STR00166## ##STR00167## 0 H A-082 H H
##STR00168## ##STR00169## 0 H A-083 H H ##STR00170## ##STR00171## 0
H A-084 H H ##STR00172## ##STR00173## 0 H A-085 H H ##STR00174##
##STR00175## 0 H A-086 H H ##STR00176## ##STR00177## 0 H A-087 H H
##STR00178## ##STR00179## 0 H A-088 H H ##STR00180## ##STR00181## 0
H A-089 H H ##STR00182## ##STR00183## 0 H A-090 H H ##STR00184##
##STR00185## 0 H A-091 H H ##STR00186## ##STR00187## 0 H A-092 H H
##STR00188## H 0 H A-093 H H ##STR00189## H 0 H A-094 H H
##STR00190## H 0 H A-095 H H ##STR00191## ##STR00192## 0 H A-096 H
H ##STR00193## Me 0 H A-097 H H ##STR00194## ##STR00195## 0 H A-098
H H ##STR00196## ##STR00197## 0 H A-099 H H ##STR00198##
##STR00199## 0 H A-100 H H ##STR00200## ##STR00201## 0 H A-101 H Cl
##STR00202## ##STR00203## 0 H A-102 H Br ##STR00204## ##STR00205##
0 H
TABLE-US-00002 TABLE B ##STR00206## Compound No. R.sup.1 R.sup.2
R.sup.3 R.sup.4 n B-001 H H ##STR00207## ##STR00208## B-002 H H
##STR00209## ##STR00210## 0 B-003 H H ##STR00211## ##STR00212## 0
B-004 H H ##STR00213## ##STR00214## 0 B-005 H H ##STR00215##
##STR00216## 0 B-006 H H ##STR00217## ##STR00218## 0 B-007 H H
##STR00219## ##STR00220## 0 B-008 H H ##STR00221## ##STR00222## 1
B-009 H H ##STR00223## ##STR00224## 0 B-010 H H ##STR00225##
##STR00226## 0 B-011 H H ##STR00227## ##STR00228## 0 B-012 H H
##STR00229## ##STR00230## 0 B-013 H H ##STR00231## ##STR00232## 0
B-014 H H ##STR00233## ##STR00234## 0 B-015 H H ##STR00235##
##STR00236## 1 B-016 H H ##STR00237## ##STR00238## 0 B-017 H H
##STR00239## ##STR00240## 0 B-018 H H ##STR00241## ##STR00242## 1
B-019 H H ##STR00243## ##STR00244## 1 B-020 H H ##STR00245##
##STR00246## 1 B-021 H H ##STR00247## ##STR00248## 0 B-022 H H
##STR00249## ##STR00250## 0 B-023 H H ##STR00251## ##STR00252## 0
B-024 H H ##STR00253## ##STR00254## 0 B-025 H H ##STR00255##
##STR00256## 0 B-026 H H ##STR00257## ##STR00258## 1 B-027 H H
##STR00259## ##STR00260## 1 B-028 H H ##STR00261## ##STR00262## 1
B-029 H F ##STR00263## ##STR00264## 0 B-030 F F ##STR00265##
##STR00266## 0 B-031 H H ##STR00267## ##STR00268## 0 B-032 H H
##STR00269## ##STR00270## 0 B-033 H H ##STR00271## ##STR00272## 0
B-034 H H ##STR00273## ##STR00274## 0 B-035 H H ##STR00275##
##STR00276## 0 B-036 H H ##STR00277## ##STR00278## 0 B-037 H H
##STR00279## ##STR00280## 0 B-038 H H ##STR00281## ##STR00282## 0
B-039 H H ##STR00283## ##STR00284## 0 B-040 H H ##STR00285##
##STR00286## 0 B-041 H H ##STR00287## ##STR00288## 0 B-042 H H
##STR00289## ##STR00290## 0 B-043 H H ##STR00291## ##STR00292## 0
B-044 H H ##STR00293## ##STR00294## 0 B-045 H H ##STR00295##
##STR00296## 0 B-046 H H ##STR00297## ##STR00298## 0 B-047 H H
##STR00299## ##STR00300## 0 B-048 H H ##STR00301## ##STR00302## 0
B-049 H H ##STR00303## ##STR00304## 0 B-050 H H ##STR00305##
##STR00306## 0 B-051 H H ##STR00307## ##STR00308## 0 B-052 H H
##STR00309## ##STR00310## 0 B-053 H H ##STR00311## ##STR00312## 0
B-054 H H ##STR00313## ##STR00314## 0 B-055 H H ##STR00315##
##STR00316## 0 B-056 H H ##STR00317## ##STR00318## 0 B-057 H H
##STR00319## ##STR00320## 0 B-058 H H ##STR00321## ##STR00322## 0
B-059 H H ##STR00323## ##STR00324## 0 B-060 H H ##STR00325##
##STR00326## 0 B-061 H H ##STR00327## ##STR00328## 0 B-062 H H
##STR00329## ##STR00330## 0 B-063 H H ##STR00331## ##STR00332## 0
B-064 H H ##STR00333## ##STR00334## 0 B-065 H H ##STR00335##
##STR00336## 0 B-066 H H ##STR00337## ##STR00338## 0 B-067 H H
##STR00339## ##STR00340## 0 B-068 H H ##STR00341## ##STR00342## 0
B-069 H H ##STR00343## ##STR00344## 0 B-070 H H ##STR00345##
##STR00346## 0 B-071 H H ##STR00347## ##STR00348## 0 B-072 H H
##STR00349## ##STR00350## 0 B-073 H H ##STR00351## ##STR00352## 0
B-074 H H ##STR00353## ##STR00354## 0 B-075 H H ##STR00355##
##STR00356## 0 B-076 H H ##STR00357## ##STR00358## 0 B-077 H H
##STR00359## ##STR00360## 0 B-078 H H ##STR00361## ##STR00362## 0
B-079 H H ##STR00363## ##STR00364## 0 B-080 H H ##STR00365##
##STR00366## 0 B-081 H H ##STR00367## ##STR00368## 0 B-082 H H
##STR00369## ##STR00370## 0 B-083 H H ##STR00371## ##STR00372## 0
B-084 H H ##STR00373## ##STR00374## 0 B-085 H H ##STR00375##
##STR00376## 0 B-086 H H ##STR00377## ##STR00378## 0 B-087 H H
##STR00379## ##STR00380## 0 B-088 H H ##STR00381## ##STR00382## 0
B-089 H H ##STR00383## ##STR00384## 0 B-090 H H ##STR00385##
##STR00386## 0 B-091 H H ##STR00387## ##STR00388## 0 B-092 H H
##STR00389## ##STR00390## 0 B-093 H H ##STR00391## ##STR00392## 0
B-094 H H ##STR00393## ##STR00394## 0 B-095 H H ##STR00395##
##STR00396## 0 B-096 H H ##STR00397## ##STR00398## 0 B-097 H H
##STR00399## ##STR00400## 0 B-098 H H ##STR00401## H 0 B-099 H H
##STR00402## H 0 B-100 H H ##STR00403## H 0
TABLE-US-00003 TABLE C ##STR00404## Compound No. R.sup.1 R.sup.2
R.sup.3 R.sup.4 n C-001 H H ##STR00405## ##STR00406## 0 C-002 H H
##STR00407## ##STR00408## 0 C-003 H H ##STR00409## ##STR00410## 0
C-004 H H ##STR00411## ##STR00412## 0 C-005 H H ##STR00413##
##STR00414## 0 C-006 H H ##STR00415## ##STR00416## 1 C-007 H H
##STR00417## ##STR00418## 0 C-008 H H ##STR00419## ##STR00420## 0
C-009 H H ##STR00421## ##STR00422## 0 C-010 H H ##STR00423##
##STR00424## 0 C-011 H H ##STR00425## ##STR00426## 0 C-012 H H
##STR00427## ##STR00428## 0 C-013 H H ##STR00429## ##STR00430## 0
C-014 H H ##STR00431## ##STR00432## 1 C-015 H H ##STR00433##
##STR00434## 1 C-016 H H ##STR00435## ##STR00436## 1 C-017 H H
##STR00437## ##STR00438## 1 C-018 H F ##STR00439## ##STR00440## 0
C-019 F F ##STR00441## ##STR00442## 0 C-020 H H ##STR00443##
##STR00444## 0 C-021 H H ##STR00445## ##STR00446## 0 C-022 H H
##STR00447## ##STR00448## 0 C-023 H H ##STR00449## ##STR00450## 0
C-024 H H ##STR00451## ##STR00452## 0 C-025 H H ##STR00453##
##STR00454## 0 C-026 H H ##STR00455## ##STR00456## 0 C-027 H H
##STR00457## ##STR00458## 0 C-028 H H ##STR00459## ##STR00460## 0
C-029 H H ##STR00461## ##STR00462## 0 C-030 H H ##STR00463##
##STR00464## 0 C-031 H H ##STR00465## ##STR00466## 0 C-032 H H
##STR00467## ##STR00468## 0 C-033 H H ##STR00469## ##STR00470## 0
C-034 H H ##STR00471## ##STR00472## 0 C-035 H H ##STR00473##
##STR00474## 0 C-036 H H ##STR00475## ##STR00476## 0 C-037 H H
##STR00477## ##STR00478## 0 C-038 H H ##STR00479## ##STR00480## 0
C-039 H H ##STR00481## ##STR00482## 0 C-040 H H ##STR00483##
##STR00484## 0 C-041 H H ##STR00485## ##STR00486## 0 C-042 H H
##STR00487## ##STR00488## 0 C-043 H H ##STR00489## ##STR00490## 0
C-044 H H ##STR00491## ##STR00492## 0 C-045 H H ##STR00493##
##STR00494## 0 C-046 H H ##STR00495## ##STR00496## 0 C-047 H H
##STR00497## ##STR00498## 0 C-048 H H ##STR00499## ##STR00500## 0
C-049 H H ##STR00501## ##STR00502## 0 C-050 H H ##STR00503##
##STR00504## 0 C-051 H H ##STR00505## ##STR00506## 0 C-052 H H
##STR00507## ##STR00508## 0 C-053 H H ##STR00509## ##STR00510## 0
C-054 H H ##STR00511## ##STR00512## 0 C-055 H H ##STR00513##
##STR00514## 0 C-056 H H ##STR00515## ##STR00516## 0 C-057 H H
##STR00517## ##STR00518## 0 C-058 H H ##STR00519## ##STR00520## 0
C-059 H H ##STR00521## ##STR00522## 0 C-060 H H ##STR00523##
##STR00524## 0 C-061 H H ##STR00525## ##STR00526## 0 C-062 H H
##STR00527## ##STR00528## 0 C-063 H H ##STR00529## ##STR00530## 0
C-064 H H ##STR00531## ##STR00532## 0 C-065 H H ##STR00533##
##STR00534## 0 C-066 H H ##STR00535## ##STR00536## 0 C-067 H H
##STR00537## ##STR00538## 0 C-068 H H ##STR00539## ##STR00540## 0
C-069 H H ##STR00541## ##STR00542## 0 C-070 H H ##STR00543##
##STR00544## 0 C-071 H H ##STR00545## ##STR00546## 0 0-072 H H
##STR00547## ##STR00548## 0 C-073 H H ##STR00549## ##STR00550## 0
C-074 H H ##STR00551## ##STR00552## 0 C-075 H H ##STR00553##
##STR00554## 0 C-076 H H ##STR00555## ##STR00556## 0 C-077 H H
##STR00557## ##STR00558## 0 C-078 H H ##STR00559## ##STR00560## 0
C-079 H H ##STR00561## ##STR00562## 0 C-080 H H ##STR00563##
##STR00564## 0 C-081 H H ##STR00565## ##STR00566## 0 C-082 H H
##STR00567## ##STR00568## 0 C-083 H H ##STR00569## ##STR00570## 0
C-084 H H ##STR00571## ##STR00572## 0 C-085 H H ##STR00573##
##STR00574## 0 C-086 H H ##STR00575## ##STR00576## 0
TABLE-US-00004 TABLE D ##STR00577## Compound No. R.sup.1 R.sup.2
R.sup.3 R.sup.4 n D-001 H H ##STR00578## ##STR00579## 0 D-002 H H
##STR00580## ##STR00581## 1 D-003 H H ##STR00582## ##STR00583## 0
D-004 H H ##STR00584## ##STR00585## 0 D-005 H H ##STR00586##
##STR00587## 1 D-006 H H ##STR00588## ##STR00589## 0 D-007 H H
##STR00590## ##STR00591## 0 D-008 H H ##STR00592## ##STR00593## 0
D-009 H H ##STR00594## ##STR00595## 0 D-010 H H ##STR00596##
##STR00597## 1 D-011 H H ##STR00598## ##STR00599## 0 D-012 H H
##STR00600## ##STR00601## 0 D-013 H H ##STR00602## ##STR00603## 0
D-014 H H ##STR00604## ##STR00605## 0 D-015 H H ##STR00606##
##STR00607## 0 D-016 H H ##STR00608## ##STR00609## 1 D-017 H H
##STR00610## ##STR00611## 1 D-018 H F ##STR00612## ##STR00613## 0
D-019 F F ##STR00614## ##STR00615## 0 D-020 H H ##STR00616##
##STR00617## 0 D-021 H H ##STR00618## ##STR00619## 0 D-022 H H
##STR00620## ##STR00621## 0 D-023 H H ##STR00622## ##STR00623## 0
D-024 H H ##STR00624## ##STR00625## 0 D-025 H H ##STR00626##
##STR00627## 0 D-026 H H ##STR00628## ##STR00629## 0 D-027 H H
##STR00630## ##STR00631## 0 D-028 H H ##STR00632## ##STR00633## 0
D-029 H H ##STR00634## ##STR00635## 0 D-030 H H ##STR00636##
##STR00637## 0 D-031 H H ##STR00638## ##STR00639## 0 D-032 H H
##STR00640## ##STR00641## 0 D-033 H H ##STR00642## ##STR00643## 0
D-034 H H ##STR00644## ##STR00645## 0 D-035 H H ##STR00646##
##STR00647## 0 D-036 H H ##STR00648## ##STR00649## 0 D-037 H H
##STR00650## ##STR00651## 0 D-038 H H ##STR00652## ##STR00653## 0
D-039 H H ##STR00654## ##STR00655## 0 D-040 H H ##STR00656##
##STR00657## 0 D-041 H H ##STR00658## ##STR00659## 0 D-042 H H
##STR00660## ##STR00661## 0 D-043 H H ##STR00662## ##STR00663## 0
D-044 H H ##STR00664## ##STR00665## 0 D-045 H H ##STR00666##
##STR00667## 0 D-046 H H ##STR00668## ##STR00669## 0 D-047 H H
##STR00670## ##STR00671## 0 D-048 H H ##STR00672## ##STR00673## 0
D-049 H H ##STR00674## ##STR00675## 0 D-050 H H ##STR00676##
##STR00677## 0 D-051 H H ##STR00678## ##STR00679## 0 D-052 H H
##STR00680## ##STR00681## 0 D-053 H H ##STR00682## ##STR00683## 0
D-054 H H ##STR00684## ##STR00685## 0 D-055 H H ##STR00686##
##STR00687## 0 D-056 H H ##STR00688## ##STR00689## 0 D-057 H H
##STR00690## ##STR00691## 0 D-058 H H ##STR00692## ##STR00693## 0
D-059 H H ##STR00694## ##STR00695## 0 D-060 H H ##STR00696##
##STR00697## 0 D-061 H H ##STR00698## ##STR00699## 0 D-062 H H
##STR00700## ##STR00701## 0 D-063 H H ##STR00702## ##STR00703## 0
D-064 H H ##STR00704## ##STR00705## 0 D-065 H H ##STR00706##
##STR00707## 0 D-066 H H ##STR00708## ##STR00709## 0 D-067 H H
##STR00710## ##STR00711## 0 D-068 H H ##STR00712## ##STR00713## 0
D-069 H H ##STR00714## ##STR00715## 0 D-070 H H ##STR00716##
##STR00717## 0 D-071 H H ##STR00718## ##STR00719## 0 D-072 H H
##STR00720## ##STR00721## 0 D-073 H H ##STR00722## ##STR00723## 0
D-074 H H ##STR00724## ##STR00725## 0 D-075 H H ##STR00726##
##STR00727## 0 D-076 H H ##STR00728## ##STR00729## 0 D-077 H H
##STR00730## ##STR00731## 0 D-078 H H ##STR00732## ##STR00733## 0
D-079 H H ##STR00734## ##STR00735## 0 D-080 H H ##STR00736##
##STR00737## 0 D-081 H H ##STR00738## ##STR00739## 0 D-082 H H
##STR00740## ##STR00741## 0 D-083 H H ##STR00742## ##STR00743## 0
D-084 H H ##STR00744## ##STR00745## 0 D-085 H H ##STR00746##
##STR00747## 0
TABLE-US-00005 TABLE E ##STR00748## Compound No. R.sup.1 R.sup.2
R.sup.3 R.sup.4 n E-001 H H ##STR00749## ##STR00750## 0 E-002 H H
##STR00751## ##STR00752## 0 E-003 H H ##STR00753## ##STR00754## 0
E-004 H H ##STR00755## ##STR00756## 0 E-005 H H ##STR00757##
##STR00758## 0 E-006 H H ##STR00759## ##STR00760## 1 E-007 H H
##STR00761## ##STR00762## 0 E-008 H H ##STR00763## ##STR00764## 0
E-009 H H ##STR00765## ##STR00766## 0 E-010 H H ##STR00767##
##STR00768## 0 E-011 H H ##STR00769## ##STR00770## 0 E-012 H H
##STR00771## ##STR00772## 0 E-013 H H ##STR00773## ##STR00774## 0
E-014 H H ##STR00775## ##STR00776## 1 E-015 H H ##STR00777##
##STR00778## 1 E-016 H H ##STR00779## ##STR00780## 1 E-017 H H
##STR00781## ##STR00782## 1 E-018 H F ##STR00783## ##STR00784## 0
E-019 F F ##STR00785## ##STR00786## 0 E-020 H H ##STR00787##
##STR00788## 0 E-021 H H ##STR00789## ##STR00790## 0 E-022 H H
##STR00791## ##STR00792## 0 E-023 H H ##STR00793## ##STR00794## 0
E-024 H H ##STR00795## ##STR00796## 0 E-025 H H ##STR00797##
##STR00798## 0 E-026 H H ##STR00799## ##STR00800## 0 E-027 H H
##STR00801## ##STR00802## 0 E-028 H H ##STR00803## ##STR00804## 0
E-029 H H ##STR00805## ##STR00806## 0 E-030 H H ##STR00807##
##STR00808## 0 E-031 H H ##STR00809## ##STR00810## 0 E-032 H H
##STR00811## ##STR00812## 0 E-033 H H ##STR00813## ##STR00814## 0
E-034 H H ##STR00815## ##STR00816## 0 E-035 H H ##STR00817##
##STR00818## 0 E-036 H H ##STR00819## ##STR00820## 0 E-037 H H
##STR00821## ##STR00822## 0 E-038 H H ##STR00823## ##STR00824## 0
E-039 H H ##STR00825## ##STR00826## 0 E-040 H H ##STR00827##
##STR00828## 0 E-041 H H ##STR00829## ##STR00830## 0 E-042 H H
##STR00831## ##STR00832## 0 E-043 H H ##STR00833## ##STR00834## 0
E-044 H H ##STR00835## ##STR00836## 0 E-045 H H ##STR00837##
##STR00838## 0 E-046 H H ##STR00839## ##STR00840## 0 E-047 H H
##STR00841## ##STR00842## 0 E-048 H H ##STR00843## ##STR00844## 0
E-049 H H ##STR00845## ##STR00846## 0 E-050 H H ##STR00847##
##STR00848## 0 E-051 H H ##STR00849## ##STR00850## 0 E-052 H H
##STR00851## ##STR00852## 0 E-053 H H ##STR00853## ##STR00854## 0
E-054 H H ##STR00855## ##STR00856## 0 E-055 H H ##STR00857##
##STR00858## 0 E-056 H H ##STR00859## ##STR00860## 0 E-057 H H
##STR00861## ##STR00862## 0 E-058 H H ##STR00863## ##STR00864## 0
E-059 H H ##STR00865## ##STR00866## 0 E-060 H H ##STR00867##
##STR00868## 0 E-061 H H ##STR00869## ##STR00870## 0 E-062 H H
##STR00871## ##STR00872## 0 E-063 H H ##STR00873## ##STR00874## 0
E-064 H H ##STR00875## ##STR00876## 0 E-065 H H ##STR00877##
##STR00878## 0 E-066 H H ##STR00879## ##STR00880## 0 E-067 H H
##STR00881## ##STR00882## 0 E-068 H H ##STR00883## ##STR00884## 0
E-069 H H ##STR00885## ##STR00886## 0 E-070 H H ##STR00887##
##STR00888## 0 E-071 H H ##STR00889## ##STR00890## 0 E-072 H H
##STR00891## ##STR00892## 0 E-073 H H ##STR00893## ##STR00894## 0
E-074 H H ##STR00895## ##STR00896## 0 E-075 H H ##STR00897##
##STR00898## 0 E-076 H H ##STR00899## ##STR00900## 0 E-077 H H
##STR00901## ##STR00902## 0 E-078 H H ##STR00903## ##STR00904## 0
E-079 H H ##STR00905## ##STR00906## 0 E-080 H H ##STR00907##
##STR00908## 0 E-081 H H ##STR00909## ##STR00910## 0 E-082 H H
##STR00911## ##STR00912## 0 E-083 H H ##STR00913## ##STR00914## 0
E-084 H H ##STR00915## ##STR00916## 0 E-085 H H ##STR00917##
##STR00918## 0
TABLE-US-00006 TABLE F ##STR00919## Compound No. R.sup.1 R.sup.2
R.sup.3 R.sup.4 n Z F-001 H H ##STR00920## ##STR00921## 0 H F-002 H
H ##STR00922## ##STR00923## 0 ##STR00924## F-003 H H ##STR00925##
##STR00926## 0 H F-004 H H ##STR00927## ##STR00928## 0 H F-005 H H
##STR00929## ##STR00930## 0 H F-006 H H ##STR00931## ##STR00932## 0
H F-007 H H ##STR00933## ##STR00934## 1 H F-008 H H ##STR00935##
##STR00936## 0 H F-009 H H ##STR00937## ##STR00938## 0 H F-010 H H
##STR00939## ##STR00940## 0 H F-011 H H ##STR00941## ##STR00942## 0
H F-012 H H ##STR00943## ##STR00944## 0 H F-013 H H ##STR00945##
##STR00946## 0 H F-014 H H ##STR00947## ##STR00948## 0 H F-015 H H
##STR00949## ##STR00950## 1 H F-016 H H ##STR00951## ##STR00952## 1
H F-017 H H ##STR00953## ##STR00954## 1 H F-018 H H ##STR00955##
##STR00956## 1 H F-019 H F ##STR00957## ##STR00958## 0 H F-020 F F
##STR00959## ##STR00960## 0 H F-021 H H ##STR00961## ##STR00962## 0
H F-022 H H ##STR00963## ##STR00964## 0 H F-023 H H ##STR00965##
##STR00966## 0 H F-024 H H ##STR00967## ##STR00968## 0 H F-025 H H
##STR00969## ##STR00970## 0 H F-026 H H ##STR00971## ##STR00972## 0
H F-027 H H ##STR00973## ##STR00974## 0 H F-028 H H ##STR00975##
##STR00976## 0 H F-029 H H ##STR00977## ##STR00978## 0 H F-030 H H
##STR00979## ##STR00980## 0 H F-031 H H ##STR00981## ##STR00982## 0
H F-032 H H ##STR00983## ##STR00984## 0 H F-033 H H ##STR00985##
##STR00986## 0 H F-034 H H ##STR00987## ##STR00988## 0 H F-035 H H
##STR00989## ##STR00990## 0 H F-036 H H ##STR00991## ##STR00992## 0
H F-037 H H ##STR00993## ##STR00994## 0 H F-038 H H ##STR00995##
##STR00996## 0 H F-039 H H ##STR00997## ##STR00998## 0 H F-040 H H
##STR00999## ##STR01000## 0 H F-041 H H ##STR01001## ##STR01002## 0
H F-042 H H ##STR01003## ##STR01004## 0 H F-043 H H ##STR01005##
##STR01006## 0 H F-044 H H ##STR01007## ##STR01008## 0 H F-045 H H
##STR01009## ##STR01010## 0 H F-046 H H ##STR01011## ##STR01012## 0
H F-047 H H ##STR01013## ##STR01014## 0 H F-048 H H ##STR01015##
##STR01016## 0 H F-049 H H ##STR01017## ##STR01018## 0 H F-050 H H
##STR01019## ##STR01020## 0 H F-051 H H ##STR01021## ##STR01022## 0
H F-052 H H ##STR01023## ##STR01024## 0 H F-053 H H ##STR01025##
##STR01026## 0 H F-054 H H ##STR01027## ##STR01028## 0 H F-055 H H
##STR01029## ##STR01030## 0 H F-056 H H ##STR01031## ##STR01032## 0
H F-057 H H ##STR01033## ##STR01034## 0 H F-058 H H ##STR01035##
##STR01036## 0 H F-059 H H ##STR01037## ##STR01038## 0 H F-060 H H
##STR01039## ##STR01040## 0 H F-061 H H ##STR01041## ##STR01042## 0
H F-062 H H ##STR01043## ##STR01044## 0 H F-063 H H ##STR01045##
##STR01046## 0 H F-064 H H ##STR01047## ##STR01048## 0 H F-065 H H
##STR01049## ##STR01050## 0 H F-066 H H ##STR01051## ##STR01052## 0
H F-067 H H ##STR01053## ##STR01054## 0 H F-068 H H ##STR01055##
##STR01056## 0 H F-069 H H ##STR01057## ##STR01058## 0 H F-070 H H
##STR01059## ##STR01060## 0 H F-071 H H ##STR01061## ##STR01062## 0
H F-072 H H ##STR01063## ##STR01064## 0 H F-073 H H ##STR01065##
##STR01066## 0 H F-074 H H ##STR01067## ##STR01068## 0 H F-075 H H
##STR01069## ##STR01070## 0 H F-076 H H ##STR01071## ##STR01072## 0
H F-077 H H ##STR01073## ##STR01074## 0 H F-078 H H ##STR01075##
##STR01076## 0 H F-079 H H ##STR01077## ##STR01078## 0 H F-080 H H
##STR01079## ##STR01080## 0 H F-081 H H ##STR01081## ##STR01082## 0
H F-082 H H ##STR01083## ##STR01084## 0 H F-083 H H ##STR01085##
##STR01086## 0 H F-084 H H ##STR01087## ##STR01088## 0 H F-085 H H
##STR01089## ##STR01090## 0 H F-086 H H ##STR01091## ##STR01092## 0
H F-87 H H ##STR01093## ##STR01094## 0 H F-88 H H ##STR01095##
##STR01096## 0 H F-89 H H ##STR01097## ##STR01098## 0 H F-90 H H
##STR01099## ##STR01100## 0 H
TABLE-US-00007 TABLE G ##STR01101## Compound No. R.sup.1 R.sup.2
R.sup.3 R.sup.4 n G-001 H H ##STR01102## ##STR01103## 0 G-002 H H
##STR01104## ##STR01105## 0 G-003 H H ##STR01106## ##STR01107## 0
G-004 H H ##STR01108## ##STR01109## 0 G-005 H H ##STR01110##
##STR01111## 0 G-006 H H ##STR01112## ##STR01113## 1 G-007 H H
##STR01114## ##STR01115## 0 G-008 H H ##STR01116## ##STR01117## 0
G-009 H H ##STR01118## ##STR01119## 0 G-010 H H ##STR01120##
##STR01121## 0 G-011 H H ##STR01122## ##STR01123## 0 G-012 H H
##STR01124## ##STR01125## 0 G-013 H H ##STR01126## ##STR01127## 0
G-014 H H ##STR01128## ##STR01129## 1 G-015 H H ##STR01130##
##STR01131## 1 G-016 H H ##STR01132## ##STR01133## 1 G-017 H H
##STR01134## ##STR01135## 1 G-018 H F ##STR01136## ##STR01137## 0
G-019 F F ##STR01138## ##STR01139## 0 G-020 H H ##STR01140##
##STR01141## 0 G-021 H H ##STR01142## ##STR01143## 0 G-022 H H
##STR01144## ##STR01145## 0 G-023 H H ##STR01146## ##STR01147## 0
G-024 H H ##STR01148## ##STR01149## 0 G-025 H H ##STR01150##
##STR01151## 0 G-026 H H ##STR01152## ##STR01153## 0 G-027 H H
##STR01154## ##STR01155## 0 G-028 H H ##STR01156## ##STR01157## 0
G-029 H H ##STR01158## ##STR01159## 0 G-030 H H ##STR01160##
##STR01161## 0 G-031 H H ##STR01162## ##STR01163## 0 G-032 H H
##STR01164## ##STR01165## 0 G-033 H H ##STR01166## ##STR01167## 0
G-034 H H ##STR01168## ##STR01169## 0 G-035 H H ##STR01170##
##STR01171## 0 G-036 H H ##STR01172## ##STR01173## 0 G-037 H H
##STR01174## ##STR01175## 0 G-038 H H ##STR01176## ##STR01177## 0
G-039 H H ##STR01178## ##STR01179## 0 G-040 H H ##STR01180##
##STR01181## 0 G-041 H H ##STR01182## ##STR01183## 0 G-042 H H
##STR01184## ##STR01185## 0 G-043 H H ##STR01186## ##STR01187## 0
G-044 H H ##STR01188## ##STR01189## 0 G-045 H H ##STR01190##
##STR01191## 0 G-046 H H ##STR01192## ##STR01193## 0 G-047 H H
##STR01194## ##STR01195## 0 G-048 H H ##STR01196## ##STR01197## 0
G-049 H H ##STR01198## ##STR01199## 0 G-050 H H ##STR01200##
##STR01201## 0 G-051 H H ##STR01202## ##STR01203## 0 G-052 H H
##STR01204## ##STR01205## 0 G-053 H H ##STR01206## ##STR01207## 0
G-054 H H ##STR01208## ##STR01209## 0 G-055 H H ##STR01210##
##STR01211## 0 G-056 H H ##STR01212## ##STR01213## 0 G-057 H H
##STR01214## ##STR01215## 0 G-058 H H ##STR01216## ##STR01217## 0
G-059 H H ##STR01218## ##STR01219## 0 G-060 H H ##STR01220##
##STR01221## 0 G-061 H H ##STR01222## ##STR01223## 0 G-062 H H
##STR01224## ##STR01225## 0 G-063 H H ##STR01226## ##STR01227## 0
G-064 H H ##STR01228## ##STR01229## 0 G-065 H H ##STR01230##
##STR01231## 0 G-066 H H ##STR01232## ##STR01233## 0 G-067 H H
##STR01234## ##STR01235## 0 G-068 H H ##STR01236## ##STR01237## 0
G-069 H H ##STR01238## ##STR01239## 0 G-070 H H ##STR01240##
##STR01241## 0 G-071 H H ##STR01242## ##STR01243## 0 G-072 H H
##STR01244## ##STR01245## 0 G-073 H H ##STR01246## ##STR01247## 0
G-074 H H ##STR01248## ##STR01249## 0 G-075 H H ##STR01250##
##STR01251## 0 G-076 H H ##STR01252## ##STR01253## 0 G-077 H H
##STR01254## ##STR01255## 0 G-078 H H ##STR01256## ##STR01257## 0
G-079 H H ##STR01258## ##STR01259## 0 G-080 H H ##STR01260##
##STR01261## 0 G-081 H H ##STR01262## ##STR01263## 0 G-082 H H
##STR01264## ##STR01265## 0 G-083 H H ##STR01266## ##STR01267## 0
G-084 H H ##STR01268## ##STR01269## 0 G-085 H H ##STR01270##
##STR01271## 0 G-086 H H ##STR01272## H 0 G-087 H H ##STR01273## Me
0 G-88 H H ##STR01274## H 0 G-089 H H ##STR01275## H 0
[0080] The pyrazolopyrimidine derivative represented by the above
formula (1) exists in tautomeric forms exemplified by the following
formula.
##STR01276##
(In the formula, R.sup.1, R.sup.2, R.sup.3, R.sup.4, n and -A-B-
are as defined for formula (1)).
[0081] These tautomers are also included in the scope of the
present invention.
[0082] As examples of compound represented by formula (2) in the
present invention, there may be mentioned compounds having R.sup.1,
R.sup.2, R.sup.3, R.sup.4, n and -A-B- listed in Tables A to G.
[0083] The compounds of the present invention can be synthesized by
the following method. In each formula, R.sup.1-R.sup.4, -A-B- and n
are as defined in the above formula (1). Reagents and solvents
shown as conditions in chemical formulae are examples, as mentioned
in the text. Each of abbreviations of substituents, reagents and
solvents in the text and tables represent the following.
Me: methyl Et: ethyl .sup.iPr: isopropyl .sup.tBu: tert-butyl Cy:
cyclohexyl Ms: methanesulfonyl Boc: tert-butoxycarbonyl TBS:
tert-butyldimethylsilyl TBAF: tetrabutylammonium fluoride TFA:
trifluoroacetic acid HATU:
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate Dess-Martin periodinane:
1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one
DMAP: 4-N,N-dimethylaminopyridine
NMO: N-methylmorpholine-N-oxide
DMF: N,N-dimethylformamide
[0084] THF: tetrahydrofuran PTLC: preparative thin layer
chromatography Grubbs reagent:
benzylidene-bis(tricyclohexylphosphine)dichlororuthenium
NBS: N-bromosuccinimide
NCS: N-chlorosuccinimide
##STR01277##
[0085] 1) The compound represented by formula (4) can be obtained
by reaction of the compound represented by formula (3) and
allylmalonic diester in an appropriate organic solvent (for
example, ethanol or methanol) under a condition from room
temperature to heating under reflux in the presence of a base (for
example, sodium ethoxide or sodium methoxide). (References: J. Med.
Chem., 1976, 19, 296 and J. Med. Chem., 1977, 20, 296) 2) The
compound represented by formula (5) can be obtained by reaction of
the compound represented by formula (4) and a halogenating agent
(for example, phosphoryl chloride) either in an appropriate organic
solvent (for example, acetonitrile) or without solvent under a
condition from room temperature to heating under reflux in the
presence or absence of an appropriate base (for example,
dimethylaniline).
##STR01278## ##STR01279##
3) The compound represented by formula (6) or (15) can be obtained
by reaction of the compound represented by formula (5) or (14),
respectively, with an oxidizing agent (for example, sodium
periodate and osmium tetraoxide) in an appropriate solvent (for
example, THF-water mixed solvent) at a temperature ranging from
0.degree. C. to room temperature. 4) The compound represented by
formula (7) or (16) can be obtained by reaction of the compound
represented by formula (6) or (15), respectively, with a reducing
agent (for example, sodium borohydride) in an appropriate organic
solvent (for example, ethanol or methanol) at a temperature ranging
from 0.degree. C. to 40.degree. C. 5) The compound represented by
formula (8) or (18) can be obtained by reaction of the compound
represented by formula (5) or (14), respectively, with a borane
agent (for example, borane-dimethylsulfide complex) in an
appropriate organic solvent (for example, THF) at a temperature
ranging from 0.degree. C. to room temperature followed by reaction
with aqueous hydrogen peroxide in aqueous sodium hydroxide
solution. 6) The compound represented by formula (10), (17), (19)
or (42) can be obtained by reaction of the compound represented by
formula (9), (16), (18) or (41), respectively, with
tert-butylchlorodimethylsilane in an appropriate organic solvent
(for example, methylene chloride or DMF) at a temperature ranging
from 0.degree. C. to 40.degree. C. in the presence of a base (for
example, triethylamine or imidazole). (Reference: Protective Groups
in Organic Synthesis, 3rd edition, John Wiley & Sons Inc.)
##STR01280## ##STR01281##
7) The compound represented by formula (11) or (13) can be obtained
by reaction of the compound represented by formula (10) or (5),
respectively, with an amine compound represented as R.sup.4NH.sub.2
in an appropriate organic solvent (for example, 2-propanol, DMF,
THF or DMF-THF mixed solvent) under a condition from room
temperature to heating under reflux in the presence of a base (for
example triethylamine or sodium hydride). 8) The compound
represented by formula (41) can be obtained by reaction of the
compound represented by formula (14) with an oxidizing agent (for
example, osmium tetraoxide and N-methylmorpholine-N-oxide) in an
appropriate solvent (for example, acetone-water mixed solvent) at a
temperature ranging from 0.degree. C. to room temperature.
(References: Tetrahedron Lett., 1973 (1976) and Org. Synth.
Collective volume 6, 342) 9) The compound represented by formula
(12) or (14) can be obtained by reaction of the compound
represented by formula (11) or (13), respectively, with
di-tert-butyl dicarbonate in an appropriate organic solvent (for
example, 1,4-dioxane) under a condition from room temperature to
heating under reflux in the presence of a base (for example
triethylamine or 4-N,N-dimethylaminopyridine). (Reference:
Protective Groups in Organic Synthesis, 3rd edition, John Wiley
& Sons Inc.) 10) The compound represented by formula (25) or
(27) can be obtained by reaction of the compound represented by
formula (15) or (26), respectively, with an oxidizing agent (for
example, sodium chlorite in the presence of 2-methyl-2-butene and
sodium dihydrogenphosphate) in an appropriate solvent (for example,
tert-butanol-water mixed solvent) at a temperature ranging from
0.degree. C. to room temperature.
##STR01282##
11) The compound represented by formula (26) can be obtained by
reaction of the compound represented by formula (18) with an
oxidizing agent [for example, Dess-Martin periodinane, i.e.,
1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one] in an
appropriate organic solvent (for example, methylene chloride) at a
temperature ranging from 0.degree. C. to room temperature.
(References: J. Org. Chem., 48, 4155 (1983); J. Am. Chem. Soc.,
113, 7277 (1991)) 12) The compound represented by formula (20),
(32) or (43) can be obtained by reaction of the compound
represented by formula (12), (14) or (42), respectively, with an
amine represented by formula R.sup.3--(CH.sub.2).sub.n--NH.sub.2 in
an appropriate organic solvent (for example, acetonitrile) or
without solvent under a condition from room temperature to heating
under reflux. (When R.sup.3 in the compound represented by formula
R.sup.3--(CH.sub.2).sub.n--NH.sub.2 contains an unprotected primary
amino group, the compound represented by formula (12), (14) or (42)
is reacted with R.sup.3--(CH.sub.2).sub.n--NH.sub.2 by the
above-mentioned method and then the amino group in R.sup.3 moiety
is protected by treatment with di-tert-butyl dicarbonate in an
appropriate organic solvent (for example, 1,4-dioxane or methylene
chloride) under a condition from room temperature to heating under
reflux in the presence of bases (for example, triethylamine and
4-N,N-dimethylaminopyridine) to obtain the corresponding
tert-butoxycarbonyl-protected compound, which is defined as the
compound represented by formula (20), (32) or (43),
respectively.)
##STR01283## ##STR01284##
13) The compound represented by formula (21) can be obtained by
reaction of the compound represented by formula (20) with a
fluoride ion agent (for example, n-tetrabutylammonium fluoride) in
an appropriate organic solvent (for example, THF) at a temperature
ranging from 0.degree. C. to room temperature. (Reference:
Protective Groups in Organic Synthesis, 3rd edition, John Wiley
& Sons Inc.) 14) The compound represented by formula (22) or
(46) can be obtained by reaction of the compound represented by
formula (21) or (43), respectively, with a mesylating agent (for
example, methanesulfonyl chloride) in an appropriate organic
solvent (for example, methylene chloride) at a temperature ranging
from 0.degree. C. to room temperature in the presence of a base
(for example, triethylamine). (Reference: Protective Groups in
Organic Synthesis, 3rd edition, John Wiley & Sons Inc.)
##STR01285##
15) The compound represented by formula (23) or (47) can be
obtained by reaction of the compound represented by formula (22) or
(46), respectively, with a base (for example, sodium hydride) in an
appropriate organic solvent (for example, DMF, THF or DMF-THF mixed
solvent) at a temperature ranging from 0.degree. C. to 60.degree.
C. 16) The compound represented by formula (29) can be obtained by
reaction of the compound represented by formula (28) with an amine
compound represented by formula R.sup.3--(CH.sub.2).sub.n--NH.sub.2
in an appropriate organic solvent (for example, DMF) at a
temperature ranging from 0.degree. C. to 40.degree. C. in the
presence of a peptide condensing agent [for example,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate] and a base (for example,
diisopropyethylamine).
##STR01286##
17) The compound represented by formula (30) can be obtained by
reaction of the compound represented by formula (29) with a base
(for example, sodium hydride) in an appropriate organic solvent
(for example, DMF, THF or DMF-THF mixed solvent) at a temperature
ranging from 0.degree. C. to 60.degree. C. 18) The compound
represented by formula (38) can be obtained by reaction of the
compound represented by formula (15) with hydroxylamine in the
presence of a reducing agent (for example, sodium cyanoborohydride)
in an appropriate organic solvent (for example, methanol or
ethanol) under a condition from 0.degree. C. to heating under
reflux.
##STR01287##
19) The compound represented by formula (40) can be obtained by
reaction of the compound represented by formula (39) with an
appropriate reagent (for example, acetic anhydride) in the presence
of a base (for example, triethylamine) in an appropriate organic
solvent (for example, methylene chloride) at a temperature ranging
from 0.degree. C. to 40.degree. C. 20) The compound represented by
formula (33) can be obtained by reaction of the compound
represented by formula (32) with an allylating agent (for example,
allyl bromide) in the presence of a base (for example, sodium
hydride) in an appropriate organic solvent (for example, DMF, THF
or DMF-THF mixed solvent) at a temperature ranging from 0.degree.
C. to 70.degree. C. 21) The compound represented by formula (34)
can be obtained by reaction of the compound represented by formula
(33) with an olefin metathesis catalyst [for example, Grubbs
catalyst, i.e.,
benzylidenebis(tricyclohexylphosphine)dichlororuthenium] in an
appropriate organic solvent (for example, toluene) at a temperature
ranging from 0.degree. C. to 40.degree. C. (Reference: Angew. Chem.
Int. Ed., 2002, 41, 176) 22) The compound represented by formula
(36) can be obtained by reaction of the compound represented by
formula (34) with hydrogen in the presence of a palladium catalyst
(for example, palladium-carbon) in an appropriate organic solvent
(for example, methanol, ethanol or 1,4-dioxane-ethanol mixed
solvent) at room temperature.
##STR01288##
23) The compound represented by formula (44) can be obtained by
reaction of the compound represented by formula (43) with an
oxidizing agent [for example, Dess-Martin periodinane, i.e.,
1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one] in an
appropriate organic solvent (for example, methylene chloride) at a
temperature ranging from 0.degree. C. to 40.degree. C.
##STR01289##
24) Each compound represented by formula (49) can be obtained by
reaction of the corresponding compound represented by formula (32)
with an oxidizing agent (for example, sodium periodate and osmium
tetraoxide) in an appropriate solvent (for example, THF-water mixed
solvent) at a temperature ranging from 0.degree. C. to 40.degree.
C.
##STR01290##
25) The compound represented by formula (52) or (53) can be
obtained by reaction of the compound represented by formula (51)
with a nucleophilic halogenatigen agent (for example,
1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane
bis(tetrafluoroborate), N-bromosuccinimide, or N-chlorosucciminde)
in an appropriate organic solvent (for example, DMF, methylene
chloride, or THF) at a temperature ranging from 0.degree. C. to
40.degree. C. (Reference: J. Chem. Soc. Perkin 1, 1996, 2069.)
##STR01291##
26) The compound represented by formula (1) can be obtained by
reaction of the compound represented by formula (2) with an acid
(for example, trifluoroacetic acid) in an appropriate organic
solvent (for example, methylene chloride) at a temperature ranging
from 0.degree. C. to room temperature. (Reference: Protective
Groups in Organic Synthesis, 3rd edition, John Wiley & Sons
Inc.)
##STR01292##
27) The compound represented by formula (45) or (48) can be
obtained by reaction of the compound represented by formula (44) or
(47), respectively, with an acid (for example, trifluoroacetic
acid) in an appropriate organic solvent (for example, methylene
chloride) at a temperature ranging from 0.degree. C. to room
temperature.
[0086] A preparation comprising the compound of the present
invention or a medically acceptable salt thereof as an active
ingredient is prepared by using carriers, excipients or other
additives usually used for formulation. As carriers and excipients
used for formulation, either solid or liquid may be used, and for
example, there may be mentioned lactose, magnesium stearate,
starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame
oil, cacao butter, ethylene glycol and others conventionally used.
The preparation may be administrated either orally as tablets,
pills, capsules, granule, powder, liquid or the like or
parenterally through injection such as an intravenous injection and
an intramuscular injection, suppository, percutaneous
administration or the like.
[0087] As diseases for which the MAPKAP-K2 inhibitor of the present
invention is effective, there may be mentioned
neurodegenerative/neurological disorders (including dementia),
sepsis, autoimmune diseases, destructive osteopathy, inflammatory
bowel disease, psoriasis, diabetes mellitus, cancer, ischemic
reperfusion injury, angiodysplasia, cachexia, obesity,
angiogenesis, asthma and/or chronic obstructive pulmonary disease
(COPD).
[0088] As autoimmune diseases, specifically, there may be mentioned
rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid
arthritis, psoriatic arthritis, graft-versus-host disease, diabetes
mellitus or Crohn's disease.
[0089] The dose of the compound of the present invention is,
although it varies depending on the kind of disease, the
administration route, the age and sex of patient and the degree of
disease, usually 1-500 mg/day for one adult.
EXAMPLES
[0090] The present invention will be explained with specific
examples, although the present invention is not limited to these
examples.
[0091] The compound number of each compound in the following
examples corresponds to the compound number given to the compound
mentioned as preferred example in Tables A to G. The structures of
novel compounds isolated were confirmed by .sup.1H NMR and/or mass
analysis measured on a single quadrupole instrumentation equipped
with an electrospray source or other appropriate analytical
methods.
[0092] For .sup.1H NMR spectra (400 MHz, DMSO-d.sub.6 or
CDCl.sub.3), chemical shifts (.delta.: ppm) and coupling constants
(J: Hz) are shown. For results of mass analysis, M+H, that is, the
measured value observed as the molecular mass of compound (M) with
one proton (H) added, is shown. "HPLC retention time" represents
the retention time (unit: min) of compound in HPLC analysis under
the following analytical conditions.
Conditions for HPLC (High performance liquid chromatography)
Instrumental system: Hewlett-Packard 1100HPLC Column: Cadenza
CD-C18 (Intact) 100 mm.times.4.6 mm (i.d.)
Column Temperature: 40.degree. C.
[0093] [HPLC condition A] Solvent: A: H.sub.2O/acetonitrile=95/5,
0.05% TFA (trifluoroacetic acid)
[0094] B: H.sub.2O/acetonitrile=5/95, 0.05% TFA (trifluoroacetic
acid)
Flow rate: 1.0 mL/min
Gradient:
[0095] 0 to 1 min; Solvent B: 10%, Solvent A: 90% 1 to 13 min;
Solvent B: 10% to 70%, Solvent A: 90% to 30% 13 to 14 min; Solvent
B: 70% to 100%, Solvent A: 30% to 0% 14 to 16 min; Solvent B: 100%,
Solvent A: 0% 16 to 19 min; Solvent B: 100% to 10%, Solvent A: 0%
to 90% [HPLC condition B] Solvent: A: H.sub.2O/acetonitrile=95/5,
0.05% TFA (trifluoroacetic acid)
[0096] B: H.sub.2O/acetonitrile=5/95, 0.05% TFA (trifluoroacetic
acid)
Flow rate: 1.0 mL/min
Gradient:
[0097] 0 to 1 min; Solvent B: 1%, Solvent A: 99% 1 to 13 min;
Solvent B: 1% to 55%, Solvent A: 99% to 45% 13 to 14 min; Solvent
B: 55% to 100%, Solvent A: 45% to 0% 14 to 16 min; Solvent B: 100%,
Solvent A: 0% 16 to 19 min; Solvent B: 100% to 1%, Solvent A: 0% to
99%
Reference Example 1
Synthesis of 6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine
##STR01293##
[0099] To an ethanolic solution (0.2 L) containing sodium ethoxide
(7.8 g, 0.11 mol), 3-aminopyrazole (5.0 g, 0.6 mol) and diethyl
allylmalonate (12 mL, 0.61 mol) were added at room temperature. The
resultant mixture was heated under reflux for 24 hr. After the
mixture was cooled down to room temperature, the solvent was
distilled off. The residue was dissolved in water (150 mL) and the
aqueous solution was washed with ethyl acetate. This aqueous layer
was acidified by adding 6 mol/L hydrochloric acid, and the
resultant precipitate was collected by filtration and dried under
reduced pressure to obtain
6-allyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine (9.3 g).
[0100] The above dihydroxy compound was suspended in phosphoryl
chloride (0.21 kg). After this suspension was stirred at
120.degree. C. for 5 hr, the excessive phosphoryl chloride was
distilled off. The residue was neutralized by adding aqueous sodium
hydrogen carbonate, and the mixture was extracted with ethyl
acetate. The combined ethyl acetate layer was washed with brine and
dried over sodium sulfate. After the sodium sulfate was filtered
off, the solvent was distilled off and the residue was purified
with column chromatography (15% ethyl acetate-hexane) to obtain the
title compound (5.2 g, yield 40% in two steps).
[0101] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.19 (d,
J=2.2 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 5.98-5.88 (m, 1H), 5.20-5.13
(m, 2H), 3.72 (dt, J=6.1 and 1.6 Hz, 2H).
Reference Example 2
Synthesis of
2-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)ethanol
##STR01294##
[0103] To a mixed solution of THF (24 mL) and water (6 mL)
containing 6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine (1.82 g,
7.89 mmol), sodium periodate (5.12 g, 23.9 mmol) and osmium
tetraoxide (2.5 w/v % in tert-butanol, 3 mL, 0.23 mmol) were added
with ice-cooling. After this mixture was stirred at room
temperature for 3 hr, aqueous sodium sulfite was added here. The
resultant mixture was extracted with ethyl acetate and the organic
layer was washed with aqueous sodium hydrogen carbonate and then
brine and dried over sodium sulfate. After the sodium sulfate was
filtered off, the solvent was distilled off to obtain
5,7-dichloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidine.
[0104] The above aldehyde (1.82 mmol) was dissolved in methanol (27
mL), and sodium borohydride (302 mg, 7.98 mmol) was added to this
solution with ice-cooling. After this mixture was stirred for 30
min, aqueous ammonium chloride was added here. The resultant
mixture was extracted with ethyl acetate, and the organic layer was
washed with brine and dried over sodium sulfate. After the sodium
sulfate was filtered off, the solvent was distilled off, and the
residue was purified with column chromatography (15% ethyl
acetate-hexane) to obtain the title compound (617 mg).
[0105] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.17 (d,
J=2.2 Hz, 1H), 6.70 (d, J=1.9 Hz, 1H), 3.90 (t, 2H), 3.21 (t,
2H).
Reference Example 3
Synthesis of
6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5,7-dichloropyrazolo[1,5-a]pyri-
midine
##STR01295##
[0107] To a methylene chloride (50 mL) solution containing
2-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)ethanol (640 mg, 2.77
mmol), triethylamine (3.86 mL, 27.7 mmol) and
tert-butylchlorodimethylsilane (1.25 g, 8.31 mmol) were added, and
this mixture was stirred at room temperature for 16 hr. After the
reaction, aqueous ammonium chloride was added to the reaction
solution, and the mixture was extracted with ethyl acetate. The
combined ethyl acetate layer was washed with saturated aqueous
sodium hydrogen carbonate and then brine and dried over sodium
sulfate. After the sodium sulfate was filtered off, the solvent was
distilled off and the residue was purified with column
chromatography (15% ethyl acetate-hexane) to obtain the title
compound (1.04 g).
[0108] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.17 (s,
J=2.4 Hz, 1H), 6.70 (d, J=2.2 Hz, 1H), 3.91 (dd, J=13.2 and 6.3 Hz,
2H), 3.24-3.19 (m, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
Reference Example 4
Synthesis of
3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-1-ol
##STR01296##
[0110] To a tetrahydrofuran (85 mL) solution containing
6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.8 g, 25 mmol),
borane-dimethyl sulfide complex (2 mol/L tetrahydrofuran solution,
20 mL, 41 mmol) was added with ice-cooling over 30 min. This
mixture was stirred at room temperature for 1 hr and again cooled
on ice. Here, aqueous sodium hydroxide (1 mol/L, 40 mL) was added
over 20 min, and hydrogen peroxide (30% aqueous solution, 3 mL) was
further added, and the mixture was stirred for 1 hr. After the
reaction, the mixture was extracted with ethyl acetate. The ethyl
acetate layer was washed with brine and dried over sodium sulfate.
After the sodium sulfate was filtered off, the solvent was
distilled off and the residue was purified with column
chromatography (25 to 50% ethyl acetate-hexane) to obtain the title
compound (3.4 g, yield 31%).
Reference Example 5
Synthesis of
{6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimid-
in-7-yl}[4-(2-methoxyethoxy)phenyl]amine
##STR01297##
[0112] To an isopropanol (3.0 mL) solution containing
6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5,7-dichloropyrazolo[1,5-a]pyri-
midine (512 mg, 1.49 mmol), triethylamine (836 .mu.L, 5.96 mmol)
and 4-(2-methoxyethoxy)phenylamine (299 mg, 1.79 mmol) were added,
and this mixture was heated at 85.degree. C. with stirring. After
the reaction, the solvent was concentrated, sodium hydrogen
carbonate was added here, and the mixture was extracted with ethyl
acetate. The combined ethyl acetate layer was dried over sodium
sulfate. After the sodium sulfate was filtered off, the solvent was
distilled off to obtain the title compound.
Reference Example 6
Synthesis of tert-butyl
{6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimid-
in-7-yl}[4-(2-methoxyethoxy)phenyl]carbamate
##STR01298##
[0114] To a 1,4-dioxane (7.0 mL) solution containing
{6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimid-
in-7-yl}[4-(2-methoxyethoxy)phenyl]amine (570 mg, 1.20 mmol),
di-tert-butyl dicarbonate (515 .mu.L, 2.24 mmol) and
N,N-dimethylaminopyridine (35.2 mg, 0.29 mmol) were added, and this
mixture was stirred with heating at 40.degree. C. After the
reaction, the solvent was concentrated, sodium hydrogen carbonate
was added here, and the mixture was extracted with methylene
chloride. The combined methylene chloride layer was washed with
brine and dried over sodium sulfate. After the sodium sulfate was
filtered off, the filtrate was concentrated to obtain the residue,
which was used for the subsequent reaction without
purification.
Reference Example 7
Synthesis of tert-butyl
(S)-3-{7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-[2-(ter-
t-butyldimethylsilanyloxy)ethyl]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperid-
ine-1-carboxylate
##STR01299##
[0116] To an acetonitrile (5 mL) solution containing tert-butyl
{6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimid-
in-7-yl}[4-(2-methoxyethoxy)phenyl]carbamate (570 mg, 1.20 mmol),
(S)-3-amino-1-tert-butoxycarbonylpiperidine (1.51 g) was added, and
this mixture was stirred at 85.degree. C. for 48 hr. The reaction
solution was concentrated, and the residue was purified with column
chromatography (35% ethyl acetate-hexane) to obtain the title
compound (204 mg).
Reference Example 8
Synthesis of tert-butyl
(S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-hydr-
oxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate
##STR01300##
[0118] To a tetrahydrofuran (5 mL) solution containing tert-butyl
(S)-3-{7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-[2-(ter-
t-butyldimethylsilanyloxy)ethyl]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperid-
ine-1-carboxylate (193 mg, 0.261 mmol), tetrabutylammonium fluoride
(474 .mu.L, 0.474 mmol) was added, and this mixture was stirred at
room temperature for 1.5 hr. After the reaction, aqueous ammonium
chloride was added to the reaction solution, and the mixture was
extracted with ethyl acetate. The combined ethyl acetate layer was
dried over sodium sulfate. After the sodium sulfate was filtered
off, the filtrate was concentrated to obtain the title compound
(233 mg).
Reference Example 9
Synthesis of tert-butyl
(S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-meth-
anesulfonyloxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carbox-
ylate
##STR01301##
[0120] To a methylene chloride (5 mL) solution containing
tert-butyl
(S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-hydr-
oxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate
(216 mg, 0.345 mmol), triethylamine (480 .mu.L, 3.45 mmol) and
methanesulfonyl chloride (80 .mu.L, 1.04 mmol) were added, and this
mixture was stirred at room temperature for 30 min. After the
reaction, aqueous ammonium chloride was added to the reaction
solution, and the mixture was extracted with methylene chloride.
The combined methylene chloride layer was dried over sodium
sulfate. After the sodium sulfate was filtered off, the filtrate
was concentrated to obtain the title compound (258 mg).
Reference Example 10
Synthesis of tert-butyl
{5-(4-tert-butoxycarbonylaminocyclohexylamino)-6-[2-(tert-butyldimethylsi-
lanyloxy)ethyl]pyrazolo[1,5-a]pyrimidin-7-yl}-(4-ethoxyphenyl)carbamate
##STR01302##
[0122] To a methylene chloride solution (0.5 mL) of tert-butyl
{5-(4-aminocyclohexylamino)-6-[2-(tert-butyldimethylsilanyloxy)ethyl]pyra-
zolo[1,5-a]pyrimidin-7-yl}-(4-ethoxyphenyl)carbamate (50 mg, 0.08
mmol), triethylamine (33 .mu.L, 0.24 mmol), di-tert-butyl
dicarbonate (32 mg, 0.16 mmol) and 4-N,N-dimethylaminopyridine (2
mg, 0.02 mmol) were added and the mixture was stirred at room
temperature. After the reaction, aqueous ammonium chloride solution
was added to the reaction solution and the mixture was extracted
with ethyl acetate. The combined ethyl acetate layer was washed
with brine and dried over sodium sulfate. The sodium sulfate was
filtered off and the filtrate was concentrated to obtain the title
compound.
Example 1
Synthesis of tert-butyl
(S)-3-(8-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6,7-dihyd-
ro-1,4,5,8a-tetraaza-s-indacen-5-yl)piperidine-1-carboxylate
##STR01303##
[0124] To a mixed solution of tetrahydrofuran (5 mL) and
N,N-dimethylformamide (1.8 mL) containing tert-butyl
(S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-meth-
anesulfonyloxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carbox-
ylate (162 mg, 0.231 mmol), sodium hydride (with 40% mineral oil
added) (22 mg, 0.55 mmol) was added, and this mixture was stirred
at room temperature for 30 min. After the reaction, aqueous
ammonium chloride was added to the reaction solution, and the
mixture was extracted with methylene chloride. The combined
methylene chloride layer was dried over sodium sulfate. After the
sodium sulfate was filtered off, the filtrate was concentrated to
obtain the title compound.
[0125] HPLC retention time (HPLC condition A): 15.42 min
[0126] ESI/MS: 610.15 (M+H, C.sub.32H.sub.44N.sub.6O.sub.8)
Example 2
Synthesis of tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-(2-methylbenzothiazol-6-yl)amino]-6,7-dihyd-
ro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate
##STR01304##
[0128] The title compound was synthesized using tert-butyl
(S)-3-[7-{tert-butoxycarbonyl-(2-methylbenzothiazol-6-yl)amino}-6-(2-meth-
anesulfonyloxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carbox-
ylate by the same method as Example 1.
[0129] HPLC retention time (HPLC condition A): 15.55 min
[0130] ESI/MS: 606.10 (M+H,
C.sub.31H.sub.39N.sub.7O.sub.4S.sub.1)
Reference Example 11
Synthesis of
(6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)amine
##STR01305##
[0132] To an isopropanol (52 mL) solution containing
6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.98 g),
triethylamine (12.7 mL) and phenetidine (4.30 g) were added, and
this mixture was stirred at 40.degree. C. for 5 hr. After the
reaction, the solvent was distilled off. Saturated aqueous sodium
hydrogen carbonate was added to the residue, and the mixture was
extracted with ethyl acetate. The combined ethyl acetate layer was
dried over sodium sulfate. After the sodium sulfate was filtered
off, the filtrate was concentrated to obtain the title compound
(8.62 g).
Reference Example 12
Synthesis of
3-[5-chloro-7-(4-ethoxyphenylamino)pyrazolo[1,5-a]pyrimidin-6-yl]propan-1-
-ol
##STR01306##
[0134] To an isopropanol (3 mL) solution containing
3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-1-ol (224 mg,
0.910 mmol), triethylamine (253 .mu.L, 1.82 mmol) and phenethidine
(128 .mu.L, 1.00 mmol) were added, and this mixture was stirred at
40.degree. C. for 5 hr. After the reaction, the solvent was
distilled off, aqueous sodium hydrogen carbonate was added to the
residue, and the mixture was extracted with ethyl acetate. The
combined ethyl acetate layer was dried over sodium sulfate. After
the sodium sulfate was filtered off, the filtrate was concentrated
and the residue was purified with column chromatography (30% ethyl
acetate-hexane) to obtain the title compound (212 mg).
[0135] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.17 (s,
1H), 7.98 (d, J=2.2 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.8
Hz, 2H), 6.48 (d, J=2.2 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.33 (t,
J=6.3 Hz, 2H), 2.49 (m, 2H), 1.59 (m, 2H), 1.44 (t, J=7.1 Hz,
2H).
Reference Example 13
Synthesis of
{6-[3-(tert-butyldimethylsilanyloxy)propyl]-5-chloropyrazolo[1,5-a]pyrimi-
din-7-yl}(4-ethoxyphenyl)amine
##STR01307##
[0137] To a methylene chloride (14 mL) solution containing
[6-(3-hydroxypropyl)-5-chloropyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxypheny-
l)amine (1.43 g, 4.12 mmol), triethylamine (861 .mu.L, 6.18 mmol)
and tert-butylchlorodimethylsilane (808 mg, 5.36 mmol) were added
with ice-cooling, and this mixture was stirred at room temperature
for 16 hr. After the reaction, 1 mol/L hydrochloric acid was added
to the reaction solution, and the mixture was extracted with ethyl
acetate. The ethyl acetate layer was washed with aqueous sodium
hydrogen carbonate and then brine and dried over sodium sulfate.
After the sodium sulfate was filtered off, the filtrate was
concentrated and the residue was purified with column
chromatography (10 to 15% ethyl acetate-hexane) to obtain the title
compound (2.03 g, yield 100%).
[0138] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.08 (s,
1H), 7.98 (d, J=2.2 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8
Hz, 2H), 6.47 (d, J=2.4 Hz, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.30 (t,
J=6.3 Hz, 2H), 2.45 (m, 2H), 1.56 (s, 9H), 1.55 (m, 2H), 1.44 (t,
J=7.1 Hz, 3H), 0.84 (s, 9H), -0.03 (s, 9H).
Reference Example 14
Synthesis of tert-butyl
(6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)
(4-ethoxyphenyl)carbamate
##STR01308##
[0140] To a 1,4-dioxane (130 mL) solution containing
(6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)amine
(8.62 g), di-tert-butoxycarboxylate (11.4 g) and
N,N-dimethylaminopyridine (0.80 g) were added, and this mixture was
stirred at room temperature for 2 hr. After the reaction, the
solvent was distilled off, and the residue was purified with column
chromatography (10% ethyl acetate-hexane) to obtain the title
compound (10.49 g, yield 93%).
[0141] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.16 (s,
1H), 7.18 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.9 Hz, 2H), 6.69 (d, J=2.2
Hz, 1H), 5.64 (s, 1H), 5.00 (td, J=15.4 and 4.2 Hz, 2H), 3.99 (q,
J=7.1 Hz, 2H), 3.44 (m, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.26 (s,
9H).
Reference Example 15
Synthesis of tert-butyl
[5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)car-
bamate
##STR01309##
[0143] To a mixed solution of tetrahydrofuran (12 mL) and water (3
mL) containing tert-butyl
(6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate
(1.5 g, 3.5 mmol), sodium periodate (2.3 g, 10.5 mmol) and osmium
tetraoxide (2.5 w/v % in tert-butanol, 1.8 mL, 0.15 mmol) were
added with ice-cooling. After the reaction mixture was stirred at
room temperature for 5 hr, aqueous sodium sulfite was added here,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with aqueous sodium hydrogen carbonate and then brine,
and dried over sodium sulfate. After the sodium sulfate was
filtered off, the solvent was distilled off, and the residue was
purified with column chromatography (20% ethyl acetate-hexane) to
obtain the title compound (895 mg, 2.08 mmol, yield 59%).
[0144] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 9.44 (s,
1H), 8.19 (s, 1H), 7.14 (dt, J=9.8 and 2.9 Hz, 2H), 6.81 (d, J=6.8
Hz, 2H), 6.73 (d, J=2.2 Hz, 1H), 3.98 (q, J=7.1 Hz, 2H), 3.84 (d,
J=37.3 Hz, 1H), 1.56 (s, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reference Example 16
Synthesis of
{7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-5-chloropyrazolo[1,5-a]pyr-
imidin-6-yl}acetic acid
##STR01310##
[0146] To a mixed solution of water (0.5 mL) and tert-butanol (5
mL) containing tert-butyl
[5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)car-
bamate (431 mg, 1.0 mmol), sodium dihydrogen phosphate (1.56 g, 10
mmol), 2-methyl-2-butene (1.1 mL, 10 mmol) and sodium chlorite (181
mg, 2.0 mmol) were added, and this mixture was stirred at room
temperature for 4 hr. After the reaction, water was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was dried over sodium sulfate. After the
sodium sulfate was filtered off, the solvent was distilled off to
obtain the title compound (468 mg).
Reference Example 17
Synthesis of tert-butyl
[5-chloro-6-(3-oxopropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)ca-
rbamate
##STR01311##
[0148] To a methylene chloride (1.7 mL) solution containing
tert-butyl
[5-chloro-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxypheny-
l)carbamate (155 mg, 0.346 mmol), Dess-Martin periodinane (152 mg,
0.381 mmol) was added with ice-cooling, and this mixture was
stirred at room temperature for 16 hr. The reaction mixture was
filtered through celite and the filtrate was concentrated. The
residue was purified with column chromatography (10 to 20% ethyl
acetate-hexane) to obtain the title compound (117 mg, yield
76%).
[0149] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 9.68 (s,
1H), 8.16 (s, 1H), 7.15 (d, J=9.0 Hz, 2H), 6.81 (d, J=9.0 Hz, 2H),
6.69 (d, J=1.9 Hz, 1H), 3.98 (q, J=6.8 Hz, 2H), 3.03 (m, 2H), 2.69
(m, 1H), 1.97 (m, 1H), 1.39 (t, 3H), 1.26 (s, 9H).
Reference Example 18
Synthesis of tert-butyl
{6-[3-(tert-butyldimethylsilanyloxy)propyl]-5-chloropyrazolo[1,5-a]pyrimi-
din-7-yl}(4-ethoxyphenyl)carbamate
##STR01312##
[0151] To a 1,4-dioxane (13 mL) solution containing
{6-[3-(tert-butyldimethylsilanyloxy)propyl]-5-chloropyrazolo[1,5-a]pyrimi-
din-7-yl}(4-ethoxyphenyl)amine (1.89 g, 4.12 mmol), were added
triethylamine (861 .mu.L, 6.18 mmol), di-tert-butyl dicarbonate
(1.08 g, 4.84 mmol) and N,N-dimethylaminopyridine (50.3 mg, 0.412
mmol), and this mixture was stirred at room temperature for 2 hr.
After the reaction, aqueous ammonium chloride was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The combined ethyl acetate layer was washed with aqueous
sodium hydrogen carbonate and then brine and dried over sodium
sulfate. After the sodium sulfate was filtered off, the solvent was
distilled off and the residue was purified with column
chromatography (10% ethyl acetate-hexane) to obtain the title
compound (2.03 g).
[0152] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.13 (d,
J=2.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 6.66
(d, J=2.2 Hz, 1H), 3.98 (q, J=7.1 Hz, 2H), 3.62 (m, 2H), 2.77 (m,
2H), 1.74 (m, 1H), 1.48 (m, 1H), 1.38 (t, J=7.1 Hz, 3H), 1.26 (s,
9H), 0.91 (s, 9H), 0.064 (s, 6H).
Reference Example 19
Synthesis of tert-butyl
[5-chloro-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxypheny-
l)carbamate
##STR01313##
[0154] To a tetrahydrofuran (23 mL) solution containing tert-butyl
(6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate
(3.0 g, 7.0 mmol), borane-dimethyl sulfide complex (2 mol/L
tetrahydrofuran solution, 5.6 mL, 23 mmol) was added over 30 min
with ice-cooling. This mixture was stirred at room temperature for
2 hr and then again cooled on ice. Here, 1 mol/L aqueous sodium
hydroxide (11.2 mL, 11.2 mmol) was added over 20 min, and hydrogen
peroxide (30% aqueous solution, 0.81 mL, 8.4 mmol) was added. The
resultant mixture was stirred for 1 hr. After the reaction, the
reaction mixture was extracted with ethyl acetate. The combined
ethyl acetate layer was washed with brine and dried over sodium
sulfate. After the sodium sulfate was filtered off, the solvent was
distilled off and the residue was purified with column
chromatography (20% ethyl acetate-hexane) to obtain the title
compound (2.02 g, yield 65%).
[0155] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.15 (s,
1H), 7.19 (d, J=8.3 Hz, 2H), 6.82 (d, J=8.3 Hz, 2H), 6.68 (d, J=2.2
Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.64 (J=6.0 Hz, 2H), 2.79 (s, 2H),
1.39 (t, J=7.0 Hz, 3H), 1.26 (s, 9H).
Reference Example 20
Synthesis of tert-butyl
[5-chloro-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl-
)carbamate
##STR01314##
[0157] To a mixed solution of tetrahydrofuran (12 mL) and water (3
mL) containing tert-butyl
(6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate
(1.5 g, 3.5 mmol), sodium periodate (2.3 g, 10.5 mmol) and osmium
tetraoxide (2.5 w/v % in tert-butanol, 1.8 mL, 0.15 mmol) were
added with ice-cooling. After this mixture was stirred at room
temperature for 5 hr, aqueous sodium sulfite was added here. The
resultant mixture was extracted with ethyl acetate. The organic
layer was washed with aqueous sodium hydrogen carbonate and then
brine and dried over sodium sulfate. After the sodium sulfate was
filtered off, the solvent was distilled off to obtain tert-butyl
[5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)car-
bamate.
[0158] The above product was dissolved in methanol (6 mL) and
sodium borohydride (0.14 g, 3.5 mmol) was added to this solution
with ice-cooling. After the reaction mixture was stirred for 30
min, aqueous ammonium chloride was added here. The mixture was
extracted with ethyl acetate, and the organic layer was washed with
brine and dried over sodium sulfate. After the sodium sulfate was
filtered off, the solvent was distilled off and the residue was
purified with column chromatography (15% ethyl acetate-hexane) to
obtain the title compound (1.0 g).
[0159] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.17 (s,
1H), 7.20 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.0 Hz, 2H), 6.70 (d, J=2.2
Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.80 (br, 1H), 3.58 (br, 1H), 3.00
(br, 2H), 1.61 (s, 9H), 1.39 (t, J=6.8 Hz, 3H).
Reference Example 21
Synthesis of tert-butyl
[5-chloro-6-(2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyp-
henyl)carbamate
##STR01315##
[0161] To a mixed solution of acetone (11 mL) and water (22 mL)
containing tert-butyl
(6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate
(1.0 g, 2.33 mmol), N-methylmorpholine-N-oxide (327 mg, 2.79 mmol)
and osmium tetraoxide (2.5 w/v % in tert-butanol, 1.46 mL, 0.116
mmol) were added with ice-cooling. The mixture was allowed to warm
to room temperature and stirred for 16 hr. After the reaction,
aqueous sodium sulfite was added here, and the mixture was
extracted with ethyl acetate. The combined ethyl acetate layer was
washed with brine and dried over sodium sulfate. After the sodium
sulfate was filtered off, the solvent was distilled off and the
residue was purified with column chromatography (50% ethyl
acetate-hexane) to obtain the title compound (947 mg).
Reference Example 22
Synthesis of tert-butyl
{6-[3-(tert-butyldimethylsilanyloxy)-2-hydroxypropyl]-5-chloropyrazolo[1,-
5-a]pyrimidin-7-yl}(4-ethoxyphenyl)carbamate
##STR01316##
[0163] To a methylene chloride (3.6 mL) solution containing
tert-butyl
[5-chloro-6-(2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyp-
henyl)carbamate (500 mg, 1.08 mmol), triethylamine (300 .mu.L, 2.16
mmol), tert-butylchlorodimethylsilane (195 mg, 1.30 mmol) and
N,N-dimethylpyridine (13 mg, 0.108 mmol) were added. After the
reaction mixture was stirred at room temperature for 5 hr, 1 mol/L
hydrochloric acid was added here, and the mixture was extracted
with ethyl acetate. The combined ethyl acetate layer was washed
with aqueous sodium hydrogen carbonate and then brine and dried
over sodium sulfate. After the sodium sulfate was filtered off, the
solvent was distilled off and the residue was purified with column
chromatography to obtain the title compound (503 mg).
Reference Example 23
Synthesis of tert-butyl
(S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-hydroxyethyl)py-
razolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate
##STR01317##
[0165] A mixture of tert-butyl
[5-chloro-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl-
)carbamate (300 mg) and (S)-3-amino-1-tert-butoxycarbonylpiperidine
(900 mg) was stirred at 90.degree. C. for 16 hr. To the reaction
solution, 1 mol/L hydrochloric acid was added, and the mixture was
extracted with ethyl acetate. The ethyl acetate layer was washed
with aqueous sodium hydrogen carbonate and then brine and dried
over sodium sulfate. After the sodium sulfate was filtered off, the
solvent was distilled off to obtain the title compound.
Reference Example 24
Synthesis of tert-butyl
(S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(3-hydroxypropyl)p-
yrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate
##STR01318##
[0167] To a tetrahydrofuran (1.3 mL) solution containing tert-butyl
(S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(3-tert-butyldimet-
hylsiloxypropyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylat-
e (13.3 mg), was added tetrabutylammonium fluoride (1 mol/L
tetrahydrofuran solution, 26 .mu.L), and the mixture was stirred at
room temperature for 3 hr. After the reaction, the mixture was
purified with PTLC (50% ethyl acetate-hexane) to obtain the title
compound (7.7 mg).
Reference Example 25
Synthesis of tert-butyl
(S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-methanesulfonyl-
oxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate
##STR01319##
[0169] To a methylene chloride (2 mL) solution containing
tert-butyl
(S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-hydroxyethyl)py-
razolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (0.693
mmol), triethylamine (290 .mu.L, 2.08 mmol) and methanesulfonyl
chloride (80 .mu.L, 1.04 mmol) were added with ice-cooling, and the
mixture was stirred for 30 min. After the reaction, 1 mol/L
hydrochloric acid was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with aqueous sodium hydrogen carbonate and then brine and
dried over sodium sulfate. After the sodium sulfate was filtered
off, the solvent was distilled off to obtain the title
compound.
Example 3
Synthesis of tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-
-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate
##STR01320##
[0171] To a mixed solution of tetrahydrofuran (3 mL) and
N,N-dimethylformamide (1 mL) containing tert-butyl
(S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-methanesulfonyl-
oxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate
(0.693 mmol), sodium hydride (with 40% mineral oil added) (55 mg)
was added with ice-cooling, and the mixture was stirred for 2 hr.
After the reaction, water was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The ethyl acetate
layer was washed with brine and dried over sodium sulfate. After
the sodium sulfate was filtered off, the solvent was distilled off
to obtain the title compound.
[0172] HPLC retention time (HPLC condition A): 15.92 min
[0173] ESI/MS: 579.20 (M+H, C.sub.31H.sub.42N.sub.6O.sub.5)
Reference Example 26
Synthesis of tert-butyl
(S)-3-(2-{7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-5-chloropyrazolo[-
1,5-a]pyrimidin-6-yl}acetylamino)piperidine-1-carboxylate
##STR01321##
[0175] To an N,N-dimethylformamide (0.5 mL) solution containing
{7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-5-chloropyrazolo[1,5-a]pyr-
imidin-6-yl}acetic acid (10.3 mg, 0.023 mmol) and
(S)-3-amino-1-tert-butoxycarbonylpiperidine (9.2 mg, 0.046 mmol),
diisopropylamine (50 .mu.L) and
O-(7-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (13.1 mg, 0.0345 mmol) were added, and the
mixture was stirred at room temperature for 16 hr. To the reaction
solution, aqueous ammonium chloride was added, and the mixture was
extracted with ethyl acetate. The organic layer was dried over
sodium sulfate. After the sodium sulfate was filtered off, the
solvent was distilled off, and the residue was purified with PTLC
(50% ethyl acetate-hexane) to obtain the title compound (10.8
mg).
[0176] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.16 (s,
1H), 7.22 (t, J=6.3 Hz, 2H), 6.92 (d, J=7.8 Hz, 2H), 6.69 (d, J=2.0
Hz, 1H), 3.97 (q, J=5.5 Hz, 2H), 3.92 (m, 1H), 3.57-3.07 (m, 6H),
2.47-2.31 (m, 1H), 1.81 (m, 1H), 1.62 (s, 9H), 1.47 (s, 9H), 1.26
(t, J=6.2 Hz, 3H).
Example 4
Synthesis of tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-oxo-6,7-dihydro-1,-
4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate
##STR01322##
[0178] To a mixed solution of tetrahydrofuran (0.3 mL) and
N,N-dimethylformamide (0.1 mL) containing tert-butyl
(S)-3-(2-{7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-5-chloropyrazolo[-
1,5-a]pyrimidin-6-yl}acetylamino)piperidine-1-carboxylate (4.3 mg),
sodium hydride (with 40% mineral oil added) (10 mg) was added, and
the mixture was stirred at room temperature for 1 hr. To the
reaction solution, aqueous ammonium chloride was added, and the
mixture was extracted with ethyl acetate. The ethyl acetate layer
was dried over sodium sulfate. After the sodium sulfate was
filtered off, the solvent was distilled off to obtain the title
compound.
Reference Example 27
Synthesis of tert-butyl
(S)-3-(allyl-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazo-
lo[1,5-a]pyrimidin-5-yl}amino)piperidine-1-carboxylate
##STR01323##
[0180] To a mixed solution of tetrahydrofuran (0.6 mL) and
N,N-dimethylformamide containing tert-butyl
(S)-3-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazolo[1,5--
a]pyrimidin-5-ylamino}piperidine-1-carboxylate (100 mg, 0.168
mmol), sodium hydride and allyl bromide were added at 0.degree. C.,
and the mixture was stirred at 70.degree. C. for 5 hr. To the
reaction solution, water was added, and the mixture was extracted
with ethyl acetate. The combined ethyl acetate layer was dried over
sodium sulfate. After the sodium sulfate was filtered off, the
solvent was distilled off to obtain the title compound (102
mg).
Example 5
Synthesis of tert-butyl
(S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,9-dihydro-1,4,5,1-
0a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate
##STR01324##
[0182] To a toluene (0.7 mL) solution containing tert-butyl
(S)-3-(allyl-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazo-
lo[1,5-a]pyrimidin-5-yl}amino)piperidine-1-carboxylate (28.5 mg,
0.035 mmol), Grubbs catalyst (8.4 mg, 0.0103 mmol) was added. After
the mixture was stirred at 40.degree. C. for 16 hr, the solvent was
distilled off, and the residue was purified with PTLC (30% ethyl
acetate-hexane) to obtain the title compound (10 mg).
Example 6
Synthesis of tert-butyl
(S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7,8,9-tetrahydro--
1,4,5,10a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate
##STR01325##
[0183] tert-Butyl
(S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,9-dihydro-1,4,5,1-
0a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate (12.5
mg) was hydrogenated in the presence of palladium-carbon (15 mg) in
ethanol (1.2 mL) under a hydrogen atmosphere. After the reaction,
the palladium-carbon was filtered off, and the filtrate was
concentrated. The residue was used for the subsequent reaction
without purification.
Example 7
Synthesis of tert-butyl
(4-ethoxyphenyl)(5-hydroxy-6,7-dichloro-5H-1,4,5,8a-tetraaza-s-indacen-8--
yl)carbamate
##STR01326##
[0185] To a methanol (30 mL) solution containing tert-butyl
[5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)car-
bamate (1.0 g, 2.3 mmol) and hydroxylamine hydrochloride (0.81 g,
11.6 mmol), sodium cyanoborohydride (0.73 g, 11.6 mmol) was added,
and the mixture was heated at 50.degree. C. for 16 hr. To the
reaction solution, aqueous sodium hydrogen carbonate was added, and
the mixture was extracted with ethyl acetate. The combined ethyl
acetate layer was washed with brine and dried over sodium sulfate.
After the sodium sulfate was filtered off, and the solvent was
distilled off to obtain the title compound.
[0186] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 7.85 (d,
J=2.0 Hz, 1H), 7.19 (dd, J=2.2 and 6.8 Hz, 2H), 6.80 (dd, J=2.2 and
6.6 Hz, 2H), 6.26 (d, 1H), 3.97 (q, J=7.1 Hz, 2H), 3.79 (t, J=7.6
Hz, 2H), 2.71 (br, 2H), 1.37 (s, 9H), 1.26 (t, J=7.1 Hz, 3H).
Example 8
Synthesis of tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-1,4,5,8a-tetraaza-s--
indacen-5-yl}piperidine-1-carboxylate
##STR01327##
[0188] To a mixed solution of tetrahydrofuran (3.2 mL) and water
(0.8 mL) containing tert-butyl
(S)-3-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazolo[1,5--
a]pyrimidin-5-ylamino}piperidine-1-carboxylate (375 mg, 0.632
mmol), sodium periodate (405 mg, 1.89 mmol) and osmium tetraoxide
(2.5 w/v % tert-butanol solution, 793 .mu.L, 0.063 mmol) were
added, and the mixture was stirred. After the reaction, aqueous
sodium sulfite was added to the solution, and the mixture was
extracted with ethyl acetate. The combined ethyl acetate layer was
washed with brine and dried over sodium sulfate. After the sodium
sulfate was filtered off, and the solvent was distilled off to
obtain the title compound.
Example 9
Synthesis of tert-butyl
(S)-3-[8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(tert-butyldimethy-
lsilanyloxymethyl)-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-1-carboxyla-
te
##STR01328##
[0190] To a methylene chloride (1 mL) solution containing
tert-butyl
(S)-3-{7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-[3-(tert-butyldime-
thylsilanyloxy)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperid-
ine-1-carboxylate (28.6 mg, 0.0495 mmol), Dess-Martin periodinane
(25.2 mg, 0.0594 mmol) was added at 0.degree. C., and the mixture
was allowed to warm to room temperature and stirred for 3 hr. After
the reaction, the reaction solution was concentrated, and the
residue was purified with PTLC (30% ethyl acetate-hexane) to obtain
the title compound (14.5 mg).
[0191] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.05 (d,
J=2.2 Hz, 1H), 7.26 (dt, J=9.8 and 2.8 Hz, 2H), 6.74 (dt, J=9.8 and
2.8 Hz, 2H), 6.40 (d, J=2.2 Hz, 1H), 6.04 (s, 1H), 4.66 (d, J=12.9
Hz, 1H), 4.58 (d, J=13.4 Hz, 1H), 4.19-4.02 (m, 2H), 3.90 (q, J=7.0
Hz, 2H), 2.84 (br, 2H), 1.91 (m, 1H), 1.80 (m, 1H), 1.38 (s, 9H),
1.30 (t, J=7.1 Hz, 3H), 1.28 (s, 9H), 0.83 (s, J=13.0 Hz, 9H), 0.02
(d, J=16.8 Hz, 6H).
Reference Example 28
Synthesis of tert-butyl
(S)-3-[7-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-{3-(tert-butyldime-
thylsilanyloxy)-2-hydroxypropyl}pyrazolo[1,5-a]pyrimidin-5-ylamino]piperid-
ine-1-carboxylate
##STR01329##
[0193] By using tert-butyl
{6-[3-(tert-butyldimethylsilanyloxy)-2-hydroxypropyl]-5-chloropyrazolo[1,-
5-a]pyrimidin-7-yl}(4-ethoxyphenyl)carbamate, the title compound
was synthesized by the same method as Reference example 7.
Reference Example 29
Synthesis of tert-butyl
(S)-3-[7-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-{3-(tert-butyldime-
thylsilanyloxy)-2-methanesulfonyloxypropyl}pyrazolo[1,5-a]pyrimidin-5-ylam-
ino]piperidine-1-carboxylate
##STR01330##
[0195] By using tert-butyl
(S)-3-[7-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-{3-(tert-butyldime-
thylsilanyloxy)-2-hydroxypropyl}pyrazolo[1,5-a]pyrimidin-5-ylamino]piperid-
ine-1-carboxylate, the title compound was synthesized by the same
method as Reference example 25.
Example 10
Synthesis of tert-butyl
(S)-3-[8-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-(tert-butyldimethy-
lsilanyloxymethyl)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-
-1-carboxylate
##STR01331##
[0197] By using tert-butyl
(S)-3-[7-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-{3-(tert-butyldime-
thylsilanyloxy)-2-methanesulfonyloxypropyl}pyrazolo[1,5-a]pyrimidin-5-ylam-
ino]piperidine-1-carboxylate, the title compound was synthesized by
the same method as Example 1.
Example 11
Synthesis of
(S)-(4-ethoxyphenyl)(5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s--
indacen-8-yl)amine (Compound No.: A-008)
##STR01332##
[0199] To a methylene chloride (4 mL) solution containing
tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-
-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (0.693 mmol),
trifluoroacetic acid (2 mL) was added with ice-cooling, and the
mixture was allowed to warm to room temperature and stirred for 16
hr. After the reaction, the reaction solution was poured into
aqueous sodium hydrogen carbonate, and the mixture was extracted
with ethyl acetate. The ethyl acetate layer was washed with brine
and dried over sodium sulfate. After the sodium sulfate was
filtered off, the solvent was distilled off and the residue was
purified with PTLC {10% (2 mol/L ammonia/methanol)-methylene
chloride} to obtain the title compound (97.0 mg).
[0200] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 7.74 (d,
J=2.2 Hz, 1H), 7.55 (s, 1H), 7.17 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8
Hz, 2H), 6.06 (d, J=2.2 Hz, 1H), 4.05 (t, J=7.1 Hz, 2H), 3.43 (m,
2H), 3.13 (m, 1H), 3.03 (m, 1H), 2.67 (t, 1H), 2.54 (m, 1H), 2.30
(t, 2H), 1.79 (m, 3H), 1.60 (m, 1H), 1.44 (t, 3H).
[0201] HPLC retention time (HPLC condition A): 7.30 min
[0202] ESI/MS: 379.15 (M+H, C.sub.21H.sub.26N.sub.6O)
Example 12
Synthesis of
(S)-(4-ethoxyphenyl)(5-piperidin-3-yl-5H-1,4,5,8a-tetraaza-s-indacen-8-yl-
)amine (Compound No.: F-001)
##STR01333##
[0204] By using tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-1,4,5,8a-tetraaza-s--
indacen-5-yl}piperidine-1-carboxylate, the title compound was
synthesized by the same method as Example 11.
[0205] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 8.30 (br,
1H), 8.04 (d, J=2.4 Hz, 1H), 7.35 (dd, J=2.2 and 6.6 Hz, 2H), 6.99
(dd, J=2.2 and 6.6 Hz, 2H), 6.82 (d, J=3.9 Hz, 1H), 6.31 (d, J=2.2
Hz, 1H), 5.42 (d, J=3.9 Hz, 1H), 4.70 (m, 1H), 4.10 (q, J=7.1 Hz,
2H), 3.33 (m, 1H), 3.10 (m, 1H), 2.80 (m, 1H), 2.68 (m, 1H),
2.13-1.67 (m, 4H), 1.47 (t, J=7.1 Hz, 3H).
[0206] HPLC retention time: 7.91 min
[0207] ESI/MS: 377.14 (M+H, C.sub.21H.sub.24N.sub.6O)
Example 13
Synthesis of
(S)-(4-ethoxyphenyl)(5-piperidin-3-yl-6,9-dihydro-5H-1,4,5,10a-tetraazacy-
clohepta[f]inden-10-yl)amine (Compound No.: G-001)
##STR01334##
[0209] By using tert-butyl
(S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,9-dihydro-1,4,5,1-
0a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate, the
title compound was synthesized by the same method as Example
11.
[0210] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 7.81 (d,
J=2.2 Hz, 1H), 7.54 (s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8
Hz, 2H), 6.16 (d, J=2.2 Hz, 1H), 5.71 (m, 2H), 4.47 (m, 1H), 4.02
(q, J=6.8 Hz, 2H), 3.82 (m, 2H), 3.31 (m, 1H), 3.05 (m, 1H), 2.98
(d, J=5.6 Hz, 2H), 2.74 (t, J=11.2 Hz, 1H), 2.55 (m, 1H), 2.02 (m,
1H), 1.96 (m, 2H), 1.67 (m, 2H), 1.42 (t, J=6.8 Hz, 3H).
[0211] HPLC retention time (HPLC condition A): 9.17 min
[0212] ESI/MS: 405.04 (M+H, C.sub.23H.sub.28N.sub.6O.sub.1)
Example 14
Synthesis of
(S)-(4-ethoxyphenyl)(5-piperidin-3-yl-6,7,8,9-tetrahydro-5H-1,4,5,10a-tet-
raazacyclohepta[f]inden-10-yl)amine (Compound No.: C-001)
##STR01335##
[0214] By using tert-butyl
(S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7,8,9-tetrahydro--
1,4,5,10a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate,
the title compound was synthesized by the same method as Example
11.
[0215] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 7.76 (d,
J=2.2 Hz, 1H), 7.50 (s, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.85 (d, J=9.0
Hz, 2H), 6.06 (d, J=2.2 Hz, 1H), 4.59 (m, 1H), 4.03 (q, J=7.1 Hz,
2H), 3.38 (m, 2H), 3.26 (m, 1H), 3.10 (m, 1H), 2.82 (m, 1H), 2.66
(t, J=11.0 Hz, 1H), 2.56 (m, 1H), 2.17 (m, 3H), 2.00 (m, 1H),
1.82-1.66 (m, 5H), 1.42 (t, J=7.1 Hz, 3H).
[0216] HPLC retention time: 8.59 min
[0217] ESI/MS: 407.12 (M+H, C.sub.23H.sub.30N.sub.6O.sub.1)
Example 15
Synthesis of
8-(4-ethoxyphenylamino)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-ol
(Compound No.: A-020)
##STR01336##
[0219] By using tert-butyl
(4-ethoxyphenyl)(5-hydroxy-6,7-dichloro-5H-1,4,5,8a-tetraaza-s-indacen-8--
yl)carbamate, the title compound was synthesized by the same method
as Example 11.
[0220] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 7.84 (d,
J=2.2 Hz, 1H), 7.82 (s, 1H), 7.16 (dd, J=2.2 and 6.6 Hz, 2H), 6.90
(dd, J=2.2 and 6.6 Hz), 6.26 (d, J=2.2 Hz, 1H), 4.05 (q, J=7.1 Hz,
2H), 3.53 (t, J=7.6 Hz, 2H), 2.23 (t, J=7.6 Hz, 2H), 1.44 (t, J=7.1
Hz, 3H).
[0221] HPLC retention time (HPLC condition A): 7.74 min
[0222] ESI/MS: 312.15 (M+H, C.sub.16H.sub.17N.sub.5O.sub.2)
Example 16
Synthesis of
8-(4-ethoxyphenylamino)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl
acetate (Compound No.: A-021)
##STR01337##
[0224] To a methylene chloride (0.5 mL) solution containing
8-(4-ethoxyphenylamino)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-ol
(2.8 mg), triethylamine (50 .mu.L) and acetic anhydride (50 .mu.L)
were added. After this solution was stirred at room temperature for
30 min, the solvent was concentrated, and the residue was purified
with PTLC (70% ethyl acetate-hexane) to obtain the title compound
(2.3 mg).
[0225] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 7.93 (s,
1H), 7.90 (d, 2H), 7.19 (dd, J=2.2 and 6.6 Hz, 2H), 6.91 (dd, J=2.2
and 6.6 Hz, 2H), 6.35 (d, 1H), 4.06 (q, J=6.8 Hz, 2H), 3.58 (t,
J=7.6 Hz, 2H), 2.36 (t, J=7.3 Hz, 2H), 2.57 (s, 3H), 1.45 (t, J=7.1
Hz, 3H).
[0226] HPLC retention time (HPLC condition A): 10.8 min
[0227] ESI/MS: 354.06 (M+H, C.sub.18H.sub.19N.sub.5O.sub.3)
Example 17
Synthesis of
[5-(4-aminocyclohexyl)-5,6,7,8-tetrahydro-1,4,5,9a-tetraazacyclopenta[b]n-
aphthalen-9-yl](4-ethoxyphenyl)amine (Compound No.: B-002)
##STR01338##
[0229] By using tert-butyl
[5-(4-tert-butoxycarbonylaminocyclohexyl)-5,6,7,8-tetrahydro-1,4,5,9a-tet-
raazacyclopenta[b]naphthalen-9-yl](4-ethoxyphenyl)carbamate, the
title compound was synthesized by the same method as Example
11.
[0230] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 7.75 (d,
J=2.2 Hz, 1H), 7.46 (s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8
Hz, 2H), 6.03 (d, J=2.2 Hz, 1H), 4.95 (m, 1H), 4.02 (q, J=7.1 Hz,
2H), 3.21 (t, J=5.6 Hz, 2H), 2.76 (m, 1H), 2.10 (t, J=6.1 Hz, 2H),
2.00 (m, 2H), 1.78 (m, 4H), 1.53 (m, 2H), 1.42 (t, J=6.8 Hz,
3H).
[0231] HPLC retention time (HPLC condition A): 7.2 min
[0232] ESI/MS: 407.34 (M+H, C.sub.23H.sub.30N.sub.6O)
Example 18
Synthesis of
(S)-(2-methylbenzothiazol-6-yl)(5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a--
tetraaza-s-indacen-8-yl)amine (Compound No.: A-022
##STR01339##
[0234] By using tert-butyl
(S)-3-(8-{tert-butoxycarbonyl-[4-(2-methylbenzothiazol-6-yl)]-6,7-dihydro-
-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate, the
title compound was synthesized by the same method as Example
11.
[0235] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 10.63 (s,
2H), 9.71 (s, 1H), 8.49 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.89 (d,
J=2.2 Hz, 2H), 7.82 (d, J=2.2 Hz, 2H), 7.41 (dd, J=8.5 and 2.2 Hz,
1H), 6.42 (d, J=2.0 Hz, 1H), 4.68 (t, J=11.3 Hz, 1H), 3.72 (dq,
J=31.1 and 9.0 Hz, 2H), 3.48-3.34 (m, 3H), 3.01 (m, 1H), 2.99 (s,
3H), 2.39 (t, J=8.5 Hz, 2H), 2.08-1.79 (m, 4H).
[0236] HPLC retention time (HPLC condition A): 6.19 min
[0237] ESI/MS: 406.10 (M+H, C.sub.21H.sub.23N.sub.7S)
Example 19
Synthesis of
(S)-[4-(2-methoxyethoxy)phenyl](5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a--
tetraaza-s-indacen-8-yl)amine (Compound No.: A-023)
##STR01340##
[0239] By using tert-butyl
(S)-3-(8-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6,7-dihyd-
ro-1,4,5,8a-tetraaza-s-indacen-5-yl)piperidine-1-carboxylate, the
title compound was synthesized by the same method as Example
11.
[0240] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.(ppm): 10.93 (s,
1H), 9.65 (s, 1H), 8.29 (s, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.26 (d,
J=7.8 Hz, 2H), 7.00 (dd, J=9.6 and 2.8 Hz, 2H), 6.39 (d, J=2.0 Hz,
1H), 4.67 (t, J=11.8 Hz, 1H), 4.17 (t, J=4.5 Hz, 2H), 3.80 (dd,
J=5.4 and 3.7 Hz, 2H), 3.71 (dq, J=28.4 and 6.8 Hz, 2H), 3.48 (s,
3H), 3.48-3.30 (m, 3H), 3.04 (m, 1H), 2.37 (t, 2H, J=8.5 Hz),
2.08-1.79 (m, 4H).
[0241] HPLC retention time (HPLC condition A): 6.19 min
[0242] ESI/MS: 409.15 (M+H, C.sub.22H.sub.28N.sub.6O.sub.2)
Example 20
Synthesis of
(S)-(4-ethoxyphenyl)(3-fluoro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-te-
traaza-s-indacen-8-yl)amine (Compound No.: A-018) and
(S)-(2,3-difluoro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-ind-
acen-8-yl)(4-ethoxyphenyl)amine (Compound No.: A-019)
##STR01341##
[0244] To an N,N-dimethylformamide (1.3 mL) solution containing
tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-
-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (78 mg, 0.14
mmol), an N,N-dimethylformamide (1.4 mL) solution containing
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (38.3 mg, 0.108 mmol) was added with
ice-cooling, and this mixture was stirred at room temperature for 4
days. After the reaction, 0.2 mol/L hydrochloric acid was added to
the reaction solution, and the mixture was extracted with ethyl
acetate. The ethyl acetate layer was washed with aqueous sodium
hydrogen carbonate and then brine and dried over sodium sulfate.
After the sodium sulfate was filtered off, the solvent was
distilled off. To the residue, methylene chloride (3.0 mL) and
trifluoroacetic acid (0.3 mL) were added, and this solution was
stirred at room temperature. The solvent was distilled off under
reduced pressure, and the residue was purified with preparative
HPLC to obtain the title compounds. [0245]
(S)-(4-Ethoxyphenyl)(3-fluoro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-te-
traaza-s-indacen-8-yl)amine (Compound No.: A-018)
[0246] Yield: 7.6 mg
[0247] HPLC retention time (HPLC condition A): 8.50 min
[0248] ESI/MS: 397.08 (M+H, C.sub.21H.sub.25FN.sub.6O) [0249]
(S)-(2,3-Difluoro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-ind-
acen-8-yl)(4-ethoxyphenyl)amine (Compound No.: A-019)
[0250] Yield: 14.9 mg
[0251] HPLC retention time (HPLC condition A): 10.23 min
[0252] ESI/MS: 415.07 (M+H,
C.sub.21H.sub.24F.sub.2N.sub.6O.sub.1)
Example 21
Synthesis of
(S)-{8-(4-ethoxyphenylamino)-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tet-
raaza-s-indacen-6-yl}methanol (Compound No.: A-024)
##STR01342##
[0254] By using tert-butyl
(S)-3-[8-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-(tert-butyldimethy-
lsilanyloxymethyl)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-
-1-carboxylate, the title compound was synthesized by the same
method as Example 11.
[0255] HPLC retention time (HPLC condition A): 6.41 min
[0256] ESI/MS: 409.10 (M+H, C.sub.22H.sub.28N.sub.6O.sub.2)
Example 22
Synthesis of tert-butyl
(S)-3-{3-chloro-8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-
-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate
##STR01343##
[0258] To a THF solution (2.0 mL) of tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-
-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (12.5 mg, 0.0216
mmol), N-chlorosuccinimide (15.3 mg, 0.114 mmol) was added at room
temperature and the mixture was stirred at room temperature for 1
hr. After the reaction, aqueous sodium thiosulfate solution was
added to the reaction solution, and the mixture was extracted with
ethyl acetate. The ethyl acetate layer was washed with water and
then brine and dried over sodium sulfate. After the sodium sulfate
was filtered off, the solvent was evaporated to obtain the title
compound.
[0259] HPLC retention time (HPLC condition A): 16.69 min
[0260] ESI/MS: 613.10 (M+H, C.sub.31H.sub.41ClN.sub.6O.sub.5)
Example 23
Synthesis of tert-butyl
(S)-3-{3-bromo-8-tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6,7-dihydro-1-
,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate
##STR01344##
[0262] To a THF solution (2.0 mL) of tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-
-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (20.0 mg, 0.0346
mmol), N-bromosuccinimide (31.4 mg, 0.176 mmol) was added on
ice-bath cooling and the mixture was stirred for 10 min. After the
reaction, aqueous sodium thiosulfate solution was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The ethyl acetate layer was washed with water and then
brine and dried over sodium sulfate. After the sodium sulfate was
filtered off, the solvent was evaporated and the residue was
purified with column chromatography (30% ethyl acetate-hexane) to
obtain the title compound (16.8 mg).
[0263] HPLC retention time (HPLC condition A): 16.79 min
[0264] ESI/MS: 657.05, 659.10 (M+H,
C.sub.31H.sub.41BrN.sub.6O.sub.5)
Example 24
Synthesis of
(S)-(4-ethoxyphenyl)-(3-chloro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-t-
etraaza-s-indacen-8-yl)amine (Compound No. A-101)
##STR01345##
[0266] The title compound was synthesized using tert-butyl
(S)-3-{3-chloro-8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-
-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate by the
same method as Example 11.
[0267] HPLC retention time (HPLC condition A): 9.82 min
[0268] ESI/MS: 413.05 (M+H, C.sub.21H.sub.25ClN.sub.6O.sub.1)
Example 25
Synthesis of
(S)-(4-ethoxyphenyl)-(3-bromo-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-te-
traaza-s-indacen-8-yl)amine (Compound No.: A-102)
##STR01346##
[0270] The title compound was synthesized using tert-butyl
(S)-3-{3-bromo-8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro--
1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate by the
same method as Example 11.
[0271] HPLC retention time (HPLC condition A): 10.04 min
[0272] ESI/MS: 456.95, 459.00 (M+H,
C.sub.21H.sub.25BrN.sub.6O.sub.1)
Example 26
Synthesis of
(S)-furan-2-yl-(5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indac-
en-8-yl)amine (Compound No.: A-095) and
(S)-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-ylamine
(Compound No.: A-092)
##STR01347##
[0274] To a methylene chloride solution (2.0 mL) of tert-butyl
(S)-3-{8-[tert-butoxycarbonyl-furan-2-ylmethylamino]-6,7-dihydro-1,4,5,8a-
-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (60.0 mg, 0.111
mmol), trifluoroacetic acid (1.0 mL) was added on ice-bath cooling
and the mixture was allowed to warm up to room temperature and
stirred for 4 hr. The reaction mixture was concentrated under
reduced pressure and the residue was purified with preparative HPLC
to obtain the two title compounds.
[0275] (Compound No.: A-095)
[0276] Yield: 18.0 mg
[0277] HPLC retention time (HPLC condition A): 5.40 min
[0278] ESI/MS: 338.95 (M+H, C.sub.18H.sub.22N.sub.6O.sub.1)
[0279] (Compound No.: A-092)
[0280] Yield: 13.4 mg
[0281] HPLC retention time (HPLC condition B): 2.51 min
[0282] ESI/MS: 259.00 (M+H, C.sub.13H.sub.18N.sub.6O.sub.1)
Example 27
Synthesis of tert-butyl
(S)-3-(3-iodo-8-[tert-butoxycarbonyl-{4-(2-methoxyethoxy)phenyl}amino]-6,-
7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl)piperidine-1-carboxylate
##STR01348##
[0284] To a THF solution (1.5 mL) of tert-butyl
(S)-3-(8-[tert-butoxycarbonyl-{4-(2-methoxyethoxy)phenyl}amino]-6,7-dihyd-
ro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (110.6
mg, 0.182 mmol), N-iodosuccinimide (49.1 mg, 0.218 mmol) was added
at room temperature and the mixture was stirred for 3 hr. After the
reaction, the reaction mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed with water and then brine and
dried over sodium sulfate. After the sodium sulfate was filtered
off, the solvent was removed under reduced pressure and the residue
was purified with column chromatography (30% ethyl acetate-hexane)
to obtain the title compound (118.9 mg).
[0285] HPLC retention time (HPLC condition A): 16.48 min
[0286] ESI/MS: 735.24 (M+H, C.sub.32H.sub.43IN.sub.6O.sub.6)
Example 28
Synthesis of tert-butyl
(S)-3-[3-iodo-8-{tert-butoxycarbonyl-(2-methylbenzothiazol-6-yl)amino}-6,-
7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-1-carboxylate
##STR01349##
[0288] To a THF solution (1.5 mL) of tert-butyl
(S)-3-[8-{tert-butoxycarbonyl-(2-methylbenzothiazol-6-yl)amino}-6,7-dihyd-
ro-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-1-carboxylate (97.6
mg, 0.161 mmol), N-iodosuccinimide (43.5 mg, 0.193 mmol) was added
at room temperature and the mixture was stirred for 3 hr. After the
reaction, the reaction mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed with water and then brine and
dried over sodium sulfate. After the sodium sulfate was filtered
off, the solvent was removed under reduced pressure and the residue
was purified with column chromatography (30% ethyl acetate-hexane)
to obtain the title compound (109.7 mg).
[0289] HPLC retention time (HPLC condition A): 16.68 min
[0290] ESI/MS: 732.18 (M+H, C.sub.31H.sub.381N.sub.7O.sub.4S)
Example 29
[0291] The compounds listed in the following Table H were
synthesized from the corresponding starting material and reagent
according to each method described in Examples 11 to 21, and 24 to
26. The compound number assigned to each compound in Table H
corresponds to the compound number of the example listed in the
above Tables A to G. The structures of novel compounds isolated
were confirmed by .sup.1H NMR and/or mass analysis on a single
quadrupole instrumentation equipped with an electrospray source or
other appropriate analytical methods.
[0292] For results of mass analysis, M+H, that is, the measured
value observed as the molecular mass of compound (M) with one
proton (H) added, is shown. "HPLC retention time" represents the
retention time (unit: min) of compound in HPLC analysis under the
above-mentioned analytical conditions. "Conditions for HPLC"
represents the conditions for HPLC analysis on that occasion.
TABLE-US-00008 TABLE H HPLC Retention Compound ESI/MS Time
Conditions NO. M + H (min) for HPLC A-001 379.30 7.22 A A-002
393.18 6.75 A A-003 393.18 6.78 A A-004 393.18 7.20 A A-005 339.16
6.44 A A-006 353.18 6.25 A A-007 381.17 8.60 A A-009 379.22 6.42 A
A-010 455.22 8.27 A A-011 393.25 7.82 A A-012 393.20 7.95 A A-013
365.20 6.87 A A-014 393.12 6.74 A A-015 393.12 7.84 A A-016 379.09
7.78 A A-017 386.10 11.25 A A-025 349.15 6.13 A A-026 329.20 6.89 A
A-027 327.20 5.69 B A-032 335.05 6.03 A A-058 375.10 5.02 A A-091
443.10 5.84 A A-096 273.10 1.55 B A-099 393.05 6.65 A A-100 391.00
9.28 A B-001 393.12 8.81 A B-003 407.28 9.12 A B-004 366.30 11.14 A
B-005 380.32 11.74 A B-006 394.29 10.24 A B-007 381.30 8.56 A B-009
368.31 9.66 A B-010 382.27 10.18 A B-011 350.32 9.72 A B-012 378.31
11.13 A B-013 407.28 7.72 A B-014 393.31 7.84 A B-015 367.27 6.77 A
B-016 469.32 11.31 A B-017 393.31 6.91 A B-018 401.30 8.77 A B-019
401.24 7.86 A B-020 401.17 8.64 A B-021 379.00 7.88 A B-022 407.06
9.10 A D-001 393.15 6.94 A D-002 407.08 7.78 A D-003 353.11 7.22 A
D-004 393.12 7.97 A D-005 407.15 8.16 A D-006 407.08 8.36 A D-007
469.06 10.19 A E-001 407.12 8.84 A F-002 407.25 8.08 A
Example 30
General Measurement Method for Determining Inhibition of MAPKAP-K2
Enzyme Activity
(Preparation of Solutions of Compounds)
[0293] Each compound was dissolved to DMSO to prepare a solution
with a concentration of 20 mmol/L and this solution was stored at
-20.degree. C. This stock solution was diluted with DMSO
successively to prepare solutions with 200-fold concentrations of a
necessary range. These solutions were further diluted with water at
a ratio of 1:20 to prepare solutions with 10-fold concentrations of
a necessary range. Each of these solutions (5 .mu.L) was used for
each reaction in 50 .mu.L-scale. Through the dilution series of all
compounds, the final DMSO concentration was kept at 0.5%.
Conventional tests for the compounds were carried out at a final
concentration ranging from 100 .mu.mol/L to 0.03 .mu.mol/L, but in
some cases, tests were carried out at lower concentrations,
depending on activity.
(Measurements of MAPKAP-K2 Enzyme Activity)
[0294] To a DMSO solution (5 .mu.L) containing a test compound at
5%, a solution (25 .mu.L) containing a peptide substrate [peptide
substrate 60 .mu.mol/L, ATP 20 .mu.mol/L, Tris buffer 60 mmol/L (pH
7.5), EGTA 0.2 mmol/L, .beta.-mercaptoethanol 0.2%, magnesium
acetate 20 mmol/L, [.gamma.-33P]ATP 0.1 .mu.Ci (specific
radioactivity ca. 110 TBq/mmol)] was added. The reaction was
initiated by further adding a solution (20 .mu.L) containing
MAPKAP-K2 enzyme [recombinant human MAPKAP-K210 mU, Tris buffer 50
mmol/L (pH 7.5), EGTA 0.1 mmol/L, .beta.-mercaptoethanol 0.1%, BSA
0.1%]. After the reaction was carried out at room temperature for
30 min, 200 mmol/L phosphoric acid (50 .mu.L) was added to quench
the reaction, and 90 .mu.L of the reaction mixture was adsorbed on
a multiscreen PH plate (Millipore). The plate was washed with 100
mmol/L phosphoric acid. After the plate was dried, 30 .mu.L of
MicroScint.TM.-O (Perkin-Elmer) was added here, and the
radioactivity (cpm) was measured on a scintillation counter to
determine the inhibitory activity. The peptide substrate was
Lys-Lys-Leu-Asn-Arg-Thr-Leu-Ser-Val-Ala.
(Note)
[0295] % Reference=(X-B)/(Tot-B).times.100
% Inhibition=100%-% Reference
X=count per minute of the well with a test compound B=count per
minute of the well without the enzyme Tot=count per minute of the
well with only DMSO solvent and without a test compound
(Calculation of MAPKAP-K2 Inhibitory Activity)
[0296] IC50 value=a concentration of compound at which 50%
inhibition is observed The efficacy of each compound in Tables A to
G against MAPKAP-K2 is listed in the following Table J. (For
activity strength in the table, +++represents IC50 value <10
.mu.mol/L, ++represents 10 .mu.mol/L.ltoreq.IC50 value <50
.mu.mol/L and +represents 50 .mu.mol/L.ltoreq.IC50 value <100
.mu.mol/L.)
TABLE-US-00009 TABLE J Compound No. Activity strength A-001 +++
A-002 +++ A-003 ++ A-004 + A-005 +++ A-006 +++ A-007 + A-008 +++
A-009 +++ A-010 ++ A-012 ++ A-013 +++ A-014 + A-018 +++ A-019 ++
A-020 +++ A-022 +++ A-023 +++ A-024 +++ A-025 +++ A-026 +++ A-027
+++ A-032 +++ A-058 +++ A-091 +++ A-092 +++ A-095 +++ A-096 +++
A-099 +++ A-100 +++ B-001 +++ B-002 +++ B-003 ++ B-007 + B-013 +
B-014 +++ B-015 ++ B-016 ++ B-017 +++ B-018 + B-021 +++ B-022 ++
C-001 +++ D-001 ++ D-002 + D-003 + D-006 ++ F-001 +++ F-002 ++
G-001 +++
FIELD OF INDUSTRIAL APPLICATION
[0297] The compounds of the present invention are useful as
MAPKAP-K2 inhibitors. Further, by using the compounds of the
present invention as active ingredients, there is provided a
therapeutic agent for neurodegenerative and/or neurological
disorders (including dementia), inflammatory disease, sepsis,
autoimmune diseases, destructive osteopathy, diabetes mellitus,
cancer, ischemic reperfusion injury, angiodysplasia, cachexia,
obesity, angiogenesis, asthma and/or chronic obstructive pulmonary
disease (COPD).
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