U.S. patent application number 12/054337 was filed with the patent office on 2009-01-29 for pyrimidine compounds and medicinal composition thereof.
Invention is credited to Hitoshi Harada, Daisuke Iida, Yoshihiko Kotake, Junichi Nagakawa, Makoto Nakagawa, Masato Ueda, Masahiro Yasuda.
Application Number | 20090030023 12/054337 |
Document ID | / |
Family ID | 19140824 |
Filed Date | 2009-01-29 |
United States Patent
Application |
20090030023 |
Kind Code |
A1 |
Harada; Hitoshi ; et
al. |
January 29, 2009 |
PYRIMIDINE COMPOUNDS AND MEDICINAL COMPOSITION THEREOF
Abstract
A compound represented by the following formula (I), a salt, or
a solvate thereof: ##STR00001## wherein, R.sup.1 and R.sup.2 are
the same as or different from each other and each represents a
hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group,
a cycloalkyl group, a cycloalkenyl group, a non-aromatic
heterocyclic group, an aromatic hydrocarbon cyclic group, an
aromatic heterocyclic group, an acyl group or an alkylsulfonyl
group all of which may be substituted and wherein one, or both, of
R.sup.1 or R.sup.2 is an aromatic, or non-aromatic, heterocyclic
group which may be substituted; R.sup.3 represents a hydrogen atom,
a halogen atom, a cyano group, an alkyl group, an alkenyl group, an
alkynyl group, an aromatic hydrocarbon cyclic group, an aromatic
heterocyclic group, a nitrogen atom, an oxygen atom or a sulfur
atom all of which may be substituted if possible; and R.sup.4 is a
pyridyl group which may be substituted.
Inventors: |
Harada; Hitoshi; (Ibaraki,
JP) ; Ueda; Masato; (Ibaraki, JP) ; Kotake;
Yoshihiko; (Ibaraki, JP) ; Yasuda; Masahiro;
(Ibaraki, JP) ; Iida; Daisuke; (Ibaraki, JP)
; Nagakawa; Junichi; (Ibaraki, JP) ; Nakagawa;
Makoto; (Ibaraki, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
19140824 |
Appl. No.: |
12/054337 |
Filed: |
March 24, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10492905 |
Apr 16, 2004 |
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PCT/JP02/10952 |
Oct 22, 2002 |
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12054337 |
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Current U.S.
Class: |
514/275 ;
435/375; 544/297 |
Current CPC
Class: |
A61P 3/04 20180101; C07D
405/14 20130101; A61K 31/506 20130101; A61P 3/10 20180101; A61P
43/00 20180101; A61P 25/16 20180101; A61P 5/50 20180101; A61P 27/02
20180101; A61P 25/24 20180101; C07D 409/14 20130101; A61P 1/10
20180101; A61P 19/10 20180101; A61P 3/00 20180101; A61P 9/10
20180101; A61P 7/10 20180101; A61P 11/06 20180101; C07D 401/04
20130101; A61P 9/12 20180101; A61P 1/00 20180101; A61P 25/28
20180101; A61P 13/02 20180101; A61P 1/04 20180101 |
Class at
Publication: |
514/275 ;
544/297; 435/375 |
International
Class: |
C07D 239/42 20060101
C07D239/42; A61K 31/505 20060101 A61K031/505; C12N 5/00 20060101
C12N005/00; A61P 1/00 20060101 A61P001/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 22, 2001 |
JP |
2001-324018 |
Claims
1. A compound represented by the following formula (I), a salt
thereof, or a solvate thereof: ##STR00234## wherein, R.sup.1 and
R.sup.2 are the same as or different from each other and each
represents a hydrogen atom, an alkyl group having one to six carbon
atoms which may be substituted, analkenyl group having two to six
carbon atoms which may be substituted, an alkynyl group having two
to six carbon atoms which may be substituted, a cycloalkyl group
having three to eight carbon atoms which may be substituted, a
cycloalkenyl group having three to eight carbon atoms which may be
substituted, a 5 to 14-membered non-aromatic heterocyclic group
which may be substituted, an aromatic hydrocarbon cyclic group
having six to fourteen carbon atoms which may be substituted, a 5
to 14-membered aromatic heterocyclic group which may be
substituted, an acyl group having one to six carbon atoms which may
be substituted or an alkylsulfonyl group having one to six carbon
atoms which may be substituted and wherein one, or both, of R.sup.1
or R.sup.2 is a 5 to 14-membered aromatic, or non-aromatic,
heterocyclic group which may be substituted; R.sup.3 represents a
hydrogen atom, a halogen atom, a cyano group, an alkyl group having
one to six carbon atoms which may be substituted, an alkenyl group
having two to six carbon atoms which may be substituted, an alkynyl
group having two to six carbon atoms which may be substituted, an
aromatic hydrocarbon cyclic group having six to fourteen carbon
atoms which may be substituted, a 5 to 14-membered aromatic
heterocyclic group which may be substituted, a nitrogen atom which
may be substituted, an oxygen atom which may be substituted or a
sulfur atom which may be substituted; R.sup.4 is a pyridyl group
which may be substituted with one to four groups selected from the
following substituent group a: substituent group a the group
consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a
nitro group, a cyano group, an alkyl group having one to six carbon
atoms which may be substituted, analkenyl group having two to six
carbon atoms which may be substituted, an alkynyl group having two
to six carbon atoms which may be substituted, an alkoxy group
having one to six carbon atoms which may be substituted, an
alkenyloxy group having two to six carbon atoms which may be
substituted, an alkynyloxy group having two to six carbon atoms
which may be substituted, an alkylthio group having one to six
carbon atoms which may be substituted, an alkenylthio group having
two to six carbon atoms which may be substituted, an alkynylthio
group having two to six carbon atoms which may be substituted, an
aliphatic acyl group having two to seven carbon atoms, a carbamoyl
group which may be substituted, an arylacyl group, a heteroarylacyl
group, an amino group which may be substituted, an alkylsulfonyl
group having one to six carbon atoms which may be substituted, an
alkenylsulfonyl group having two to six carbon atoms which may be
substituted, an alkynylsulfonyl group having two to six carbon
atoms which may be substituted, an alkylsulfinyl group having one
to six carbon atoms which may be substituted, an alkenylsulfinyl
group having two to six carbon atoms which may be substituted, an
alkynylsulfinyl group having two to six carbon atoms which may be
substituted, a formyl group, a cycloalkyl group having three to
eight carbon atoms which may be substituted, a cycloalkenyl group
having three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted and a 5 to
14-membered aromatic heterocyclic group which may be substituted or
a pyridyl group which may be substituted with 1 to 4 groups
selected from the above substituent group a; and R.sup.5 represents
an aromatic hydrocarbon cyclic group having six to fourteen carbon
atoms which may be substituted or a 5 to 14-membered aromatic
heterocyclic group which may be substituted, provided that the
compound where R.sup.1, R.sup.2 and R.sup.3 are hydrogen atom,
R.sup.4 is 4-pyridyl and R.sup.5 being 4-fluorophenyl or furyl is
excluded.
2. A pharmaceutical composition comprising the compound according
to claim 1, a salt thereof or a solvate thereof.
3. A method for promoting defecation, which comprises administering
a pharmacologically effective amount of the compound according to
claim 1, a salt thereof or a solvate thereof to a patient in need
thereof.
4. The Compound according to claim 1, a salt thereof or a solvate
thereof, wherein R.sup.3 represents a hydrogen atom, an amino
group, a cyano group, or an alkyl group having one to six carbon
atoms, an alkoxyl group having one to six carbon atoms, phenyl, or
naphthyl, each of which may be substituted.
5. The compound according to claim 1, a salt thereof or a solvate
thereof, wherein R.sup.3 is a hydrogen atom.
6. The compound according to claim 1, a salt thereof or a solvate
thereof, wherein R.sup.5 represents a phenyl, 2-furyl or 3-furyl,
each of which may be substituted.
7. The compound according to claim 1, a salt thereof or a solvate
thereof, wherein R.sup.5 represents a phenyl, or 2-furyl, each of
which may be substituted.
8. The compound according to claim 1, a salt thereof or a solvate
thereof, wherein the Substituent group a consists of a hydrogen
atom, a halogen atom, an alkyl group having one to six carbon atoms
which may be substituted, an alkenyl group having two to six carbon
atoms which may be substituted, an alkynyl group having two to six
carbon atoms which may be substituted, an alkoxy group having one
to six carbon atoms which may be substituted, a carbamoyl group
which may be substituted, and an amino group which may be
substituted.
9. A method for treating Parkinson's disease or depression
comprising administering a pharmacologically effective amount of a
compound according to claim 1, a salt thereof or a solvate thereof,
to a patient in need thereof.
10. A method for treating constipation comprising administering a
pharmacologically effective amount of a compound according to claim
1, a salt thereof or a solvate thereof, to a patient in need
thereof.
11. The method of claim 10, wherein the constipation is functional
constipation.
12. A method for treating irritable bowel syndrome, constipation
accompanying irritable bowel syndrome, organic constipation,
constipation accompanying enteroparalytic ileus, constipation
accompanying congenital digestive tract dysfunction or constipation
accompanying ileus comprising administering a pharmacologically
effective amount of a compound according to claim 1, a salt thereof
or a solvate thereof, to a patient in need thereof.
13. A method for evacuating intestinal tracts at the time of
examination of digestive tracts or before and after an operation
comprising administering a pharmacologically effective amount of a
compound according to claim 1, a salt thereof or a solvate thereof,
to a patient in need thereof.
14. A method for antagonizing an adenosine A.sub.2 receptor in
vitro comprising administering a compound according to claim 1, a
salt thereof or a solvate thereof, to an adenosine A.sub.2 receptor
in vitro.
15. A method for antagonizing an adenosine A.sub.2A receptor in
vitro comprising administering a compound according to claim 1, a
salt thereof or a solvate thereof, to an adenosine A.sub.2A
receptor in vitro.
16. A method for antagonizing an adenosine A.sub.2B receptor in
vitro comprising administering a compound according to claim 1, a
salt thereof or a solvate thereof, to an adenosine A.sub.2B
receptor in vitro.
Description
[0001] This application is a divisional of U.S. application Ser.
No. 10/492,905, filed Apr. 16, 2004, which is the national phase
under 35 U.S.C. .sctn. 371 of PCT International Application No.
PCT/JP02/10952 which has an International filing date of Oct. 22,
2002, which designated the United States of America, and for which
priority is claimed under 35 U.S.C .sctn. 119 on Japanese Patent
Application No. 2001-324018, filed Oct. 22, 2001. The entire
contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates to a novel pyrimidine
compound, a production process thereof, and a pharmaceutical
preparation containing it and use thereof.
PRIOR ART
[0003] Adenosine is an important regulatory factor involved in many
intracellular metabolisms in the living body such as regulation of
energy levels, cAMP levels, opening and closing potassium channels,
and inflow of calcium ions into cells, and its interaction with G
protein-coupled adenosine receptors on the surface of a cell is
essential for exhibiting these physiological activities. Adenosine
receptors were classified under two subtypes, A.sub.1 receptor and
A.sub.2 receptor based on the involvement in adenylate cyclase (J.
Neurochem., 33, 999-1003, (1979)), and thereafter, the A.sub.2
receptor has been classified under two subtypes, A.sub.2A and
A.sub.2B, based on the affinity for A.sub.2 receptor agonists, NECA
and CGS-21680 (Mol. Pharmacol., 29, 331-346, (1986); J. Neurochem.,
55, 1763-1771, (1990)). Four receptor subtypes, A.sub.1, A.sub.2
(A.sub.2A and A.sub.2B) and A.sub.3, have been identified until
now. The A.sub.1 receptor is a protein coupled with G.sub.i/o
family proteins. It serves to inhibit the adenylate cyclase as a
result of binding with a ligand to thereby decrease the CAMP level
and serves to activate phospholipase C (PLC) to thereby promote the
production of inositol-1,4,5-triphosphate (IP.sub.3) and to release
the intracellular calcium ions. The A.sub.3 receptor is a receptor
serving to decrease the cAMP level and to activate PLC to thereby
promote the IP.sub.3 production and the release of calcium ions, as
the A.sub.1 receptor. In contrast, the A.sub.2A and A.sub.2B
receptors are receptors serving to activate the adenylate cyclase
and promote the production of CAMP. There is a report that the
A.sub.2B receptor couples with PLC via a G.sub.q/G.sub.11 protein
or promotes the production of IP.sub.3 and the flow of calcium ions
into cells (J. Clin. Invest., 96, 1979-1986 (1995)). These subtypes
are different from one another in their distribution in tissues;
that is, the A.sub.1 receptor occurs relatively abundantly, for
example, in the heart, aorta and bladder, the A.sub.2A receptor is
distributed relatively abundantly, for example, in the eyeballs and
skeletal muscles, the A.sub.3 receptor, for example, in the spleen,
uterus, and prostate, and the A.sub.2B receptor, for example, in
the proximal colon, and subsequently in the eyeballs, lung, uterus
and bladder (Br. J. Pharmacol., 118, 1461-1468 (1996)). It is
believed that these adenosine receptor subtypes can exhibit
specific functions, respectively, due to the difference in
distribution in the tissues as well as the difference in adenosine
level among the locations and the difference in affinity for the
ligand among the subtypes. Adenosine is involved in a variety of
physiological functions such as platelet aggregation, heart rate,
smooth muscle tonus, inflammation, release of neurotransmitters,
neurotransmission, hormone release, cell-differentiation, cell
growth, cell death, and DNA biosynthesis. Accordingly, the relation
between adenosine and diseases such as central nervous system
diseases, cardiovascular diseases, inflammatory diseases,
respiratory diseases, and immune diseases has been suggested, and
the efficacy of agonists/antagonists of the adenosine receptors on
these diseases has been expected. Antagonists against the adenosine
receptors, particularly those against the adenosine A.sub.2
receptor have been discussed as effective as an agent for treating
or preventing diabetes mellitus, diabetic complications, diabetic
retinopathy, obesity or asthma and have been expected useful as,
for example, a hypoglycemic agent an agent for improving glucose
intolerance, an insulin sensitizer, a hypotensive agent, a diuretic
agent, an antidepressant, an agent for treating osteoporosis, an
agent for treating Parkinson's disease, an agent for treating
Alzheimer's disease, an agent for treating an inflammatory bowel
disease, or an agent for treating Crohn's disease.
[0004] Certain important reports have been made on the relation
between the adenosine A.sub.2 receptor and the intestinal tract.
For example, certain reports have been made that the A.sub.2
receptor mediates a colon longitudinal muscle relaxation action
(Naunyn-Schmiedeberg's Arch. Pharmacol., 359, 140-146 (1999)), and
that the A.sub.1 receptor, and the A.sub.2B receptor occurring in
the longitudinal muscle mediate a relaxation action of adenosine
against the contraction of distal colon longitudinal muscle of a
guinea pig (Br. J. Pharmacol., 129, 871-876 (2000)). Such A.sub.2B
receptor antagonists do not induce diarrhea, have an excellent
defecation-promoting action and are expected as an agent for
treating and/or preventing various constipation. They are also
expected as being useful for treating and/or preventing irritable
bowel syndrome, constipation accompanying irritable bowel syndrome,
organic constipation or constipation accompanying enteroparalytic
ileus and for evacuating intestinal tracts at the time of
examination of digestive tracts or before and after an
operation.
[0005] Furthermore, in the formation of clinical condition of
Parkinson's disease, it has been importantly reported that,
adenosine is extremely closely involved through the adenosine
A.sub.2A receptor in addition to dopamine. For instance, it has
been reported that the effects for improving the symptoms of
Parkinson's disease will be enhanced by use of L-DOPA together with
theophylline which is known as a non-selective adenosine receptor
antagonist (J. Pharm. Pharmacol., 46, 515-517, (1994)). Also, it
has been reported that selective adenosine A.sub.2A receptor
Antagonists are effective to various kinds of Parkinson's disease
animal models (JP 1994-211856 A) Parkinson's disease is caused by
the degradation or death of dopaminergic neurons projected from the
compact layer of midbrain substantia nigra to the corpus striatum.
Although the progress of the disease cannot be prevented, the
symptomatic treatment with L-DOPA preparations is nevertheless a
fundamental treatment making up for a shortage to dompamine.
However, the long-term usage of the L-DOPA preparations will reduce
the effectiveness thereof and produce some side effects such as
involuntary movements and mental symptoms. Therefore, the biggest
problem is that sufficient therapeutic effects cannot be attained
by the L-DOPA preparations.
[0006] The distribution of adenosine A.sub.2A receptors in the
brain is confined in the corpus striatum, nucleus accumbens, and
olfactory tubercle (Eur. J. Pharmacol., 168, 243-246 (1989)), so
that the adenosine A.sub.2A receptors have been estimated to play
an important role in motor function control in the corpus striatum.
In addition, it has been reported that the degradation of
dopaminergic neurons in the compact layer of midbrain substantia
nigra does not affect the adenosine A.sub.2A receptor binding
ability of the corpus striatum and there is no difference between
Parkinson's disease subjects and normal healthy subjects with
respect to the total number of adenosine A.sub.2A receptors
(Neuroscience, 42, 697-706, 1991). Recently, it has been also
reported that selective adenosine A.sub.2A receptor antagonists are
harmless and improve the motor functions of the subjects suffering
from progressive Parkinson's disease without exaggerating
dyskinesia with L-DOPA preparations (Neurology, 58 (suppl. 3)
S21.001 (2002.4)). As is evident from these findings, it is
expected that the adenosine A.sub.2A receptor antagonists are
useful as therapeutic agents for Parkinson's disease.
[0007] Following compounds have been reported as those having
antagonistic action on adenosine A.sub.2A and/or adenosine A.sub.2B
receptors:
(1) Compounds represented by the following formulae:
##STR00002## ##STR00003##
(2) A purine derivative represented by the formula:
##STR00004##
(wherein R.sup.1 represents (1) the formula:
##STR00005##
(wherein X represents a hydrogen atom, a hydroxyl group, a lower
alkyl group which may be substituted, a lower alkoxy group which
may be substituted, etc.; and R.sup.5 and R.sup.6 are the same as
or different from each other and each represents a hydrogen atom, a
lower alkyl group which may be substituted, a saturated or
unsaturated cycloalkyl group having three to eight carbon atoms
which may be substituted, etc.) or (2) a 5 or 6-membered aromatic
ring which may have one or more substituents and a hetero atom; W
represents the formula: --CH.sub.2CH.sub.2--, --CH.dbd.CH-- or
--C.ident.C--; R.sup.2 represents an amino group which may be
substituted with a lower alkyl group which may be substituted,
etc.; R.sup.3 represents a cycloalkyl group having three to eight
carbon atoms which may be substituted, an aryl group which may be
substituted, etc.; and R.sup.4 represents a lower alkyl group which
may be substituted, etc.), a pharmacologically acceptable salt
thereof or a hydrate of them (JP-A 11-263789). (3) A purine
compound represented by the formula:
##STR00006##
(wherein R.sup.1 represents a hydrogen atom, a hydroxyl group, a
halogen atom, an alkyl group having one to eight carbon atoms which
may be substituted, etc.; R.sup.2 represents an amino group which
may be substituted with an alkyl group having one to eight carbon
atoms, etc.; R.sup.3 represents an alkynyl group having three to
eight carbon atoms which may be substituted with a halogen atom, a
hydroxyl group or an alkyl group having one to four carbon atoms,
etc.; Ar represents an aryl group which may be substituted, a
heteroaryl group which may be substituted, etc.; and Q and W are
the same as or different from each other and each represents N or
CH), a pharmacologically acceptable salt thereof or a hydrate of
them (JP-A 11-188484). (4) A.sub.2B receptor antagonists described
in Drug Development Research, 48: 95-103 (1999) and J. Med. Chem.,
43: 1165-1172 (2000). (5) A.sub.2A receptor antagonists represented
by the following formula:
##STR00007##
(JP-A 6-211856).
[0008] As pyrimidine compounds, there are only reports relating to
5,6-aromatic substituted pyrimidine compounds in publications such
as WO97/33883, WO98/24782 and WO99/65897. However, the relation
between these compounds and the adenosine receptors has been
neither reported nor suggested and has not yet been known.
[0009] As is described above, compounds having an adenosine
receptor antagonism, among them, compounds having an adenosine
A.sub.2 receptor antagonism, that is compounds having an A.sub.2A
and/or A.sub.2B receptor antagonism are expected to exhibit an
excellent action as a medicament, and strong demands have been made
to provide such compounds. However, compounds which have an
excellent antagonism against the adenosine receptors and
effectively act as a medicament have not yet been found.
Accordingly, an object of the present invention is to search for
and find compounds which serve to inhibit the adenosine receptors
(A.sub.2A and A.sub.2B receptors) and are useful as an agent for
treating or preventing a disease to which the adenosine receptors
relate.
DISCLOSURE OF THE INVENTION
[0010] After intensive investigations under these circumstances,
the present inventors have succeeded, for the first time, to
synthesize a compound represented by the formula:
##STR00008##
(in the formula, R.sup.1 and R.sup.2 are the same as or different
from each other and each represents a hydrogen atom, an alkyl group
having one to six carbon atoms which may be substituted, analkenyl
group having two to six carbon atoms which may be substituted, an
alkynyl group having two to six carbon atoms which may be
substituted, a cycloalkyl group having three to eight carbon atoms
which may be substituted, a cycloalkenyl group having three to
eight carbon atoms which may be substituted, a 5 to 14-membered
non-aromatic heterocyclic group which may be substituted, an
aromatic hydrocarbon cyclic group having six to fourteen carbon
atoms which may be substituted, a 5 to 14-membered aromatic
heterocyclic group which may be substituted, an acyl group having
one to six carbon atoms which may be substituted or an
alkylsulfonyl group having one to six carbon atoms which may be
substituted; R.sup.3 represents a hydrogen atom, a halogen atom, a
cyano group, an alkyl group having one to six carbon atoms which
may be substituted, an alkenyl group having two to six carbon atoms
which may be substituted, an alkynyl group having two to six carbon
atoms which may be substituted, an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted,
a 5 to 14-membered aromatic heterocyclic group which may be
substituted, a nitrogen atom which may be substituted, an oxygen
atom which may be substituted or a sulfur atom which may be
substituted; R.sup.4 represents an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted,
a 5 to 14-membered aromatic heterocyclic group which may be
substituted or a 5 to 14-membered non-aromatic heterocyclic group
having at least one or more unsaturated bonds which may be
substituted; and R.sup.5 represents an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted
or a 5 to 14-membered aromatic heterocyclic group which may be
substituted), a salt thereof or a solvate of them. They have
unexpectedly found that the compound, a salt thereof or a solvate
them have an excellent antagonism against the adenosine A.sub.2
receptors, that is against the A.sub.2A and/or A.sub.2B receptor.
After further intensive investigations, they have found that the
compound, a salt thereof or a solvate of them has a remarkable
efficacy on diseases to which the adenosine receptors, particularly
the adenosine A.sub.2 receptors, further particularly the adenosine
A.sub.2A and/or A.sub.2B receptor relates, and that it is
efficacious for preventing and/or treating various constipation
(constipation, irritable bowel syndrome, constipation accompanying
irritable bowel syndrome, organic constipation, constipation
accompanying enteroparalytic ileus, constipation accompanying
congenital digestive tract dysfunction, or constipation
accompanying ileus) and is also useful as an agent for treating,
preventing or improving, for example, diabetes mellitus, diabetic
complications, diabetic retinopathy, obesity or asthma, and as a
hypoglycemic agent, an agent for improving glucose intolerance, an
insulin sensitizer, a hypotensive agent, a diuretic agent, an
antidepressant, an agent for treating osteoporosis, an agent for
treating Parkinson's disease, an agent for treating Alzheimer's
disease, an agent for treating an inflammatory intestinal disease
or an agent for treating Crohn's disease. The present invention has
been accomplished based on these findings.
[0011] That is, the present invention relates to (1) a compound
represented by the formula:
##STR00009##
(in the formula, R.sup.1 and R.sup.2 are the same as or different
from each other and each represents a hydrogen atom, an alkyl group
having one to six carbon atoms which may be substituted, analkenyl
group having two to six carbon atoms which may be substituted, an
alkynyl group having two to six carbon atoms which may be
substituted, a cycloalkyl group having three to eight carbon atoms
which may be substituted, a cycloalkenyl group having three to
eight carbon atoms which may be substituted, a 5 to 14-membered
non-aromatic heterocyclic group which may be substituted, an
aromatic hydrocarbon cyclic group having six to fourteen carbon
atoms which may be substituted, a 5 to 14-membered aromatic
heterocyclic group which may be substituted, an acyl group having
one to six carbon atoms which may be substituted or an
alkylsulfonyl group having one to six carbon atoms which may be
substituted; R.sup.3 represents a hydrogen atom, a halogen atom, a
cyano group, an alkyl group having one to six carbon atoms which
may be substituted, an alkenyl group having two to six carbon atoms
which may be substituted, an alkynyl group having two to six carbon
atoms which may be substituted, an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted,
a 5 to 14-membered aromatic heterocyclic group which may be
substituted, a nitrogen atom which may be substituted, an oxygen
atom which may be substituted or a sulfur atom which may be
substituted; R.sup.4 represents an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted,
a 5 to 14-membered aromatic heterocyclic group which may be
substituted or a 5 to 14-membered non-aromatic heterocyclic group
having at least one or more unsaturated bonds which may be
substituted; and R.sup.5 represents an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted
or a 5 to 14-membered aromatic heterocyclic group which may be
substituted), a salt thereof or a solvate of them; (2) the compound
described in (1), a salt thereof or a solvate of them, wherein
R.sup.1 and R.sup.2 are the same as or different from each other
and each represents a hydrogen atom, an alkyl group having one to
six carbon atoms which may be substituted, an alkenyl group having
two to six carbon atoms which may be substituted, an alkynyl group
having two to six carbon atoms which may be substituted, a
cycloalkyl group having three to eight carbon atoms which may be
substituted, a cycloalkenyl group having three to eight carbon
atoms which may be substituted, a 5 to 14-membered non-aromatic
heterocyclic group which may be substituted, an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted, a 5 to 14-membered aromatic heterocyclic group
which may be substituted, an acyl group having one to six carbon
atoms which may be substituted or an alkylsulfonyl group having one
to six carbon atoms which may be substituted (provided that a group
represented by the formula:
##STR00010##
(wherein A represents an aromatic hydrocarbon cyclic group having
six to fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
X.sup.1 and X.sup.2 are the same as or different from each other
and each represents a carbon atom which may be substituted; and
X.sup.3 represents a nitrogen atom which may be substituted, an
oxygen atom, or a carbon atom which may be substituted) is
excluded); R.sup.3 represents a cyano group; and R.sup.4 represents
an aromatic hydrocarbon cyclic group having six to fourteen carbon
atoms which may be substituted, a 5 to 14-membered aromatic
heterocyclic group which may be substituted or a 5 to 14-membered
non-aromatic heterocyclic group having one or more unsaturated
bonds which may be substituted; (3) the compound described in (1),
a salt thereof or a solvate of them, wherein R.sup.1 and R.sup.2
are the same as or different from each other and each represents a
hydrogen atom, an alkyl group having one to six carbon atoms which
may be substituted, an alkenyl group having two to six carbon atoms
which may be substituted, an alkynyl group having two to six carbon
atoms which may be substituted, a cycloalkyl group having three to
eight carbon atoms which may be substituted, a cycloalkenyl group
having three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted, a 5 to 14-membered
aromatic heterocyclic group which may be substituted, an acyl group
having one to six carbon atoms which may be substituted or an
alkylsulfonyl group having one to six carbon atoms which may be
substituted (provided that a group represented by the formula:
##STR00011##
(wherein A represents an aromatic hydrocarbon cyclic group having
six to fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
X.sup.1 and X.sup.2 are the same as or different from each other
and each represents a carbon atom which may be substituted; and
X.sup.3 represents a nitrogen atom which may be substituted, an
oxygen atom or a carbon atom which may be substituted) is
excluded); R.sup.3 represents a halogen atom, an alkyl group having
one to six carbon atoms which may be substituted, an alkenyl group
having two to six carbon atoms which may be substituted, an alkynyl
group having two to six carbon atoms which may be substituted, an
aromatic hydrocarbon cyclic group having six to fourteen carbon
atoms which may be substituted, a 5 to 14-membered aromatic
heterocyclic group which may be substituted, an oxygen atom which
may be substituted or a sulfur atom which may be substituted; and
R.sup.4 represents a 4-pyridyl group, a 4-pyrimidinyl group, a
4-quinazolinyl group, a 4-quinolyl group or a 6-isoquinolinyl, each
of which may have one or two substituents; (4) the compound
described in (1), a salt thereof or a solvate of them, wherein
R.sup.1 and R.sup.2 are the same as or different from each other
and each represents a hydrogen atom, an alkyl group having one to
six carbon atoms which may be substituted, an alkenyl group having
two to six carbon atoms which may be substituted, an alkynyl group
having two to six carbon atoms which may be substituted, a
cycloalkyl group having three to eight carbon atoms which may be
substituted, a cycloalkenyl group having three to eight carbon
atoms which may be substituted, a 5 to 14-membered non-aromatic
heterocyclic group which may be substituted, an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted, a 5 to 14-membered aromatic heterocyclic group
which may be substituted, an acyl group having one to six carbon
atoms which may be substituted or an alkylsulfonyl group having one
to six carbon atoms which may be substituted (provided that a group
represented by the formula:
##STR00012##
(wherein A represents an aromatic hydrocarbon cyclic group having
six to fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
X.sup.1 and X.sup.2 are the same as or different from each other
and each represents a carbon atom which may be substituted; and
X.sup.3 represents a nitrogen atom which may be substituted, an
oxygen atom or a carbon atom which may be substituted) is
excluded); and R.sup.4 represents a 5 to 14-membered non-aromatic
heterocyclic group having at least one or more unsaturated bonds
which may be substituted (provided that the group represented by
the above formula (II) is excluded); (5) the compound described in
(1), a salt thereof or a solvate of them, wherein R.sup.1 and
R.sup.2 are the same as or different from each other and each
represents a hydrogen atom, an alkyl group having one to six carbon
atoms which may be substituted, an alkenyl group having two to six
carbon atoms which may be substituted, an alkynyl group having two
to six carbon atoms which may be substituted, a cycloalkyl group
having three to eight carbon atoms which may be substituted, a
cycloalkenyl group having three to eight carbon atoms which may be
substituted, a 5 to 14-membered non-aromatic heterocyclic group
which may be substituted, an aromatic hydrocarbon cyclic group
having six to fourteen carbon atoms which may be substituted, a 5
to 14-membered aromatic heterocyclic group which may be
substituted, an acyl group having one to six carbon atoms which may
be substituted or an alkylsulfonyl group having one to six carbon
atoms which may be substituted (provided that a group represented
by the formula:
##STR00013##
(wherein A represents an aromatic hydrocarbon cyclic group having
six to fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
X.sup.1 and X.sup.2 are the same as or different from each other
and each represents a carbon atom which may be substituted; and
X.sup.3 represents a nitrogen atom which may be substituted, an
oxygen atom or a carbon atom which may be substituted) is
excluded); and R.sup.4 represents a 4-pyridyl group, a
4-pyrimidinyl group, a 4-quinazolinyl group, a 4-quinolyl group or
a 6-isoquinolinyl, each of which may have one or two substituents
including at least one of a cyano group and a carbamoyl group
represented by the formula:
##STR00014##
(wherein R.sup.6 and R.sup.7 are the same as or different from each
other and each represents a hydrogen atom, an alkyl group having
one to six carbon atoms which may be substituted, an alkenyl group
having two to six carbon atoms which may be substituted, an alkynyl
group having two to six carbon atoms which may be substituted, a
cycloalkyl group having three to eight carbon atoms which may be
substituted, a cycloalkenyl group having three to eight carbon
atoms which may be substituted, a 5 to 14-membered non-aromatic
heterocyclic group which may be substituted, an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted); (6) the compound described in (2),
a salt thereof or a solvate of them, wherein R.sup.4 represents a 5
to 14-membered aromatic heterocyclic group which may be substituted
or a 5 to 14-membered non-aromatic heterocyclic group having at
least one or more unsaturated bonds which may be substituted; and
R.sup.5 represents a 5 to 14-membered aromatic heterocyclic group
which may be substituted; (7) the compound described in (3), a salt
thereof or a solvate of them, wherein R.sup.3 represents a halogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a 5 to 14-membered aromatic heterocyclic
group which may be substituted, an oxygen atom which may be
substituted or a sulfur atom which may be substituted; and R.sup.5
represents a 5 to 14-membered aromatic heterocyclic group which may
be substituted; (8) the compound described in (4), a salt thereof
or a solvate of them, wherein R.sup.3 represents a hydrogen atom, a
halogen atom, a cyano group, an alkyl group having one to six
carbon atoms which may be substituted, an alkenyl group having two
to six carbon atoms which may be substituted, an alkynyl group
having two to six carbon atoms which may be substituted, a 5 to
14-membered aromatic heterocyclic group which may be substituted, a
nitrogen atom which may be substituted, an oxygen atom which may be
substituted or a sulfur atom which may be substituted; and R.sup.5
represents a 5 to 14-membered aromatic heterocyclic group which may
be substituted; (9) the compound described in (5), a salt thereof
or a solvate of them, wherein R.sup.3 represents a hydrogen atom, a
halogen atom, a cyano group, an alkyl group having one to six
carbon atoms which may be substituted, an alkenyl group having two
to six carbon atoms which may be substituted, an alkynyl group
having two to six carbon atoms which may be substituted, a 5 to 14
membered aromatic heterocyclic group which may be substituted, an
oxygen atom which may be substituted or a sulfur atom which may be
substituted; and R.sup.5 represents a 5 to 14-membered aromatic
heterocyclic group which may be substituted; (10) the compound
described in any one of (1) to (9), wherein R.sup.1 and/or R.sup.2
represents a hydrogen atom, an alkyl group having one to six carbon
atoms which may be substituted or an acyl group having one to six
carbon atoms which may be substituted (provided that a group
represented by the formula:
##STR00015##
(wherein A represents an aromatic hydrocarbon cyclic group having
six to fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
X.sup.1 and X.sup.2 are the same as or different from each other
and each represents a carbon atom which may be substituted; and
X.sup.3 represents a nitrogen atom which may be substituted, an
oxygen atom, or a carbon atom which may be substituted) is
excluded), a salt thereof or a solvate of them; (11) the compound
described in any one of (1), (4) and (8), wherein R.sup.4 is a
group represented by the formula (IV):
##STR00016##
(wherein R.sup.8 represents a group selected from the following
substituent group a; and the ring B may be substituted with one to
four groups selected from the following substituent group a.
Substituent Group a
[0012] The group consisting of a hydrogen atom, a halogen atom, a
hydroxyl group, a nitro group, a cyano group, an alkyl group having
one to six carbon atoms which may be substituted, analkenyl group
having two to six carbon atoms which may be substituted, an alkynyl
group having two to six carbon atoms which may be substituted, an
alkoxy group having one to six carbon atoms which may be
substituted, an alkenyloxy group having two to six carbon atoms
which may be substituted, an alkynyloxy group having two to six
carbon atoms which may be substituted, an alkylthio group having
one to six carbon atoms which may be substituted, an alkenylthio
group having two to six carbon atoms which may be substituted, an
alkynylthio group having two to six carbon atoms which may be
substituted, an aliphatic acyl group having two to seven carbon
atoms, a carbamoyl group which may be substituted, an arylacyl
group, a heteroarylacyl group, an amino group which may be
substituted, an alkylsulfonyl group having one to six carbon atoms
which may be substituted, an alkenylsulfonyl group having two to
six carbon atoms which may be substituted, an alkynylsulfonyl group
having two to six carbon atoms which may be substituted, an
alkylsulfinyl group having one to six carbon atoms which may be
substituted, an alkenylsulfinyl group having two to six carbon
atoms which may be substituted, an alkynylsulfinyl group having two
to six carbon atoms which may be substituted, a formyl group, a
cycloalkyl group having three to eight carbon atoms which may be
substituted, a cycloalkenyl group having three to eight carbon
atoms which may be substituted, a 5 to 14-membered non-aromatic
heterocyclic group which may be substituted, an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted and a 5 to 14-membered aromatic heterocyclic
group which may be substituted), a salt thereof or a solvate of
them; (12) the compound described in (11), a salt thereof or a
solvate of them, wherein R.sup.3 is a hydrogen atom, a halogen
atom, a cyano group, an alkyl group having one to six carbon atoms
which may be substituted, a 5 to 14-membered aromatic heterocyclic
group which may be substituted, an amino group or an oxygen atom
which may be substituted; (13) the compound described in (11) or
(12), wherein R.sup.4 is a group represented by the formula:
##STR00017##
or the formula:
##STR00018##
(in the formulae (V) and (VI), R.sup.8 represents a group selected
from the following substituent group a; and the ring B may be
substituted with one to four groups selected from the following
substituent group a.
Substituent Group a
[0013] The group consisting of a hydrogen atom, a halogen atom, a
hydroxyl group, a nitro group, a cyano group, an alkyl group having
one to six carbon atoms which may be substituted, analkenyl group
having two to six carbon atoms which may be substituted, an alkynyl
group having two to six carbon atoms which may be substituted, an
alkoxy group having one to six carbon atoms which may be
substituted, an alkenyloxy group having two to six carbon atoms
which may be substituted, an alkynyloxy group having two to six
carbon atoms which may be substituted, an alkylthio group having
one to six carbon atoms which may be substituted, an alkenylthio
group having two to six carbon atoms which may be substituted, an
alkynylthio group having two to six carbon atoms which may be
substituted, an aliphatic acyl group having two to seven carbon
atoms, a carbamoyl group which may be substituted, an arylacyl
group, a heteroarylacyl group, an amino group which may be
substituted, an alkylsulfonyl group having one to six carbon atoms
which may be substituted, an alkenylsulfonyl group having two to
six carbon atoms which may be substituted, an alkynylsulfonyl group
having two to six carbon atoms which may be substituted, an
alkylsulfinyl group having one to six carbon atoms which may be
substituted, an alkenylsulfinyl group having two to six carbon
atoms which may be substituted, an alkynylsulfinyl group having two
to six carbon atoms which may be substituted, a formyl group, a
cycloalkyl group having three to eight carbon atoms which may be
substituted, a cycloalkenyl group having three to eight carbon
atoms which may be substituted, a 5 to 14-membered non-aromatic
heterocyclic group which may be substituted, an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms and a
5 to 14-membered aromatic heterocyclic group which may be
substituted), a salt thereof or a solvate of them; (14) the
compound described in any one of (1), (3) and (7), a salt thereof
or a solvate of them, wherein R.sup.4 is 4-pyridyl group which may
have one or two substituents; (15) the compound described in (14),
a salt thereof or a solvate of them, wherein R.sup.3 is a halogen
atom, a cyano group, an alkyl group having one to six carbon atoms
which may be substituted, a 5 to 14-membered aromatic heterocyclic
group which may be substituted or an oxygen atom which may be
substituted; (16) the compound described in (14) or (15), wherein
R.sup.4 is a 4-pyridyl group which may have one or two substituents
comprising at least one of a cyano group and a carbamoyl group
represented by the formula (III):
##STR00019##
(wherein R.sup.6 and R.sup.7 are the same as or different from each
other and each represents a hydrogen atom, an alkyl group having
one to six carbon atoms which may be substituted, an alkenyl group
having two to six carbon atoms which may be substituted, an alkynyl
group having two to six carbon atoms which may be substituted, a
cycloalkyl group having three to eight carbon atoms which may be
substituted, a cycloalkenyl group having three to eight carbon
atoms which may be substituted, a 5 to 14-membered non-aromatic
heterocyclic group which may be substituted, an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted), a salt thereof or a solvate of
them; (17) the compound described in any one of (1) to (5), a salt
thereof or a solvate of them, wherein R.sup.5 is a naphthyl group
or a phenyl group, each of which may be substituted; (18) the
compound described in any one of (1) to (16), a salt thereof or a
solvate of them, wherein R.sup.5 is pyrrolyl group, pyridyl group,
pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl
group, thiazolyl group, furyl group, quinolinyl group,
isoquinolinyl group, phthalazinyl group, naphthyridinyl group,
indolyl group or isoindolyl group, each of which may be
substituted; (19) a pharmaceutical composition comprising the
compound described in any one of (1) to (18), a salt thereof or a
solvate of them; (20) the composition described in (19), which is
an agent for treating or preventing a disease to which an adenosine
receptor relates; (21) the composition described in (19), which is
an agent for treating or preventing a disease to which an adenosine
A.sub.2 receptor relates; (22) the composition described in (19),
which is an agent for treating or preventing a disease to which an
adenosine A.sub.2A receptor relates; (23) the composition described
in (19), which is an agent for treating or preventing a disease to
which an adenosine A.sub.2B receptor relates; (24) the composition
described in (19), which is an adenosine receptor antagonist; (25)
the composition described in (19), which is an adenosine A.sub.2
receptor antagonist; (26) the composition described in (19), which
is adenosine A.sub.2A receptor antagonist; (27) the composition
described in (19), which is adenosine A.sub.2B receptor antagonist;
(28) the composition described in any one of (19) to (22), (24) to
(26), which is an agent for treating Parkinson's disease or an
antidepressant; (29) the composition described in any one of (19)
to (21), (23) to (25) and (27), which is a defecation-promoting
agent; (30) the composition described in any one of (19) to (21),
(23) to (25) and (27), which is an agent for treating, preventing
or improving constipation; (31) the composition described in (30),
wherein the constipation is functional constipation; (32) the
composition described in (30), which is an agent for treating,
preventing or improving irritable bowel syndrome, constipation
accompanying irritable bowel syndrome, organic constipation,
constipation accompanying enteroparalytic ileus, constipation
accompanying congenital digestive tract dysfunction or constipation
accompanying ileus; (33) the composition described in (19), which
is used for evacuating intestinal tracts at the time of examination
of digestive tracts or before and after an operation; (34) use of
the compound described in any one of (1) to (18), a salt thereof or
a solvate of them for producing a defecation-promoting agent; (35)
the composition described in (19), which is an agent for treating
or preventing diabetes mellitus, diabetic complications, diabetic
retinopathy, obesity or asthma; (36) the composition described in
(19), which is a hypoglycemic agent, an agent for improving glucose
intolerance or an insulin sensitizer; and (37) the composition
described in (19), which is a hypotensive agent, a diuretic agent,
an agent for treating osteoporosis, an agent for treating
Alzheimer's disease, an agent for treating an inflammatory bowel
disease or an agent for treating Crohn's disease.
[0014] Hereinafter, the meanings of symbols, terms, etc. used in
the present description will be described, and the present
invention will be illustrated in detail.
[0015] In the present description, the "antagonist" refers to an
agent which has affinity for and inactivates an adenosine receptor,
preferably an adenosine A.sub.2 receptor, that is, an A.sub.2A
and/or A.sub.2B receptor.
[0016] The "disease to which an adenosine receptor relates" used in
the present description refers to a disease to which an adenosine
A.sub.1 receptor, A.sub.2A receptor, A.sub.2B receptor or A.sub.3
receptor relates, and includes various constipation (e.g.,
functional constipation, irritable bowel syndrome, constipation
accompanying irritable bowel syndrome, organic constipation,
constipation accompanying enteroparalytic ileus, constipation
accompanying congenital digestive tract dysfunction and
constipation accompanying ileus), diabetes mellitus, diabetic
complications, diabetic retinopathy, obesity, asthma, as well as
diseases against which a hypoglycemic agent, agent for improving
glucose intolerance, insulin sensitizer, antihypertensive drug,
diuretic agent, antidepressant, agent for treating osteoporosis,
agent for treating Parkinson's disease, agent for treating
Alzheimer's disease, agent for treating an inflammatory bowel
disease or agent for treating Crohn's disease is efficacious.
[0017] The present invention provides a method for treating or
preventing a disease to which an adenosine receptor relates, and a
method for promoting defecation, which comprises administering a
pharmacologically effective dose of the compound represented by the
formula (I), a salt thereof or a solvate of them to a patient.
[0018] The present invention further provides use of the compound
represented by the formula (I), a salt thereof or a solvate of them
for producing an agent for treating or preventing a disease to
which an adenosine receptor relates, or a defecation-promoting
agent.
[0019] The compound represented by the formula (I), a salt thereof
or a solvate of them is also useful as a defecation-promoting agent
and is used for evacuating intestinal tracts at the time of
examination of digestive tracts or before and after an
operation.
[0020] The term "and/or" used in the present description means and
includes both the cases of "and" and "or".
[0021] In the present description, there is the case where the
structural formula of a compound represents a definite isomer for
the sake of convenience. However, the present invention includes
all isomers such as geometrical isomers, optical isomers based on
asymmetric carbon, rotational isomer, stereoisomers and tautomers,
and mixtures of these isomers and is not limited by the description
of the formula illustrated for the sake of convenience. The
compound can be any of isomers or a mixture thereof. Accordingly,
although it is possible that an a symmetric carbon atom is present
in a molecule and that optically active substance and racemic
substance may therefore be present, the present invention is not
limited thereto but covers any of them. Further, crystal
polymorphism may be present but, again, there is no limitation but
any of single crystal form or a mixture will do. The compound (I)
or its salt according to the present invention may be a non-solvate
or a solvate, and either of them are included in the scope of
claims for patent in the present invention. A metabolite which is
generated by decomposing the compound (I) according to the present
invention in vivo, and a prodrug of the compound (I) or its salt
according to the present invention are also included in the scope
of claims for patent in the present invention.
[0022] The "halogen atom" used in the present description
represents an atom such as fluorine atom, chlorine atom, bromine
atom or iodine atom, and fluorine atom, chlorine atom and bromine
atom are preferred.
[0023] The "C.sub.1-6 alkyl group" used in the present description
represents an alkyl group having one to six carbon atoms, including
linear or branched alkyl groups such as methyl group, ethyl group,
n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,
sec-butyl group, t-butyl group, n-pentyl group, 1,1-dimethylpropyl
group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group,
1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group,
1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group,
1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl
group, 2-methylbutyl group, 1,1-dimethylbutyl group,
1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl
group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl
group or 3-methylpentyl group.
[0024] The "C.sub.2-6 alkenyl group" used in the present
description represents an alkenyl group having two to six carbon
atoms, and suitable examples of the group are vinyl group, allyl
group, 1-propenyl group, 2-propenyl group, isopropenyl group,
2-methyl-1-propenyl group, 3-methyl-1-propenyl group,
2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl
group, 2-butenyl group, 3-butenyl group, 1-pentenyl group,
1-hexenyl group, 1,3-hexadienyl group and 1,6-hexadienyl group.
[0025] The "C.sub.2-6 alkynyl group" used in the present
description represents an alkynyl group having two to six carbon
atoms, and suitable examples of the group are ethynyl group,
1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl
group, 3-butynyl group, 3-methyl-1-propynyl group,
1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl
group, 1-hexynyl group, 1,3-hexadiynyl group, and 1,6-hexadiynyl
group.
[0026] The "C.sub.1-6 alkoxy group" used in the present description
represents an alkoxy group having one to six carbon atoms, such as
methoxy group, ethoxy group, n-propoxy group, iso-propoxy group,
sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy
group, t-butoxy group, n-pentyloxy group, iso-pentyloxy group,
sec-pentyloxy group, n-hexoxy group, iso-hexoxy group,
1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group,
2,2-dimethylpropyloxy group, 2-ethylpropoxy group,
1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group,
1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group,
1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group,
2,3-dimethylbutyloxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy
group, 2-methylpentoxy group, 3-methylpentoxy group or hexyloxy
group.
[0027] The "C.sub.2-6 alkenyloxy group" used in the present
description represents an alkenyloxy group having two to six carbon
atoms, and suitable examples of the group are vinyloxy group,
allyloxy group, 1-propenyloxy group, 2-propenyloxy group,
isopropenyloxy group, 2-methyl-1-propenyloxy group,
3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group,
3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy
group, 3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group,
1,3-hexadienyloxy group, and 1,6-hexadienyloxy group.
[0028] The "C.sub.2-6 alkynyloxy group" used in the present
description represents an alkynyloxy group having two to six carbon
atoms, and suitable examples thereof are ethynyloxy group,
1-propynyloxy group, 2-propynyloxy group, 1-butynyloxy group,
2-butynyloxy group, 3-butynyloxy group, 3-methyl-1-propynyloxy
group, 1-ethynyl-2-propynyloxy group, 2-methyl-3-propynyloxy group,
1-pentynyloxy group, 1-hexynyloxy group, 1,3-hexadiynyloxy group,
and 1,6-hexadiynyloxy group.
[0029] The "alkylthio group having one to six carbon atoms" used in
the present description refers to an alkylthio group having one to
six carbon atoms, such as methylthio group, ethylthio group,
n-propylthio group, iso-propylthio group, sec-propylthio group,
n-butylthio group, iso-butylthio group, sec-butylthio group,
t-butylthio group, n-pentylthio group, iso-pentylthio group,
sec-pentylthio group, n-hexylthio group, iso-hexylthio group,
1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group,
2,2-dimethylpropylthio group, 2-ethylpropylthio group,
1-methyl-2-ethylpropylthio group, 1-ethyl-2-methylpropylthio group,
1,1,2-trimethylpropylthio group, 1,1-dimethylbutylthio group,
1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group,
2,3-dimethylbutylthio group, 1,3-dimethylbutylthio group,
2-ethylbutylthio group, 2-methylpentylthio group or
3-methylpentylthio group.
[0030] The "alkenylthio group having two to six carbon atoms" used
in the present description refers to an alkenylthio group having
two to six carbon atoms, and suitable examples thereof are
vinylthio group, allylthio group, 1-propenylthio group,
2-propenylthio group, isopropenylthio group,
2-methyl-1-propenylthio group, 3-methyl-1-propenylthio group,
2-methyl-2-propenylthio group, 3-methyl-2-propenylthio group,
1-butenylthio group, 2-butenylthio group, 3-butenylthio group,
1-pentenylthio group, 1-hexenylthio group, 1,3-hexadienylthio
group, and 1,6-hexadienylthio group.
[0031] The "alkynylthio group having two to six carbon atoms" used
in the present description represents an alkynylthio group having
two to six carbon atoms, and suitable examples thereof are
ethynylthio group, 1-propynylthio group, 2-propynylthio group,
1-butynylthio group, 2-butynylthio group, 3-butynylthio group,
3-methyl-1-propynylthio group, 1-ethynyl-2-propynylthio group,
2-methyl-3-propynylthio group, 1-pentynylthio group, 1-hexynylthio
group, 1,3-hexadiynylthio group, and 1,6-hexadiynylthio group.
[0032] The "cycloalkyl group having three to eight carbon atoms"
used in the present description represents a cycloalkyl group
comprising three to eight carbon atoms, such as cyclopropyl group,
cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl
group or cyclooctyl group.
[0033] The "cycloalkenyl group having three to eight carbon atoms"
used in the present invention represents a cycloalkenyl group
comprising three to eight carbon atoms, such as cyclopropen-1-yl,
cyclopropen-3-yl, cyclobuten-1-yl, cyclobuten-3-yl,
1,3-cyclobutadien-1-yl, cyclopenten-1-yl, cyclopenten-3-yl,
cyclopenten-4-yl, 1,3-cyclopentadien-1-yl, 1,3-cyclopentadien-2-yl,
1,3-cyclopentadien-5-yl, cyclohexen-1-yl, cyclohexen-3-yl,
cyclohexen-4-yl, 1,3-cyclohexadien-1-yl, 1,3-cyclohexadien-2-yl,
1,3-cyclohexadien-5-yl, 1,4-cyclohexadien-3-yl,
1,4-cyclohexadien-1-yl, cyclohepten-1-yl, cyclohepten-3-yl,
cyclohepten-4-yl, cyclohepten-5-yl, 1,3-cyclohepten-2-yl,
1,3-cyclohepten-1-yl, 1,3-cycloheptadien-5-yl,
1,3-cycloheptadien-6-yl, 1,4-cycloheptadien-3-yl,
1,4-cycloheptadien-2-yl, 1,4-cycloheptadien-1-yl,
1,4-cycloheptadien-6-yl, 1,3,5-cycloheptatrien-3-yl,
1,3,5-cycloheptatrien-2-yl, 1,3,5-cycloheptatrien-1-yl,
1,3,5-cycloheptatrien-7-yl, cycloocten-1-yl, cycloocten-3-yl,
cycloocten-4-yl, cycloocten-5-yl, 1,3-cyclooctadien-2-yl,
1,3-cyclooctadien-1-yl, 1,3-cyclooctadien-5-yl,
1,3-cyclooctadien-6-yl, 1,4-cyclooctadien-3-yl,
1,4-cyclooctadien-2-yl, 1,4-cyclooctadien-1-yl,
1,4-cyclooctadien-6-yl, 1,4-cyclooctadien-7-yl,
1,5-cyclooctadien-3-yl, 1,5-cyclooctadien-2-yl,
1,3,5-cyclooctatrien-3-yl, 1,3,5-cyclooctatrien-2-yl,
1,3,5-cyclooctatrien-1-yl, 1,3,5-cyclooctatrien-7-yl,
1,3,6-cyclooctatrien-2-yl, 1,3,6-cyclooctatrien-1-yl,
1,3,6-cyclooctatrien-5-yl or 1,3,6-cyclooctatrien-6-yl group.
[0034] The "5 to 14-membered non-aromatic heterocyclic group" used
in the present description refers to a monocyclic, bicyclic or
tricyclic 5 to 14-membered non-aromatic heterocyclic group and
containing one or more hetero atoms selected from the group
consisting of nitrogen atom, sulfur atom and oxygen atom. Specific
examples of the group are pyrrolidinyl group, piperidinyl group,
piperazinyl group, pyrazolinyl group, morpholinyl group,
tetrahydrofuryl group, tetrahydropyranyl group, dihydrofuryl group,
dihydropyranyl group, imidazolinyl group, and oxazolinyl group. The
non-aromatic heterocyclic group also includes a group derived from
pyridone ring, and a non-aromatic fused ring (e.g., a group derived
from phthalimide ring or succinimide ring).
[0035] The "aromatic cyclic hydrocarbon group having six to
fourteen carbon atoms" and the "aryl" used in the present
description represent an aromatic cyclic hydrocarbon group
comprising six to fourteen carbon atoms and include monocyclic
groups, as well as fused groups such as bicyclic groups and
tricyclic groups. Specific examples of the group include phenyl
group, indenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl
group, heptalenyl group, biphenyl group, indacenyl group,
acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenyl
group, anthracenyl group, cyclopentacyclooctenyl group, and
benzocyclooctenyl group.
[0036] The "5 to 14-membered aromatic heterocyclic group" and the
"heteroaryl" used in the present description represent a
monocyclic, bicyclic or tricyclic 5 to 14-membered aromatic
heterocyclic group containing one or more hetero atoms selected
from nitrogen atom, sulfur atom and oxygen atom. Specific examples
of the group include 1) a nitrogen-containing aromatic heterocyclic
group such as pyrrolyl group, pyridyl group, pyridazinyl group,
pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl
group, benzotriazolyl group, pyrazolyl group, imidazolyl group,
benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl
group, purinyl group, indazolyl group, quinolyl group, isoquinolyl
group, quinolizyl group, phthalazyl group, naphthyridinyl group,
quinoxalyl group, quinazolinyl group, cinnolinyl group, pteridinyl
group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl
group, phenanthridinyl group, carbazolyl group, carbazolinyl group,
perimidinyl group, phenanthrolinyl group, phenacinyl group,
imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl
group or pyrazolopyridinyl group; 2) a sulfur-containing aromatic
heterocyclic group such as thienyl group or benzothienyl group; 3)
an oxygen-containing aromatic heterocyclic group such as furyl
group, pyranyl group, cyclopentapyranyl group, benzofuryl group or
isobenzofuryl group; and 4) an aromatic heterocyclic group
containing two or more different hetero atoms, such as thiazolyl
group, isothiazolyl group, benzothiazolyl group, benzthiadiazolyl
group, phenothiazinyl group, isoxazolyl group, furazanyl group,
phenoxazinyl group, oxazolyl group, isoxazoyl group, benzoxazolyl
group, oxadiazolyl group, pyrazolooxazolyl group, imidazothiazolyl
group, thienofuranyl group, furopyrrolyl group or pyridooxazinyl
group.
[0037] The "aliphatic acyl group having two to seven carbon atoms"
used in the present description represents an atomic group derived
from an aliphatic carboxyl group having two to seven carbon atoms
by removing OH group from its carboxyl group, and suitable examples
thereof are acetyl group, propionyl group and butyroyl group.
[0038] The "arylacyl group" used in the present description
represents a carbonyl group substituted with an aromatic cyclic
hydrocarbon group having six to fourteen carbon atoms, and the
"heteroarylacyl group" represents a carbonyl group substituted with
a 5 to 14-membered aromatic heterocyclic group. The "aromatic
cyclic hydrocarbon group having six to fourteen carbon atoms" and
the "15 to 14-membered aromatic heterocyclic group" as used herein
have the same meanings as defined above.
[0039] Suitable examples of the "alkylsulfonyl group having one to
six carbon atoms", "alkenylsulfonyl group having two to six carbon
atoms" and "alkynylsulfonyl group having two to six carbon atoms"
used in the present description include methylsulfonyl group,
ethylsulfonyl group, n-propylsulfonyl group, iso-propylsulfonyl
group, n-butylsulfonyl group, t-butylsulfonyl group, vinylsulfonyl
group, allylsulfonyl group, iso-propenylsulfonyl group,
iso-pentenylsulfonyl group, and ethynylsulfonyl group. Suitable
examples of the "alkylsulfinyl group having one to six carbon
atoms", "alkenylsulfinyl group having two to six carbon atoms" and
"alkynylsulfinyl group having two to six carbon atoms" used in the
present description include methylsulfinyl group, ethylsulfinyl
group, n-propylsulfinyl group, iso-propylsulfinyl group,
n-butylsulfinyl group, t-butylsulfinyl group, vinylsulfinyl group,
allylsulfinyl group, iso-propenylsulfinyl group,
iso-pentenylsulfinyl group, and ethynylsulfinyl group.
[0040] Examples of the "substituents" in the "amino group which may
be substituted" used in the present description represents one or
two groups selected from an alkyl group having one to six carbon
atoms, analkenyl group having two to six carbon atoms, an alkynyl
group having two to six carbon atoms, an alkylsulfonyl group having
one to six carbon atoms, an alkenylsulfonyl group having two to six
carbon atoms, alkynylsulfonyl group having two to six carbon atoms,
an alkylcarbonyl group having one to six carbon atoms, an
alkenylcarbonyl group having two to six carbon atoms, an
alkynylcarbonyl group having two to six carbon atoms, each of which
may be substituted. In this connection, the substituents may be
combined to form a 3 to 8-membered nitrogen-containing ring.
Suitable examples of the "substituents" in the alkyl group having
one to six carbon atoms, alkenyl group having two to six carbon
atoms, alkynyl group having two to six carbon atoms, alkylsulfonyl
group having one to six carbon atoms, alkenylsulfonyl group having
two to six carbon atoms, alkynylsulfonyl group having two to six
carbon atoms, C.sub.1-6 alkylcarbonyl group, C.sub.2-6
alkeynylcarbonyl group and C.sub.2-6 alkynylcarbonyl group include
a hydroxyl group, a halogen atom, a nitrile group, an alkoxy group
and C.sub.1-6 alkylthio group. Particularly preferable examples of
the above-mentioned "amino group which may be substituted" include
methylamino group, ethylamino group, n-propylamino group,
iso-propylamino group, n-butylamino group, iso-butylamino group,
tert-butylamino group, n-pentylamino group, iso-pentylamino group,
neopentylamino group, n-hexylamino group, 1-methylpropylamino
group, 1,2-dimethylpropylamino group, 2-ethylpropylamino group,
1-methyl-2-ethylpropylamino group, 1-ethyl-2-methylpropylamino
group, 1,1,2-trimethylpropylamino group, 1-methylbutylamino group,
2-methylbutylamino group, 1,1-dimethylbutylamino group,
2,2-dimethylbutylamino group, 2-ethylbutylamino group,
1,3-dimethylbutylamino group, 2-methylpentylamino group,
3-methylpentylamino group, N,N-dimethylamino group,
N,N-diethylamino group, N,N-di(n-propyl)amino group,
N,N-di(iso-propyl)amino group, N,N-di(n-butyl)amino group,
N,N-di(iso-butyl)amino group, N,N-di(t-butyl)amino group,
N,N-di(n-pentyl)amino group, N,N-di(iso-pentyl)amino group,
N,N-di(neopentyl)amino group, N,N-di(n-hexyl)amino group,
N,N-di(1-methylpropyl)amino group, N,N-di(1,2-dimethylpropyl)amino
group, N-methyl-N-ethylamino group, N-ethyl-N-(n-propyl)amino
group, N-methyl-N-(i-propyl)amino group, vinylamino group,
allylamino group, (1-propenyl)amino group, isopropenylamino group,
(1-buten-1-yl)amino group, (1-buten-2-yl)amino group,
(1-buten-3-yl)amino group, (2-buten-1-yl)amino group,
(2-buten-2-yl)amino group, N,N-divinylamino group, N,N-diallylamino
group, N,N-di(1-propenyl)amino group, N,N-isopropenylamino group,
N-vinyl-N-allylamino group, ethynylamino group, 1-propynylamino
group, 2-propynylamino group, butynylamino group, pentynylamino
group, hexynylamino group, N,N-diethynylamino group,
N,N-(1-propynyl)amino group, N,N-(2-propynyl)amino group,
N,N-dibutynylamino group, N,N-dipentynylamino group,
N,N-dihexynylamino group, hydroxymethylamino group,
1-hydroxyethylamino group, 2-hydroxyethylamino group,
3-hydroxy-n-propyl group, methylsulfonylamino group,
ethylsulfonylamino group, n-propylsulfonylamino group,
iso-propylsulfonylamino group, n-butylsulfonylamino group,
t-butylsulfonylamino group, vinylsulfonylamino group,
allylsulfonylamino group, iso-propenylsulfonylamino group,
iso-pentenylsulfonylamino group, ethynylsulfonylamino group,
methylcarbonylamino group, ethylcarbonylamino group,
n-propylcarbonylamino group, iso-propylcarbonylamino group,
n-butylcarbonylamino group, t-butylcarbonylamino group,
vinylcarbonylamino group, allylcarbonylamino group,
iso-propenylcarbonylamino group, iso-pentenylcarbonylamino group,
and ethynylcarbonylamino group.
[0041] Examples of the "substituents" in the phrase "which may be
substituted" used in the present description include a halogen atom
such as fluorine atom, chlorine atom, bromine atom or iodine atom;
a hydroxyl group; a nitro group; a cyano group; an alkyl group
having one to six carbon atoms such as methyl group, ethyl group,
n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,
sec-butyl group, t-butyl group, n-pentyl group, 1,1-dimethylpropyl
group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group,
1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group or
1-methyl-2-ethylpropyl group; analkenyl group having two to six
carbon atoms such as vinyl group, allyl group, 1-propenyl group,
2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group,
3-methyl-1-propenyl group, 2-methyl-2-propenyl group,
3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group,
3-butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexadienyl
group or 1,6-hexadienyl group; an alkynyl group having two to six
carbon atoms such as ethynyl group, 1-propynyl group, 2-propynyl
group, 1-butynyl group, 2-butynyl group, 3-butynyl group,
3-methyl-1-propynyl group, 1-ethynyl-2-propynyl group,
2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl group,
1,3-hexadiynyl group or 1,6-hexadiynyl group; an alkoxy group
having one to six carbon atoms such as methoxy group, ethoxy group,
n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy
group, iso-butoxy group, sec-butoxy group, t-butoxy group,
n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group or
n-hexyloxy group; an alkenyloxy group having two to six carbon
atoms such as vinyloxy group, allyloxy group, 1-propenyloxy group,
2-propenyloxy group or isopropenyloxy group; an alkynyloxy group
having two to six carbon atoms such as ethynyloxy group,
1-propynyloxy group or 2-propynyloxy group; an alkylthio group
having one to six carbon atoms such as methylthio group, ethylthio
group, n-propylthio group, iso-propylthio group, sec-propylthio
group, n-butylthio group, iso-butylthio group, sec-butylthio group
or t-butylthio group; an alkenylthio group having two to six carbon
atoms such as vinylthio group, allylthio group, 1-propenylthio
group or 2-propenylthio group; an alkynylthio group having two to
six carbon atoms such as ethynylthio group, 1-propynylthio group or
2-propynylthio group; an aliphatic acyl group having two to seven
carbon atoms such as acetyl group, propionyl group or butyroyl
group; carbamoyl group; an arylacyl group; a heteroarylacyl group;
an amino group; an alkylsulfonyl group having one to six carbon
atoms, an alkenylsulfonyl group having two to six carbon atoms, an
alkynylsulfonyl group having two to six carbon atoms, an
alkylsulfinyl group having one to six carbon atoms, an
alkenylsulfinyl group having two to six carbon atoms or an
alkynylsulfinyl group having two to six carbon atoms, such as
methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group,
iso-propylsulfonyl group, n-butylsulfonyl group, t-butylsulfonyl
group, vinylsulfonyl group, allylsulfonyl group,
iso-propenylsulfonyl group, iso-pentenylsulfonyl group,
ethynylsulfonyl group, methylsulfinyl group, ethylsulfinyl group,
n-propylsulfinyl group, iso-propylsulfinyl group, n-butylsulfinyl
group, t-butylsulfinyl group, vinylsulfinyl group, allylsulfinyl
group, iso-propenylsulfinyl group, iso-pentenylsulfinyl group or
ethynylsulfinyl group; a formyl group, a cycloalkyl group having
three to eight carbon atoms such as cyclopropyl group, cyclobutyl
group, cyclopentyl group, cyclohexyl group, cycloheptyl group or
cyclooctyl group; a cycloalkenyl group having three to eight carbon
atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl or
cyclohexenyl group; a 5 to 14-membered non-aromatic heterocyclic
group, such as pyrrolidinyl group, pyrrolyl group, piperidinyl
group, piperazinyl group, imidazolyl group, pyrazolidyl group,
imidazolidyl group, morpholinyl group, tetrahydrofuryl group,
tetrahydropyranyl group, pyrrolinyl group, dihydrofuryl group,
dihydropyranyl group, imidazolinyl group, oxazolinyl group, a group
derived from pyridone ring, and a group derived from phthalimide
ring or succinimide ring; an aromatic cyclic hydrocarbon group
having six to fourteen carbon atoms such as phenyl group, indenyl
group, 1-naphthyl group, 2-naphthyl group, biphenyl group or
indacenyl group; a 5 to 14-membered aromatic heterocyclic group,
such as pyrrolyl group, pyridyl group, pyridazinyl group,
pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl
group, benzotriazolyl group, pyrazolyl group, imidazolyl group,
benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl
group, purinyl group, indazolyl group, quinolyl group, isoquinolyl
group, quinolizinyl group, phthalazinyl group, naphthyridinyl
group, quinoxalyl group, quinazolinyl group, cinnolinyl group,
pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl
group, acridinyl group, phenanthridinyl group, carbazolyl group,
carbazolinyl group, perimidinyl group, phenanthrolinyl group,
phenacynyl group, imidazopyridyl group, imidazopyrimidinyl group,
pyrazolopyridyl group, pyrazolopyridyl group, thienyl group,
benzothienyl group, furyl group, pyranyl group, cyclopentapyranyl
group, benzofuryl group, isobenzofuryl group, thiazolyl group,
isothiazolyl group, benzothiazolyl group, benzothiadiazolyl group,
phenothiazinyl group, isoxazolyl group, furazanyl group,
phenoxazinyl group, oxazolyl group, isoxazolyl group, benzoxazolyl
group, oxadiazolyl group, pyrazolooxazolyl group, imidazothiazolyl
group, thienofuranyl group, furopyrrolyl group or pyridooxazinyl
group. Each of these substituents may be further substituted.
[0042] In the formula (I), suitable examples of the "substituents"
in the "carbamoyl group which may be substituted" are groups
selected from an alkyl group having one to six carbon atoms which
may be substituted, an alkenyl group having two to six carbon atoms
which may be substituted, an alkynyl group having two to six carbon
atoms which may be substituted, a cycloalkyl group having three to
eight carbon atoms which may be substituted, a cycloalkenyl group
having three to eight carbon atoms which may be substituted, an
aromatic cyclic hydrocarbon group having six to fourteen carbon
atoms which may be substituted, and a 5 to 14-membered aromatic
heterocyclic group which may be substituted. The nitrogen atom of
the carbamoyl group may be substituted with one or two groups
selected from the above group of substituents. The substituents may
be combined to form a 3 to 14-membered nitrogen-containing ring,
such as pyrrolidyl group, pyrrolinyl group, piperidyl group,
piperazinyl group, imidazolyl group, pyrazolidyl group,
imidazolidyl group, morpholinyl group, tetrahydropyranyl group,
aziridinyl group, oxiranyl group, oxathiolanyl group, phthalimidyl
group, succinimidyl group, pyrrolyl group, pyridyl group,
pyridazinyl group, pyrimidinyl group, pyrazinyl group or pyrazolyl
group. In addition, the nitrogen-containing ring may be
substituted.
[0043] In the formula (I), a preferred group in R.sup.1 and/or
R.sup.2 is not specifically limited, of which a hydrogen atom, an
alkyl group having one to six carbon atoms and an aliphatic acyl
group having two to seven carbon atoms, each of which may be
substituted, are more preferred, and a hydrogen atom is typically
preferred.
[0044] In the formula (I), a preferred group in R.sup.3 is not
specifically limited, of which a hydrogen atom, an amino group, a
cyano group, and an alkyl group having one to six carbon atoms, an
alkoxy group having one to six carbon atoms, a phenyl group, a
naphthyl group, a pyridyl group, a pyridazyl group, a pyrimidyl
group, a pyrazyl group, a thienyl group, a furyl group, an
imidazolyl group etc., each of which may be substituted are more
preferred, and a hydrogen atom is further preferred.
[0045] In the formula (I), R.sup.4 represents an aromatic cyclic
hydrocarbon group having six to fourteen carbon atoms which may be
substituted, a 5 to 14-membered non-aromatic heterocyclic group
having one or more unsaturated bonds or a 5 to 14-membered aromatic
heterocyclic group which may be substituted, and suitable examples
thereof are an aromatic cyclic hydrocarbon group having six to
fourteen carbon atoms such as phenyl group or naphthyl group; a 5
to 14-membered non-aromatic heterocyclic group, such as
pyrrolidinyl group, pyrrolinyl group, piperidinyl group,
piperazinyl group, imidazolinyl group, pyrazolidinyl group,
imidazolidinyl group, morpholinyl group, tetrahydropyranyl group,
aziridinyl group, oxiranyl group, oxathiolanyl group,
6-oxo-1,6-dihydropyridinyl group in which the nitrogen atom may be
substituted or 2-oxo-1,2-dihydropyridinyl group in which the
nitrogen atom may be substituted; or a 5 to 14-membered aromatic
heterocyclic group, such as pyrrolyl group, pyridyl group,
pyridazinyl group, pyrimidinyl group, pyrazinyl group, pyrazolyl
group, imidazolyl group, indolyl group, isoindolyl group,
indolizinyl group, quinolyl group, isoquinolyl group, quinolizinyl
group, phthalazinyl group, naphthyridyl group, quinoxalyl group,
quinazolyl group, imidazotriazinyl group, pyrazinopyridazinyl
group, thienyl group, benzothienyl group, furyl group, pyranyl
group, cyclopentapyranyl group, benzofuryl group, isobenzofuryl
group, thiazolyl group, isothiazolyl group, benzothiazolyl group,
benzothiadiazolyl group, phenothiazyl group, isoxazolyl group,
pyrazolooxazolyl group, imidazothiazolyl group, thienofuryl group,
furopyrrolyl group or pyridooxazinyl group. Each of these groups
may be further substituted. More preferred examples of R.sup.4
include groups represented by the formulae:
##STR00020##
each of which may be substituted. When the 6-oxo-1,6-dihydropyridyl
group or 2-oxo-1,2-dihydropyridyl group has a substituent, the
substituent may also be combined with the nitrogen atom.
[0046] In the formula (I), R.sup.5 refers to an aromatic cyclic
hydrocarbon group having six to fourteen carbon atoms or a 5 to
14-membered aromatic heterocyclic group, each of which may be
substituted, and suitable examples thereof include an aromatic
cyclic hydrocarbon group having six to fourteen carbon atoms such
as phenyl group or naphthyl group, or a 5 to 14-membered aromatic
heterocyclic group, such as pyrrolyl group, pyridyl group,
pyridazinyl group, pyrimidinyl group, pyrazinyl group, pyrazolyl
group, imidazolyl group, indolyl group, isoindolyl group,
indolizinyl group, quinolyl group, isoquinolyl group, quinolizinyl
group, phthalazinyl group, naphthyridyl group, quinoxalyl group,
quinazolyl group, imidazotriazinyl group, pyrazinopyridazinyl
group, thienyl group, benzothienyl group, furyl group, pyranyl
group, cyclopentapyranyl group, benzofuryl group, isobenzofuryl
group, thiazolyl group, isothiazolyl group, benzothiazolyl group,
benzothiadiazolyl group, phenothiazyl group, isoxazolyl group,
pyrazolooxazolyl group, imidazothiazolyl group, thienofuryl group,
furopyrrolyl group or pyridooxazinyl group. Each of these groups
may be substituted. More preferred examples of R.sup.5 include
groups represented by the formulae:
##STR00021##
each of which may be substituted.
[0047] In the "substituents" in the "aromatic cyclic hydrocarbon
group having six to fourteen carbon atoms which may be substituted"
and the "5 to 14-membered aromatic heterocyclic group which may be
substituted" in R.sup.3, R.sup.4 and R.sup.5, (1) preferred
examples are one or more groups selected from a hydroxyl group, a
halogen atom, a cyano group, a nitro group, an alkyl group having
one to six carbon atoms which may be substituted, analkenyl group
having two to six carbon atoms which may be substituted, an alkynyl
group having two to six carbon atoms which may be substituted, an
alkoxy group having one to six carbon atoms which may be
substituted, an alkenyloxy group having two to six carbon atoms
which may be substituted, an alkylthio group having one to six
carbon atoms which may be substituted, an alkenylthio group having
two to six carbon atoms which may be substituted, an alkynylthio
group having two to six carbon atoms which may be substituted, a
substituted carbonyl group, an amino group which may be
substituted, an alkylsulfonyl group having one to six carbon atoms
which may be substituted, an alkenylsulfonyl group having two to
six carbon atoms which may be substituted, an alkynylsulfonyl group
having two to six carbon atoms which may be substituted, an
alkylsulfinyl group having one to six carbon atoms which may be
substituted, an alkenylsulfinyl group having two to six carbon
atoms which may be substituted, an alkynylsulfinyl group having two
to six carbon atoms which may be substituted, a formyl group, a
cycloalkyl group having three to eight carbon atoms which may be
substituted, a cycloalkenyl group having three to eight carbon
atoms which may be substituted, a 5 to 14-membered non-aromatic
heterocyclic group which may be substituted, an aromatic cyclic
hydrocarbon group having six to fourteen carbon atoms which may be
substituted and a 5 to 14-membered aromatic heterocyclic group
which may be substituted; (2) more preferably, one or more groups
selected from (1) a hydroxyl group, (2) a halogen atom, (3) a cyano
group, (4) a nitro group, (5) an alkyl group having one to six
carbon atoms, an alkenyl group having two to six carbon atoms or an
alkynyl group having two to six carbon atoms, each of which may be
substituted with one or more groups selected from (i) a hydroxyl
group, (ii) a cyano group, (iii) a halogen atom, (iv) an alkylamino
group having one to six carbon atoms, (v) a di(C.sub.1-6
alkyl)amino group, (vi) a C.sub.2-6 alkenylamino group, (vii) a
di(C.sub.2-6 alkenyl)amino group, (viii) an alkynylamino group
having two to six carbon atoms, (ix) a di(C.sub.2-6 alkynyl)amino
group, (x) an N--C.sub.1-6 alkyl-N--C.sub.2-6 alkenylamino group,
(xi) an N--C.sub.1-6 alkyl-N--C.sub.2-6 alkynylamino group, (xii)
an N--C.sub.2-6 alkenyl-N--C.sub.2-6 alkynylamino group, (xiii) an
aralkyloxy group, (xiv) a t-butyldimethylsilyloxy (TBDMS-oxy)
group, (xv) a C.sub.1-6 alkylsulfonylamino group, (xvi) a C.sub.1-6
alkylcarbonyloxy group, (xvii) a C.sub.2-6 alkenylcarbonyloxy
group, (xviii) a C.sub.2-6 alkynylcarbonyloxy group, (xix) an
N--C.sub.1-6 alkylcarbamoyl group, (xx) an N--C.sub.2-6
alkenylcarbamoyl group and (xxi) an N--C.sub.1-6 alkynylcarbamoyl
group, (6) an alkoxy group having one to six carbon atoms, an
alkenyloxy group having two to six carbon atoms or an alkynyloxy
group having two to six carbon atoms, each of which may be
substituted with one or more groups selected from (i) an alkylamino
group having one to six carbon atoms, (ii) an aralkyloxy group and
(iii) a hydroxyl group, (7) an alkylthio group having one to six
carbon atoms, an alkenylthio group having two to six carbon atoms
or an alkynylthio group having two to six carbon atoms, each of
which may be substituted with one or more groups selected from (i)
a hydroxyl group, (ii) a nitrile group, (iii) a halogen atom, (iv)
an alkylamino group having one to six carbon atoms, (v) an
aralkyloxy group, (vi) a TBDMS-oxy group, (vii) a C.sub.1-6
alkylsulfonylamino group, (viii) a C.sub.1-6 alkylcarbonyloxy group
and (ix) a C.sub.1-6 alkylcarbamoyl group, (8) carbonyl group
substituted with a group selected from (i) an alkoxy group having
one to six carbon atoms, (ii) an amino group, (iii) an alkylamino
group having one to six carbon atoms, (iv) a di(C.sub.1-6
alkyl)amino group, (v) an alkenylamino group having two to six
carbon atoms, (vi) a di(C.sub.2-6 alkenyl)amino group, (vii) an
alkynylamino group having two to six carbon atoms, (viii) a
di(C.sub.2-6 alkynyl)amino group, (ix) an N--C.sub.1-6
alkyl-N--C.sub.2-6 alkenylamino group, (x) an N--C.sub.1-6
alkyl-N--C.sub.2-6 alkynylamino group and (xi) an N--C.sub.2-6
alkenyl-N--C.sub.2-6 alkynylamino group, (9) an amino group which
may be substituted with one or two groups selected from (i) an
alkyl group having one to six carbon atoms, (ii) an alkenyl group
having two to six carbon atoms, (iii) an alkynyl group having two
to six carbon atoms, (iv) an alkylsulfonyl group having one to six
carbon atoms, (v) an alkenylsulfonyl group having two to six carbon
atoms, (vi) an alkynylsulfonyl group having two to six carbon
atoms, (vii) a C.sub.1-6 alkylcarbonyl group, (viii) a C.sub.2-6
alkenylcarbonyl group and (ix) a C.sub.2-6 alkynylcarbonyl group,
(10) an alkylsulfonyl group having one to six carbon atoms, (11) an
alkenylsulfonyl group having two to six carbon atoms, (12) an
alkynylsulfonyl group having two to six carbon atoms, (13) an
alkylsulfinyl group having one to six carbon atoms, (14) an
alkenylsulfinyl group having two to six carbon atoms, (15) an
alkynylsulfinyl group having two to six carbon atoms, (16) a formyl
group, (17) a cycloalkyl group having three to eight carbon atoms
or cycloalkenyl group having three to eight carbon atoms, each of
which may be substituted with one or more groups selected from (i)
a hydroxyl group, (ii) a halogen atom, (iii) a nitrite group, (iv)
an alkyl group having one to six carbon atoms, (v) an alkoxy group
having one to six carbon atoms, (vi) a C.sub.1-6 alkoxy-C.sub.1-6
alkyl group and (vii) an aralkyl group, (18) a 5 to 14-membered
non-aromatic heterocyclic group which may be substituted with one
or more groups selected from (i) a hydroxyl group, (ii) a halogen
atom, (iii) a nitrile group, (iv) an alkyl group having one to six
carbon atoms, (v) an alkoxy group having one to six carbon atoms,
(vi) a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group and (vii) an aralkyl
group, (19) an aromatic cyclic hydrocarbon group having six to
fourteen carbon atoms which may be substituted with one or more
groups selected from (i) a hydroxyl group, (ii) a halogen atom,
(iii) a nitrile group, (iv) an alkyl group having one to six carbon
atoms, (v) an alkoxy group having one to six carbon atoms, (vi) a
C.sub.1-6 alkoxy-C.sub.1-6 alkyl group and (vii) an aralkyl group,
and (20) a 5 to 14-membered aromatic heterocyclic group which may
be substituted with one or more groups selected from (i) a hydroxyl
group, (ii) a halogen atom, (iii) a nitrile group, (iv) an alkyl
group having one to six carbon atoms, (v) an alkoxy group having
one to six carbon atoms, (vi) a C.sub.1-6 alkoxy-C.sub.1-6 alkyl
group and (vii) an aralkyl group; and (3) most preferably, one or
more groups selected from a hydroxyl group, a halogen atom (e.g.,
fluorine atom, chlorine atom bromine atom or iodine atom), a cyano
group, a nitro group, an alkyl group having one to six carbon atoms
(e.g., methyl group, ethyl group, n-propyl group, iso-propyl group,
n-butyl group, iso-butyl group, t-butyl group, n-pentyl group,
i-pentyl group, neopentyl group or n-hexyl group), an alkenyl group
having two to six carbon atoms (e.g., vinyl group, allyl group,
1-propenyl group or isopropenyl group), an alkynyl group having two
to six carbon atoms (e.g., ethynyl group, 1-propynyl group,
2-propynyl group, butynyl group, pentynyl group or hexynyl group),
an alkoxy group having one to six carbon atoms (e.g., methoxy
group, ethoxy group, n-propoxy group, iso-propoxy group or n-butoxy
group) and an alkenyloxy group having two to six carbon atoms
(e.g., vinyloxy group, allyloxy group, 1-propenyloxy group or
isopropenyloxy group).
[0048] Preferred embodiments of the compound represented by the
formula (I) according to the present invention, a salt thereof or a
solvate of them are not specifically limited, of which more
preferred embodiments are compounds wherein R.sup.4 is a
6-oxo-1,6-dihydropyridinyl group or a 2-oxo-1,2-dihydropyridinyl
group represented by the formula:
##STR00022##
or the formula:
##STR00023##
(wherein, R.sup.8 represents a group selected from the
above-mentioned substituent group a, and the ring B represents a
nitrogen-containing 6-membered ring which may be substituted with
one to four groups selected from the above-mentioned substituent
group a) or a 4-pyridyl group which may have one or two
substituents; or salts thereof or solvates of that. The preferred
embodiments of R.sup.8 are those mentioned above.
[0049] The "salt" used in the present description is a salt formed
from the compound according to the present invention, of which a
pharmacologically acceptable salt is preferred. Preferred examples
thereof are a hydrohalogenic acid salt such as hydrofluoride,
hydrochloride, hydrobromide or hydroiodide; an inorganic acid salt
such as sulfate, nitrate, perchlorate, phosphate, carbonates or
hydrogencarbonate; an organic carboxylic acid salt such as acetate,
trifluoroacetate, oxalate, maleate, tartrate, fumarate or citrate;
an organic sulfonic acid salt such as methanesulfonate,
trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate,
toluenesulfonate or camphorsulfonate; an amino acid salt such as
aspartate or glutamate; a quaternary amine salt; an alkali metal
salt such as sodium salt or potassium salt; an alkaline earth metal
salt such as magnesium salt or calcium salt. More preferred
examples of the "pharmacologically acceptable salt" are
hydrochloride and oxalate.
[0050] The "solvate" used in the present description is a solvate
of the compound according to the present invention or a salt
thereof and is not specifically limited. Preferably, the solvate is
a hydrate, a solvate with an alcohol such as methanol, ethanol,
propanol, or isopropanol, a solvate with an ester such as ethyl
acetate, a solvate with an ether such as methyl ether, ethyl ether
or THF (tetrahydrofuran) or a solvate with DMF (dimethylformamide),
of which a hydrate or a solvate with an alcohol such as methanol or
ethanol is more preferred. A solvent for constituting the solvate
is preferably a pharmacologically acceptable solvent.
Production Process
[0051] Typical production processes for the compounds represented
by the formula (I) according to the present invention will be
illustrated below. The "room temperature" as used hereinafter
represents a temperature from about 0.degree. C. to about
40.degree. C.
(Production Process A)
##STR00024##
[0052] In the above formulae, Ar.sup.1a represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; X.sup.a represents an alkyl group
having one to six carbon atoms; and R.sup.1a represents a 5 to
14-membered aromatic heterocyclic group having a nitrogen atom at
4-position thereof and which may be substituted (such as a
4-pyridyl group, a 4-pyrimidinyl group or a 4-pyridazinyl group).
The compound (A.sub.3), which is provided as a raw material for the
production of the compound represented by the above formula (I) of
the present invention, can be produced through
dealcoholization-condensation by reacting an aromatic carboxylate
(A1) with a 4-methyl aromatic heterocyclic compound (A.sub.2)
represented by the formula of R.sup.1a--CH.sub.3 in a solvent in
the presence of a base. The base used varies depending on the
starting materials, solvent used, and so on in the production.
Preferable bases include secondary amine metal salts such as
lithium bis(trimethylsilyl) amide and lithium diisopropylamide
although not specifically limited to as far as the reaction is not
inhibited. The solvent used varies depending on, for example, the
starting materials and reagents used. Preferable solvents include
ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and
diethylene glycol, although not particularly limited insofar as the
reaction is not inhibited and the starting materials are dissolved
to a certain degree. The reaction temperature is generally
-78.degree. C. to room temperature, preferably around 0.degree.
C.
(Production Process B)
##STR00025##
[0054] In the above formulae, Ar.sup.1b and R.sup.1b are the same
as or different from each other and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; and X.sup.b represents a halogen
atom, an alkylsulfonyloxy group or an arylsulfonyloxy group. The
compound (B3) which is provided as a raw material for the
production of the compound represented by the above formula (I) of
the present invention, can be produced by this Production Process B
instead of Production Process A. That is, the compound (B3) is
produced by the condensation between an aromatic trialkylsilyl
cyanohydrin compound prepared from an aromatic aldehyde (B1) and
the compound (B2) represented by the formula of
R.sup.1b--CH.sub.2X.sup.b in the presence of a base, followed by
reacting with a fluorine compound to cause
de(trialkylsilyl)cyanidation. As an agent for preparing an aromatic
trialkylsilyl cyanohydrin from the compound (B1), a trialkylsilyl
cyanide compound such as trimethylsilyl cyanide, is preferably
used. At this time, it is also preferable to use a metal salt such
as zinc (II) iodide as a catalyst, allowing the reaction to proceed
quickly. The base used varies depending on the starting materials,
solvent used, and so on. Preferable bases include secondary amine
metal salts such as lithium bis(trimethylsilyl)amide or lithium
diisopropylamide although not specifically limited to as far as the
reaction is not inhibited. The fluorine compound used varies
depending on the starting materials, solvents used, and so on.
Preferable fluorine compounds include hydrofluoric acid and
hydrofluoride of amine, more preferably tetrabutylammonium fluoride
although not specifically limited to as far as the reaction is not
inhibited. The solvent used varies depending on the starting
materials, reagents, and so on. Preferable examples of the solvent
used, although not specifically limited to as far as the starting
materials are dissolved to a certain degree, include ethers such as
tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diethylene glycol.
The reaction temperature is preferably -78.degree. C. to room
temperature.
(Production Process C)
##STR00026##
[0056] In the above formulae, Ar.sup.1c and R.sup.1c are the same
as or different from each other and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted. 3-(Dimethylamino)-2-propen-1-one
derivative (C2) is a raw material for the production of the
compound (I) of the present invention. The compound (C2) can be
produced by allowing N,N-dimethylformamide dimethylacetal to act on
active methylene of the compound (C1) produced in Production
Process A or B. Most preferable is to perform this reaction without
any solvent. However, a preferable result can be obtained even
though the compound (C1) is diluted with a solvent (such as
N,N-dimethylformamide, tetrahydrofuran, dioxane,
N-methylpyrrolidone, benzene or toluene) that dissolves the
starting materials to a certain degree without inhibiting the
reaction. The reaction temperature is generally room temperature to
120.degree. C., preferably around 100.degree. C.
(Production Process D)
##STR00027##
[0058] In the above formulae, Ar.sup.1d and R.sup.1d are the same
as or different from each other and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; and R.sup.2d and R.sup.3d are the
same as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted.
The compound (D3) of the present invention can be produced by
allowing a guanidine derivative (D2) to react with
3-(dimethylamino)-2-propen-1-one derivative (D1) produced by
Production Process C in the presence of a base. The guanidine
derivative (D2) used may form a salt with an acid such as
hydrochloric acid, hydrobromic acid, sulfuric acid or acetic acid.
The base used varies depending on the starting materials, solvent
used, and so on. Preferable examples of the base include an alkali
metal carbonate such as potassium carbonate or sodium carbonate, or
an alkali metal alkoxide such as sodium methoxide, sodium ethoxide
or potassium t-butoxide although not specifically limited to as far
as the reaction is not inhibited. The solvent used varies depending
on the starting materials, reagents, and so on. Preferable examples
of the solvent include N,N-dimethylformamide, N-methylpyrrolidone,
dimethylsulfoxide and ethanol, although not specifically limited to
as far as the reaction is not inhibited and the starting materials
and bases are dissolved to a certain degree. The reaction
temperature is preferably room temperature to 120.degree. C., more
preferably around 70.degree. C.
(Production Process E)
##STR00028##
[0060] In the above formulae, Ar.sup.1e, R.sup.1e and R.sup.4e are
the same as or different from each other and each represents an
aromatic hydrocarbon cyclic group having six to fourteen carbon
atoms which may be substituted or a 5 to 14-membered aromatic
heterocyclic group which may be substituted; and R.sup.2e and
R.sup.3e are the same as or different from each other and each
represents a hydrogen atom, an alkyl group having one to six carbon
atoms which may be substituted, an alkenyl group having two to six
carbon atoms which may be substituted, an alkynyl group having two
to six carbon atoms which may be substituted, a cycloalkyl group
having three to eight carbon atoms which may be substituted, a
cycloalkenyl group having three to eight carbon atoms which may be
substituted, a 5 to 14-membered non-aromatic heterocyclic group
which may be substituted, an aromatic hydrocarbon cyclic group
having six to fourteen carbon atoms which may be substituted or a 5
to 14-membered aromatic heterocyclic group which may be
substituted. The compound (E4) of the present invention can be
produced by allowing an aldehyde (E2) and a guanidine derivative
(E3) to react with the compound (E1) produced by the above
Production Process A or B in the presence of the base, followed by
aromatizing with an oxidant. The guanidine derivative (E3) used may
form a salt with an acid such as hydrochloric acid, hydrobromic
acid, sulfuric acid or acetic acid. The base used varies depending
on the starting materials, solvent used, and so on. Preferably,
although not specifically limited to as far as the reaction is not
inhibited, the base used may be an alkali metal alkoxide such as
sodium methoxide, sodium ethoxide or potassium t-butoxide, or
alternatively an alkali metal carbonate such as potassium carbonate
or sodium carbonate. Examples of oxidant used include manganese
compounds such as active manganese dioxide, quinones such as
2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and sulfur. The solvent
used is not specifically limited to as far as the reaction is not
inhibited and the starting materials and intermediates are
dissolved to a certain degree. Examples of the solvents may include
ethanol, methanol, tetrahydrofuran, dichloromethane,
dichloroethane, chloroform, N,N-dimethylformamide,
N-methylpyrrolidone, dimethylsulfoxide, and mixed solvents thereof.
The reaction temperature is preferably 0.degree. C. to 120.degree.
C.
(Production Process F)
##STR00029##
[0061] In the above formulae, Ar.sup.1f and R.sup.1f are the same
as or different from each other and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; and R.sup.2f and R.sup.3f are the
same as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted.
The compound (F5) of the present invention and the compound (F6),
which is provided as a raw material for the production of the
compound (I) of the present invention, can be produced by Steps F-1
and F-2 in Production Process F. Step F-1: This step is to produce
the compound (F3) by dehydration-condensation between the compound
(F1) and the aldehyde compound (F2) in the presence of a base.
Preferable examples of the base used in the reaction include alkali
metal alkoxides such as sodium methoxide, sodium ethoxide or
potassium t-butoxide. Alternatively, alkali metal carbonates such
as potassium carbonate or sodium carbonate may be used. The
reaction is carried out in a solvent which is not specifically
limited to as far as the reaction is not inhibited and the starting
materials and intermediates are dissolved to a certain degree. The
solvents may include ethanol, methanol, tetrahydrofuran,
dichloromethane, chloroform, N,N-dimethylformamide,
N-methylpyrrolidone, dimethylsulfoxide, and mixed solvents thereof.
The reaction is carried out at a temperature of 0.degree. C. to
120.degree. C. Step F-2: This step is to produce the pyrimidine
derivative (F5) by reacting the compound (F3) obtained in Step F-1
with the guanidine derivative (F4) in the presence of the base,
followed by aromatizing with an oxidant. The guanidine derivative
(F4) used may form a salt with an acid such as hydrochloric acid,
hydrobromic acid, sulfuric acid or acetic acid. Preferable examples
of the base used in the reaction include alkali metal alkoxides
such as sodium methoxide, sodium ethoxide or potassium t-butoxide.
Alternatively, alkali metal carbonates such as potassium carbonate
or sodium carbonate may be used. Examples of the oxidant used in
the reaction include manganese compounds such as active manganese
dioxide, quinones such as
2,3-dichloro-5,6-dicyanao-1,4-benzoquinone, and sulfur. The
reaction is carried out in a solvent which is not specifically
limited to as far as the reaction is not inhibited and the starting
materials and intermediates are dissolved to a certain degree. The
solvents may include ethanol, methanol, tetrahydrofuran,
dichloromethane, chloroform, N,N-dimethylformamide,
N-methylpyrrolidone, dimethylsulfoxide, and mixed solvents thereof.
The reaction temperature is 0.degree. C. to 120.degree. C.
Alternatively, in Step F-1, even if the guanidine derivative (F4)
is provided in the reaction mixture from the beginning of the
reaction, followed by the aromatization with the oxidant, the
pyrimidine derivative (5) can be produced without isolating the
compound (F3). Furthermore, in step F-2, the reaction between the
compound (F3) and the guanidine derivative (F4) in the presence of
a base, the reaction (under heating) was carried out for a long
period of two to seven days under moisture conditions, followed by
an oxidative reaction, to give the pyrimidinone derivative
(F6).
(Production Process G)
##STR00030##
[0063] In the above formulae, Ar.sup.1g and R.sup.1g are the same
as or different from each other, and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; and X.sup.g represents a halogen
atom, an alkylsulfonyloxy group or an arylsulfonyloxy group. The
present production method is an alternative method for the
synthesis of the compound (F3) in Production Process F described
above. That is, the method includes the step of allowing
cyanomethylphosphonic acid diester to react with the compound (G1)
in the presence of a base and a palladium catalyst, followed by
dephosphorylation-condensation with an aldehyde compound
represented by the formula of Ar.sup.1g--CHO to produce a compound
(G2). The base used in the reaction is preferably sodium hydride,
and the palladium catalyst used is preferably
tetrakis(triphenylphosphine)palladium (O), respectively.
Preferably, the reaction solvents include ethers such as
dimethoxyethane, diethyl ether or tetrahydrofuran. The reaction is
carried out at a temperature of 0.degree. C. to 120.degree. C.
(Production Process H)
##STR00031##
[0065] In the above formulae, Ar.sup.1h and R.sup.1h are the same
as or different from each other and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2h and R.sup.3h are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
and X.sup.h represents an alkyl group having one to six carbon
atoms. The present production method is another synthetic method
for the compound (F6) in Production Process F.
Step H-1: This step is to produce the compound (H3) by
dehydration-condensation between the compound (H1) and the compound
(H2) using carboxylic anhydride in the presence of a base. Examples
of the base used in the reaction include amines such as
triethylamine, pyrrolidine, piperidine or diisopropylethylamine.
The carboxylic anhydride is preferably acetic anhydride. The
reaction is carried out at room temperature to 120.degree. C. Step
H-2: This step is to produce the pyrimidinone derivative (H5) as a
raw material for the production of the compound represented by the
above formula (I) of the present invention, by reacting the
compound (H3) obtained in Step H-1 with the guanidine derivative
(H4) in the presence of a base, followed by aromatization with an
oxidant. The guanidine derivative (H4) to be used may form a salt
with an acid such as hydrochloric acid, hydrobromic acid, sulfuric
acid or acetic acid. Preferable examples of the base to be used in
the reaction include alkali metal alkoxides such as sodium
methoxide, sodium ethoxide or potassium t-butoxide. Alternatively,
an alkali metal carbonate such as potassium carbonate or sodium
carbonate may be used. Examples of the oxidant to be used in the
reaction include manganese compounds such as active manganese
dioxide; quinones such as
2,3-dichloro-5,6-dicyanao-1,4-benzoquinone; and sulfur. The
reaction is carried out in a solvent which does not inhibit the
reaction and which dissolves the starting materials and
intermediates to a certain degree. Examples of the solvents include
ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform,
N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and
mixed solvents thereof. The reaction is performed in temperatures
of 0.degree. C. to 120.degree. C.
(Production Process I)
##STR00032##
[0067] In the above formulae, Ar.sup.1i and R.sup.1i are the same
as or different from each other and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2i and R.sup.3i are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
R.sup.4i represents an oxygen atom which may be substituted; and
X.sup.i represents a halogen atom. The compounds (I2) and (I3) of
the present invention can be produced by Production Process I.
Step I-1: This step is to produce a 4-halogenopyrimidine derivative
(I2) of the present invention from the pyrimidinone derivative (I1)
obtained in Production Process F or H by converting the oxo group
of the pyrimidinone derivative (I1) into a halogen atom. The
reaction is carried out in the absence of a solvent or in a
suspension with a solvent such as acetonitrile, dioxane or
tetrahydrofuran by allowing a halogenating agent such as
phosphorous oxychloride or, phosphorous oxybromide at a temperature
of 70.degree. C. to 120.degree. C. The reaction can be accelerated
by the addition of a tertiary amine such as dimethylaniline,
diisopropylethylamine or tripropylamine; a quaternary ammonium salt
such as tetraethylammonium chloride; or N,N-dimethylformamide. Step
I-2: This step is to produce a 4-alkoxy pyrimidine derivative (I3)
of the present invention from the 4-halogenopyrimidine derivative
(I2) obtained in Step I-1 described above by allowing an alkali
metal alkoxide to act on the 4-chloropyrimidine derivative to
convert the halogen atom at position 4 thereof into an alkoxy
group. The alkali metal alkoxide can be prepared by allowing a base
or an alkali metal to act on an alcohol in a solvent or in the
absence of the solvent. The alkali metal used is preferably sodium
or potassium. The base used in the reaction varies depending on the
starting materials, solvents used, and so on. Preferable bases
include alkali metal hydride such as sodium hydride and so on,
although not specifically limited to as far as the reaction is not
inhibited. Alternatively alkali metal alkoxides such as sodium
methoxide, sodium ethoxide or potassium t-butoxide may be used. The
solvent used varies depending on the starting materials, reagents,
and so on. Preferably, although not specifically limited to as far
as the reaction is not inhibited and the starting materials and
bases are dissolved to a certain degree, examples of the solvents
include N,N-dimethylformamide, N-methylpyrrolidone,
dimethylsulfoxide, alcohols such as methanol or ethanol; ethers
such as tetrahydrofuran or 1,4-dioxane; and mixed solvents thereof.
The reaction temperature is preferably room temperature to
120.degree. C.
(Production Process J)
##STR00033##
[0069] In the above formulae, Ar.sup.1j and R.sup.1j are the same
as or different from each other and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.21 and R.sup.31 are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
and R.sup.4j represents an alkyl group which may be substituted.
The compounds (J4) of the present invention can be produced by
Production Process J.
Step j-1: This step is to produce the compound (J2) by allowing a
Grignard reagent to react with the compound (J1) obtained in Step
H-1 of the Production Process H described above. The reaction is
carried out in a solvent which does not inhibit the reaction and
dissolves the starting materials and intermediates to a certain
degree. The solvents may include ethers such as tetrahydrofuran,
diethyl ether or dimethoxyethane. The reaction temperature is
-78.degree. C. to room temperature. Step J-2: This step is to
produce the pyrimidine derivative (J4) of the present invention by
reacting the compound (J2) obtained in Step J-1 with the guanidine
derivative (J3) in the presence of a base, followed by
aromatization with an oxidant. The guanidine derivative (J3) to be
used may form a salt with an acid such as hydrochloric acid,
hydrobromic acid, sulfuric acid or acetic acid. Preferable examples
of the base to be used in the reaction include alkali metal
alkoxides such as sodium methoxide, sodium ethoxide or potassium
t-butoxide. Alternatively, an alkali metal carbonate such as
potassium carbonate or sodium carbonate may be used. Examples of
the oxidant to be used in the reaction include: manganese compounds
such as active manganese dioxide; quinones such as
2,3-dichloro-5,6-dicyanao-1,4-benzoquinone; and sulfur. The
reaction is carried out in a solvent which does not inhibit the
reaction and which dissolves the starting materials and
intermediates to a certain degree. Examples of the solvents include
ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform,
N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and
mixed solvents thereof. The reaction is performed in the
temperature of 0.degree. C. to 120.degree. C.
(Production Process K)
##STR00034##
[0070] In the above formulae, Ar.sup.1k represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2k and R.sup.3k are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
R.sup.4k represents a hydrogen atom, a cyano group, an alkyl group
having one to six carbon atoms which may be substituted, an alkenyl
group having two to six carbon atoms which may be substituted, an
alkynyl group having two to six carbon atoms which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted, a 5 to 14-membered
aromatic heterocyclic group which may be substituted, a nitrogen
atom which may be substituted, an oxygen atom which may be
substituted or a sulfur atom which may be substituted; the ring
A.sup.k represents a pyridyl group, a pyrimidinyl group, a
pyrazinyl group or a pyridazinyl group; the ring A'.sup.k
represents a dihydrooxopyridinyl group, a dihydrooxopyrimidinyl
group, a dihydrooxopyrazinyl group or a dihydrooxopyridazinyl
group; and X.sup.k represents a halogen atom. This step is to
produce the 5-(.alpha.-oxo nitrogen-containing
heterocyclyl)pyrimidine (K2) of the present invention by converting
halogen atom (X.sup.k) in 5-(.alpha.-halogeno nitrogen-containing
heteroaryl)pyrimidine (K1) into 4-methoxybenzyloxy group while
substituting the halogen atom (X.sup.k) of 5-(.alpha.-halogeno
nitrogen-containing heteroaryl)pyrimidine (K1) with
4-methoxybenzylalkoxide, followed by treatment with an acid. The
4-methoxybenzylalkoxide is prepared using an alkali metal such as
sodium or potassium or a base such as sodium hydride in the absence
of a solvent or by dilution with a solvent such as
N,N-dimethylformamide or dimethylsulfoxide at a temperature of room
temperature to 120.degree. C. The acid used in the reaction may be
trifluoroacetic acid, hydrochloric acid, bromic acid, or the like.
The reaction is carried out in the absence of a solvent or by
dilution with a solvent such as dichloromethane, dichloroethane or
tetrahydrofuran at a temperature of room temperature to 150.degree.
C.
(Production Process L)
##STR00035##
[0072] In the above formulae, Ar.sup.1l represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2l and R.sup.3l are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
R.sup.4l represents a hydrogen atom, a cyano group, an alkyl group
having one to six carbon atoms which may be substituted, an alkenyl
group having two to six carbon atoms which may be substituted, an
alkynyl group having two to six carbon atoms which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted, a 5 to 14-membered
aromatic heterocyclic group which may be substituted, a nitrogen
atom which may be substituted, an oxygen atom which may be
substituted or a sulfur atom which may be substituted; R.sup.5l
represents an alkyl group having one to six carbon atoms which may
be substituted; the ring A.sup.l represents a pyridyl group, a
pyrimidinyl group, a pyrazinyl group or a pyridazinyl group; and
the ring A'.sup.l represents a dihydrooxopyridinyl group, a
dihydrooxopyrimidinyl group, a dihydrooxopyrazinyl group or a
dihydroxoopyridazinyl group. This step is to produce the
5-(.alpha.-oxo nitrogen-containing heterocyclyl)pyrimidine (L2) of
the present invention by hydrolyzing the alkyl group of
5-(.alpha.-alkoxy nitrogen-containing heteroaryl)pyrimidine (L1).
The reaction is carried out in an aqueous solution of a mineral
acid such as hydrochloric acid, hydrobromic acid or sulfuric acid,
or in a mixed solvent of water with acetic acid or the like at a
temperature of room temperature to 120.degree. C.
(Production Process M)
##STR00036##
[0074] In the above formulae, Ar.sup.1m represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2m and R.sup.3m are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
R.sup.4m represents a hydrogen atom, a cyano group, an alkyl group
having one to six carbon atoms which may be substituted, an alkenyl
group having two to six carbon atoms which may be substituted, an
alkynyl group having two to six carbon atoms which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted, a 5 to 14-membered
aromatic heterocyclic group which may be substituted, a nitrogen
atom which may be substituted, an oxygen atom which may be
substituted or a sulfur atom which may be substituted; R.sup.5m
represents an alkyl group which may be substituted, an alkenyl
group which may be substituted or an alkynyl group which may be
substituted; and the ring A.sup.m represents a dihydrooxopyridinyl
group, a dihydrooxopyrimidinyl group, a dihydrooxopyrazinyl group
or a dihydrooxopyridazinyl group. This step is to produce the
compound (M3) of the present invention by introducing a substituent
to the nitrogen atom on the ring A.sup.m of 5-(.alpha.-oxo
nitrogen-containing heterocyclyl)pyrimidine (M1).
[0075] The reaction is carried out through the reaction with a
halogenated alkyl compound or the like in a solvent in the presence
of a base. The bases include sodium methoxide, sodium ethoxide,
potassium t-butoxide, sodium hydride, sodium hydroxide, potassium
hydroxide, sodium bicarbonate, sodium carbonate and potassium
carbonate. The solvents include alcohols such as methanol or
ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane
or diethylene glycol dimethyl ether, N,N-dimethylformamide,
dimethylsulfoxide, N-methylpyrrolidone, and mixed solvents thereof.
The reaction is carried out at a temperature of 0.degree. C. to
100.degree. C.
(Production Process N)
##STR00037##
[0077] In the above formulae, R.sup.n represents an alkyl group
having one to six carbon atoms which may be substituted; the ring
A.sup.n represents a pyridyl group, a pyrimidinyl group, a
pyrazinyl group or a pyridazinyl group; and X.sup.1n and X.sup.2n
are the same as or different from each other and each represents a
halogen atom. This step is to produce an .alpha.-alkoxy
nitrogen-containing heteroaryl compound (N2) as a raw material for
the production of the compound represented by the formula (I) of
the present invention by allowing alkali metal alkoxide to react
with an .alpha.-halogeno nitrogen-containing heteroaryl compound
(N1) in a solvent. The alkali metal alkoxide is prepared by
allowing an alkali metal or base to react with an alcohol in a
solvent or in the absence of the solvent. Preferably, for example,
the alkali metal used is sodium or potassium. The base used in the
reaction varies depending on the starting materials, solvents used,
and so on. Preferable bases include an alkali metal hydride such as
sodium hydride, although not specifically limited to as far as the
reaction is not inhibited. Alternatively, alkali metal alkoxides
such as sodium methoxide, sodium ethoxide or potassium t-butoxide
may be used. The solvent used varies depending on the starting
materials, reagents, and so on. Preferably, although not
specifically limited to as far as the reaction is not inhibited and
the starting materials and bases are dissolved to a certain degree,
the solvents include alcohols such as N,N-dimethylformamide,
N-methylpyrrolidone, dimethylsulfoxide, alcohols such as methanol
or ethanol, ethers such as tetrahydrofuran or 1,4-dioxane, and
mixed solvents thereof. The reaction temperature is preferably room
temperature to 120.degree. C.
(Production Process O)
##STR00038##
[0079] In the above formulae, R.sup.5o represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; X.sup.o represents a halogen atom;
and Y.sup.o represents an alkyl group having one to six carbon
atoms. A tin reagent (O2) as a raw material for the production of
the compound represented by the above formula (X) of the present
invention can be produced by lithiating the compound (O1) and then
allowing a halogenotrialkyltin to react with the lithiated
compound. In the lithiation reaction, it is preferable to use
alkyllithium such as n-butyllithium, s-butyllithium or
t-butyllithium. The halogenotrialkyltin used varies depending on
the starting materials, solvents used, and soon. Preferably,
tributyltin chloride, trimethyltin chloride, trimethyltin bromide,
or the like may be proposed, although not specifically limited to
as far as the reaction is not inhibited. The solvent used in the
reaction varies depending on the starting materials, reagents, and
so on. Preferably, the solvents include ethers such as
tetrahydrofuran and diethyl ether, or hydrocarbons such as hexane
and heptane, and mixed solvents thereof, although not specifically
limited to as far as the reaction is not inhibited and the starting
material is dissolved to a certain degree. The reaction temperature
is preferably -100.degree. C. to room temperature.
(Production Process P)
##STR00039##
[0081] In the above formulae, Ar.sup.1p represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted. A 3-(dimethylamino)-2-propen-1-one
derivative (P2) as a raw material for the production of the
compound represented by the above formula (I) of the present
invention can be produced by allowing N,N-dimethylformamide
dimethylacetal to react with the compound (P1). Most preferably,
the reaction is carried out in the absence of a solvent.
Alternatively, a preferable result can be also obtained by dilution
with a solvent which dissolves starting materials to some degree
without inhibiting the reaction (e.g., N,N-dimethylformamide,
tetrahydrofuran, dioxane, N-methylpyrrolidone, benzene, or
toluene). The reaction temperature is generally room temperature to
120.degree. C., preferably around 100.degree. C.
(Production Process Q)
##STR00040##
[0083] In the above formulae, Ar.sup.1q represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; and R.sup.2q and R.sup.3q are the
same as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted.
This step is to produce a pyrimidine derivative (Q3) as a raw
material for the production of the compound represented by the
above formula (I) of the present invention by allowing a guanidine
derivative (Q2) to react with the 3-(dimethylamino)-2-propen-1-one
derivative (Q1) obtained from Production Process P described above.
The guanidine derivative (Q2) used may form a salt with an acid
such as hydrochloric acid, hydrobromic acid, sulfuric acid or
acetic acid. The base used varies depending on the starting
materials, solvents used, and so on. Preferably, although not
specifically limited to as far as the reaction is not inhibited,
the base is alkali metal carbonate such as potassium carbonate or
sodium carbonate, or alternatively alkali metal alkoxide such as
sodium methoxide, sodium ethoxide or potassium t-butoxide. The
solvent used varies depending on the starting materials, reagents,
and so on. Preferable examples of the solvent include
N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and
ethanol although not specifically limited to as far as the reaction
is not inhibited and the starting materials and bases are dissolved
to a certain degree. The reaction temperature is preferably room
temperature to 120.degree. C., more preferably around 100.degree.
C.
(Production Process R)
##STR00041##
[0085] In the above formulae, Ar.sup.1r and R.sup.4r are the same
as or different from each other and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; and R.sup.2r and R.sup.3r are the
same as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be
substituted.
[0086] The compound (R.sup.4) as a raw material for the production
of the compound represented by the above formula (I) of the present
invention can be produced by allowing the aldehyde (R.sup.2) and
the guanidine derivative (R.sup.3) to react with the compound
(R.sup.1) in the presence of a base, followed by aromatizing with
an oxidant. The guanidine derivative (R.sup.3) to be used may form
a salt with an acid such as hydrochloric acid, hydrobromic acid,
sulfuric acid or acetic acid. The base used varies depending on the
starting materials, the solvent to be used, and soon. Preferably,
although not specifically limited to as far as the reaction is not
inhibited, the base to be used may be an alkali metal alkoxide such
as sodium methoxide, sodium ethoxide or potassium t-butoxide, or
alternatively an alkali metal carbonate such as potassium carbonate
or sodium carbonate. Examples of the oxidant to be used include:
manganese compounds such as active manganese dioxide; quinones such
as 2,3-dichloro-5,6-dicyanao-1,4-benzoquinone; and sulfur. The
solvent to be used is not specifically limited to as far as the
reaction is not inhibited and the starting materials and
intermediates are dissolved to a certain degree. Examples of the
solvents include ethanol, methanol, tetrahydrofuran,
dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide,
N-methylpyrrolidone, dimethylsulfoxide, and mixed solvents thereof.
The reaction temperature is preferably 0.degree. C. to 120.degree.
C.
(Production Process S)
##STR00042##
[0088] In the above formulae, Ar.sup.1s and R.sup.1s are the same
as or different from each other and each represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2s and R.sup.3s are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
R.sup.4s represents a hydrogen atom, an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted
or a 5 to 14-membered aromatic heterocyclic group which may be
substituted; and XS represents a halogen atom. The compound (S3) of
the present invention can be produced by Production Process S.
Step S-1: This step is to produce a 5-halogenopyrimidine derivative
(S2) by halogenation at 5-position of the pyrimidine ring of the
pyrimidine derivative (S1) obtained by Production Process Q or R
described above using a halogenating agent in a solvent. The
halogenating agent used is preferably N-bromosuccinimide, bromine,
or the like. The solvent used varies depending on the starting
materials, reagents, and so on. Preferably, although not
specifically limited to as far as the reaction is not inhibited and
the starting materials are dissolved to a certain degree, the
solvents include alcohols such as methanol or ethanol; ethers such
as tetrahydrofuran, dioxane, dimethoxyethane or diethyleneglycol
dimethylether; N,N-dimethylformamide; and N-methylpyrrolidinone.
The reaction temperature is generally -20.degree. C. to room
temperature. Step S-2: This step is to produce the pyrimidine
derivative (S3) of the present invention by allowing a tin reagent
or the like, such as the compound (O2) obtained in Production
Process O, to react with the 5-halogenopyrimidine derivative (S2)
obtained in the production step S-1 in a solvent in the presence of
a palladium catalyst. The palladium catalyst used varies depending
on the starting materials, solvents used, and so on. Preferably,
although not specifically limited to as far as the reaction is not
inhibited, the palladium catalysts include
dichlorobis(triphenylphosphine)palladium (II), palladium (II)
acetate, tetrakis(triphenylphosphine)palladium (0), and
tris(dibenzylideneacetone)dipalladium (0). The solvent used varies
depending on the starting materials, reagents, and so on.
Preferably, although not specifically limited to as far as the
reaction is not inhibited and the starting materials are dissolved
to a certain degree, the solvents include alcohols such as methanol
or ethanol; ethers such as tetrahydrofuran, dioxane,
dimethoxyethane or diethyleneglycol dimethylether; toluene; xylene;
N,N-dimethylformamide; and N-methylpyrrolidinone. The reaction
temperature is generally room temperature to 150.degree. C.,
preferably around 100.degree. C.
(Production Process T)
##STR00043##
[0090] In the above formulae, Ar.sup.1t represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2t and R.sup.3t are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted, a 5 to 14-membered
aromatic heterocyclic group which may be substituted, an acyl group
having one to six carbon atoms which may be substituted or an
alkylsulfonyl group having one to six carbon atoms which may be
substituted; R.sup.4t represents a hydrogen atom, a halogen atom, a
cyano group, an alkyl group having one to six carbon atoms which
may be substituted, an alkenyl group having two to six carbon atoms
which may be substituted, an alkynyl group having two to six carbon
atoms which may be substituted, an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted,
a 5 to 14-membered aromatic heterocyclic group which may be
substituted, a nitrogen atom which may be substituted, an oxygen
atom which may be substituted or a sulfur atom which may be
substituted; R.sup.5t represents an alkenyl group having two to six
carbon atoms which may be substituted, an aromatic hydrocarbon
cyclic group having six to fourteen carbon atoms or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
and the ring A.sup.t represents a dihydrooxopyridinyl group, a
dihydrooxopyrimidinyl group, a dihydrooxopyrazinyl group or a
dihydrooxopyridazinyl group. The compound (T2) of the present
invention can be produced by the reaction between the compound (T1)
and a boron reagent in a solvent in the presence of a base and a
copper catalyst. The base used in the reaction varies depending on
the starting materials, solvent used, and so on in the production.
Preferably, although not specifically limited to as far as the
reaction is not inhibited, the bases include tertiary amines such
as pyridine, diisopropylethylamine or triethylamine. The copper
catalyst used varies depending on the starting materials, solvent
used, and so on in the production. Preferably, although not
specifically limited to as far as the reaction is not inhibited,
the copper catalysts include divalent copper compounds such as
copper acetate, copper bromide or copper sulfate, and copper
acetate is more preferred. The solvent used varies depending on the
starting materials, reagents, and so on in the production.
Preferably, although not specifically limited to as far as the
reaction is not inhibited and the starting materials are dissolved
to a certain degree, the solvents include N,N-dimethylformamide,
tetrahydrofuran, ethylacetate, and dichloromethane dioxane. The
reaction temperature is preferably room temperature to 120.degree.
C.
(Production Process U)
##STR00044##
[0092] In the above formulae, Ar.sup.1u represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2u and R.sup.3u are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl having two to six carbon atoms group which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted, a 5 to 14-membered
aromatic heterocyclic group which may be substituted, an acyl group
having one to six carbon atoms which may be substituted or an
alkylsulfonyl group having one to six carbon atoms which may be
substituted; R.sup.4u represents a hydrogen atom, a cyano group, an
alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, an aromatic hydrocarbon cyclic group
having six to fourteen carbon atoms which may be substituted, a 5
to 14-membered aromatic heterocyclic group which may be
substituted, a nitrogen atom which may be substituted or an oxygen
atom which may be substituted; R.sup.5u represents a nitrogen atom
which may be substituted, an oxygen atom which may be substituted
or a sulfur atom which may be substituted; the ring A.sup.u
represents a pyridyl group, a pyrimidinyl group, a pyrazinyl group
or a pyridazinyl group; and X.sup.u represents a halogen atom, an
alkylsulfonyloxy group or an arylsulfonyloxy group. The compound
(U2) of the present invention can be produced by the reaction
between the compound (U1) and a nucleophilic reagent in a solvent
or in the absence of the solvent. The nucleophilic reagent used in
the reaction is primary or secondary amine or alkali metal
alkoxide. The alkali metal alkoxide is prepared by allowing an
alkali metal or base to react with alcohol in a solvent or in the
absence of the solvent. Preferably, an alkali metal used in the
preparation of the alkali metal alkoxide is sodium or potassium.
The base used in the preparation of the alkali metal alkoxide
varies depending on the starting materials, solvents used, and so
on in the production. Preferably, although not specifically limited
to as far as the reaction is not inhibited, the base is an alkali
metal hydride such as sodium hydride, or alternatively alkali metal
alkoxide such as sodium methoxide, sodium ethoxide or potassium
t-butoxide. The solvent used varies depending on the starting
materials, reagents, and so on. Preferably, although not
specifically limited to as far as the reaction is not inhibited and
the starting materials and reagents are dissolved to a certain
degree, the solvents include N,N-dimethylformamide,
N-methylpyrrolidone, dimethylsulfoxide, alcohols such as methanol
or ethanol, ethers such as tetrahydrofuran, 1,2-dimethoxyethane or
1,4-dioxane, water, and a mixed solvent thereof. The reaction
temperature is preferably room temperature to 200.degree. C.
(Production Process V)
##STR00045##
[0094] In the above formulae, Ar.sup.1v represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2v and R.sup.3v are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted, a 5 to 14-membered
aromatic heterocyclic group which may be substituted, an acyl group
having one to six carbon atoms which may be substituted or an
alkylsulfonyl group having one to six carbon atoms which may be
substituted; R.sup.dv represents a hydrogen atom, a halogen atom, a
cyano group, an alkyl group having one to six carbon atoms which
may be substituted, an alkenyl group having two to six carbon atoms
which may be substituted, an alkynyl group having two to six carbon
atoms which may be substituted, an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted,
a 5 to 14-membered aromatic heterocyclic group which may be
substituted, a nitrogen atom which may be substituted, an oxygen
atom which may be substituted or a sulfur atom which may be
substituted; R.sup.5v represents an alkyl group having one to six
carbon atoms, the ring A.sup.v represents a pyridyl group, a
pyrimidynyl group, a pyrazinyl group, a pyridazinyl group, a
dihydrooxopyridinyl group, a dihydrooxopyrimidinyl group, a
dihydrooxopyrazinyl group or a dihydrooxopyridazinyl group; and
B.sup.v represents an alkyl group having one to six carbon atoms
which may be substituted, analkenyl group having two to six carbon
atoms which may be substituted, an alkynyl group having two to six
carbon atoms which may be substituted, a cycloalkyl group having
three to eight carbon atoms which may be substituted, a
cycloalkenyl group having three to eight carbon atoms which may be
substituted, a 5 to 14-membered non-aromatic heterocyclic group
which may be substituted, an aromatic hydrocarbon cyclic group
having six to fourteen carbon atoms which may be substituted or a 5
to 14-membered aromatic heterocyclic group which may be
substituted. The compound (V2) of the present invention can be
produced by allowing a base to react with the compound (V1) in a
solvent. The base used in the reaction varies depending on the
starting materials, solvent used, and so on. Preferably, although
not specifically limited to as far as the reaction is not
inhibited, the base is alkali metal hydroxide such as sodium
hydroxide or potassium hydroxide. The solvent used varies depending
on the starting materials, reagents, and so on. Preferably,
although not specifically limited to as far as the reaction is not
inhibited and the starting materials are dissolved to a certain
degree, the solvents include methanol, tetrahydrofuran,
dichloromethane, 1,2-dimethoxyethane, 1,4-dioxane, water, and mixed
solvents thereof. The reaction temperature is preferably 0.degree.
C. to 120.degree. C.
(Production Process W)
##STR00046##
[0096] In the above formulae, Ar.sup.1w represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2w and R.sup.3w are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
R.sup.4w represents a hydrogen atom, a halogen atom, a cyano group,
an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, an aromatic hydrocarbon cyclic group
having six to fourteen carbon atoms which may be substituted, a 5
to 14-membered aromatic heterocyclic group which may be
substituted, a nitrogen atom which may be substituted, an oxygen
atom which may be substituted or a sulfur atom which may be
substituted; the ring A.sup.w represents a pyridyl group, a
pyrimidinyl group, a pyrazinyl group or a pyridazinyl group; the
ring A.sup.'w represents a dihydrooxopyridinyl group, a
dihydrooxopyrimidinyl group, a dihydrooxopyrazinyl group or a
dihydrooxopyridazinyl group; and X.sup.w represents a halogen atom.
The compound (W2) of the present invention can be produced, for
example, by this Production Process W. That is, the compound (W2)
can be produced by hydrolyzing the compound (W1) as a starting
material under acidic conditions. The acid used varies depending on
the starting materials, reagents, solvent, and so on used.
Preferably, although not specifically limited to as far as the
reaction is not inhibited, the acid is hydrochloric acid,
hydrobromic acid, sulfuric acid, or the like. This reaction is
preferably carried out in water, or alternatively carried out in a
mixed solvent of water with acetic acid or alcohols such as
ethanol, for instance. Furthermore, the reaction temperature is
generally room temperature to about 120.degree. C., preferably
80.degree. C. to 100.degree. C.
(Production Process X)
##STR00047##
[0098] In the above formulae, Ar.sup.1x represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2x and R.sup.3x are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted, a 5 to 14-membered
aromatic heterocyclic group which may be substituted, an acyl group
having one to six carbon atoms which may be substituted or an
alkylsulfonyl group having one to six carbon atoms which may be
substituted; R.sup.4x represents a hydrogen atom, a halogen atom, a
cyano group, an alkyl group having one to six carbon atoms which
may be substituted, an alkenyl group having two to six carbon atoms
which may be substituted, an alkynyl group having two to six carbon
atoms which may be substituted, an aromatic hydrocarbon cyclic
group having six to fourteen carbon atoms which may be substituted,
a 5 to 14-membered aromatic heterocyclic group which may be
substituted, a nitrogen atom which may be substituted, an oxygen
atom which may be substituted or a sulfur atom which may be
substituted; R.sup.9x and R.sup.10x are the same as or different
from each other and each represents a hydrogen atom, an alkyl group
having one to six carbon atoms which may be substituted, an alkenyl
group having two to six carbon atoms which may be substituted, an
alkynyl group having two to six carbon atoms which may be
substituted, a cycloalkyl group having three to eight carbon atoms
which may be substituted, a cycloalkenyl group having three to
eight carbon atoms which may be substituted, a 5 to 14-membered
non-aromatic heterocyclic group which may be substituted, an
aromatic hydrocarbon cyclic group having six to fourteen carbon
atoms which may be substituted or a 5 to 14-membered aromatic
heterocyclic group which may be substituted; the ring A.sup.x
represents a pyridyl group, a pyrimidinyl group, a pyrazinyl group,
a pyridazinyl group, a dihydrooxopyridinyl group, a
dihydrooxopyrimidinyl group, a dihydrooxopyrazinyl group or a
dihydrooxopyridazinyl group; and B.sup.x represents an alkyl group
having one to six carbon atoms which may be substituted, an alkenyl
group having two to six carbon atoms which may be substituted, an
alkynyl group having two to six carbon atoms which may be
substituted, a cycloalkyl group having three to eight carbon atoms
which may be substituted, a cycloalkenyl group having three to
eight carbon atoms which may be substituted, a 5 to 14-membered
non-aromatic heterocyclic group which may be substituted, an
aromatic hydrocarbon cyclic group having six to fourteen carbon
atoms which may be substituted or a 5 to 14-membered aromatic
heterocyclic group which may be substituted. The compound (X2) of
the present invention can be produced by dehydration-condensation
of a carboxylic acid derivative (X1) with amine in the presence of
a condensing agent in a solvent. The condensing agent used is
preferably 3-(3'-dimethylaminopropyl)-1-ethylcarbodiimide. The
reaction can be accelerated by the addition of
1-hydroxybenzotriazole or the like. Furthermore, when the amine to
be condensed with the carboxylic acid forms a salt with hydrogen
chloride or the like, an appropriate amount of tertiary amine such
as triethylamine is added. Preferable examples of the solvent used
include ethers such as tetrahydrofuran, dioxane,
1,2-dimethoxyethane or diethylene glycol, N,N-dimethylformamide and
1-methylpyrrolidinone. The reaction temperature is generally
0.degree. C. to 50.degree. C., preferably around room
temperature.
(Production Process Y)
##STR00048##
[0100] In the above formulae, R.sup.1y represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2y represents a hydrogen atom
or an alkyl group having one to six carbon atoms; R.sup.3y
represents an alkyl group having one to six carbon atoms which may
be substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted or a 5 to
14-membered aromatic heterocyclic group which may be substituted;
and X.sup.y represents a halogen atom. The compound (Y4) as a raw
material for the production of the compound represented by the
formula (I) of the present invention can be produced by this
Production Process Y.
Step Y-1: This step is to produce the compound (Y2) by allowing a
reducing agent to react with the compound (Y1) in a solvent to
convert the ester or carboxyl group of the compound (Y1) into a
hydroxymethyl group. The reducing agent used is preferably sodium
tetrahydroborate, lithium aluminum hydride, a
borane-tetrahydrofuran complex, or the like. The solvent used
varies depending on the starting materials, reagents, and so on.
Preferably, although not specifically limited to insofar as the
reaction is not inhibited and the starting materials are dissolved
to a certain degree, the solvents include alcohols such as ethanol
and ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane.
The reaction temperature is preferably -20.degree. C. to room
temperature. Step Y-2: This step is to produce the sulfonic acid
ester derivative (Y4) by allowing the compound (Y2) to react with
the sulfonyl halide derivative (Y3) in a solvent in the presence of
a base. The base used in the reaction is preferably tertiary amine
such as triethylamine. The solvent used varies depending on the
starting materials, reagents, and so on. Preferably, although not
specifically limited to insofar as the reaction is not inhibited
and the starting materials are dissolved to a certain degree, the
solvents include dichloromethane, dichloroethane, diethyl ether,
tetrahydrofuran, and 1,4-dioxane. The reaction temperature is
preferably -20.degree. C. to room temperature.
(Production Process Z)
##STR00049##
[0102] In the above formulae, Ar.sup.1z represents an aromatic
hydrocarbon cyclic group having six to fourteen carbon atoms which
may be substituted or a 5 to 14-membered aromatic heterocyclic
group which may be substituted; R.sup.2z and R.sup.3z are the same
as or different from each other and each represents a hydrogen
atom, an alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, a cycloalkyl group having three to eight
carbon atoms which may be substituted, a cycloalkenyl group having
three to eight carbon atoms which may be substituted, a 5 to
14-membered non-aromatic heterocyclic group which may be
substituted, an aromatic hydrocarbon cyclic group having six to
fourteen carbon atoms which may be substituted, a 5 to 14-membered
aromatic heterocyclic group which may be substituted, an acyl group
having one to six carbon atoms which may be substituted or an
alkylsulfonyl group having one to six carbon atoms which may be
substituted; R.sup.4z represents a hydrogen atom, a cyano group, an
alkyl group having one to six carbon atoms which may be
substituted, an alkenyl group having two to six carbon atoms which
may be substituted, an alkynyl group having two to six carbon atoms
which may be substituted, an aromatic hydrocarbon cyclic group
having six to fourteen carbon atoms which may be substituted, a 5
to 14-membered aromatic heterocyclic group which may be
substituted, a nitrogen atom which may be substituted, an oxygen
atom which may be substituted or a sulfur atom which may be
substituted; the ring A.sup.z represents a pyridyl group, a
pyrimidinyl group, a pyrazinyl group or a pyridazinyl group; and
X.sup.z represents a halogen atom. The compound (Z2) of the present
invention can be produced by the reaction of the compound (Z1) and
alkali metal cyanide in a solvent. The alkali metal cyanide used in
the reaction is preferably sodium cyanide or potassium cyanide. The
solvent used varies depending on the starting materials, regents,
and so on. Preferably, although not specifically limited to insofar
as the reaction is not inhibited and the starting materials are
dissolved to a certain degree, the solvents include
dimethylsulfoxide, N,N-dimethylformamide and N-methylpyrrolidone.
The reaction temperature is preferably 100.degree. C. to
200.degree. C.
[0103] Typical examples of the production processes for the
compounds (I) according to the present invention have been
illustrated above. The material compounds used in the production of
the compounds of the present invention may form salts and/or
solvates and are not specifically limited, as long as they do not
adversely affect the reaction. When the compounds (I) according to
the present invention are obtained as free form, they can be
converted into possible salts of the above-mentioned compounds (I)
according to a conventional procedure. Various isomers such as
geometrical isomers, optical isomers based on an asymmetric carbon,
rotational isomers, stereoisomers, and tautomers obtained as the
compounds (I) according to the present invention can be purified
and isolated according to a conventional separation means. Such
separation means include, for example, recrystallization,
diastereomeric salt method, enzymatic resolution, and a variety of
chromatography such as thin layer chromatography, column
chromatography or gas chromatography.
[0104] The compounds represented by the formula (I) according to
the present invention, salts thereof or solvates of them can be
formulated into pharmaceutical preparations as intact or as a
mixture with, for example, a known pharmacologically acceptable
carrier according to a conventional procedure. Preferred dosage
forms are tablets, powders, subtle granules, granules, coated
tablets, capsules, syrups, troches, inhalants, suppositories,
injections, ointments, ophthalmic ointments, eye drops, nasal
drops, ear drops, cataplasms, and lotions. In the formulation,
generally used fillers, binders, disintegrators, lubricants,
coloring agents, and flavoring agents, as well as stabilizers,
emulsifiers, absorbefacients, surfactants, pH adjusting agents,
antiseptics, and antioxidants according to necessity can be used.
They can be formulated according to a conventional procedure using
components generally used as raw materials for pharmaceutical
preparations. Examples of such components include (1) animal and
vegetable oils such as soybean oil, beef tallow and synthetic
glycerides; (2) hydrocarbons such as liquid paraffins, squalane and
solid paraffins; (3) ester oils such as octyldodecyl myristate and
isopropyl myristate; (4) higher alcohols such as cetostearyl
alcohol and behenyl alcohol; (5) silicone resins; (6) silicone
oils; (7) surfactants such as polyoxyethylene fatty acid esters,
sorbitan fatty acid esters, glycerin fatty acid esters,
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene
hydrogenated castor oils and polyoxyethylene-polyoxypropylene block
copolymers; (8) water-soluble polymers such as hydroxyethyl
cellulose, poly(acrylic acid)s, carboxyvinyl polymers, polyethylene
glycol, polyvinylpyrrolidone and methylcellulose; (9) lower
alcohols such as ethanol and isopropanol; (10) polyhydric alcohols
such as glycerol, propylene glycol, dipropylene glycol and
sorbitol; (11) sugars such as glucose and sucrose; (12) inorganic
powders such as silicic anhydride, magnesium aluminium silicate and
aluminium silicate; and (13) purified water. 1) The fillers
include, for example, lactose, corn starch, sucrose, glucose,
mannitol, sorbitol, crystalline cellulose and silicon dioxide; 2)
the binders include, for example, polyvinyl alcohol, polyvinyl
ether, methylcellulose, ethylcellulose, gum arabic, gum tragacanth,
gelatin, shellac, hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, polyvinylpyrrolidone, polypropylene
glycol-polyoxyethylene block polymers, meglumine, calcium citrate,
dextrin and pectin; 3) the disintegrators include, for example,
starch, agar, gelatin powder, crystalline cellulose, calcium
carbonate, sodium hydrogencarbonate, calcium citrate, dextrin,
pectin and carboxymethylcellulose calcium; 4) the lubricants
include, for example, magnesium stearate, talc, polyethylene
glycol, silica, and hardened vegetable oils; 5) the coloring agents
can be any coloring agents which are approved to add to
pharmaceutical preparations; 6) the flavoring agents include, for
example, cocoa powder, menthol, aromatic powder (empasm),
peppermint oil, camphol (borneol) and cinnamon powder; and 7) the
antioxidants can be any antioxidants which are approved to add to
pharmaceutical preparations, such as ascorbic acid and
.alpha.-tocopherol.
[0105] 1) The oral preparation is produced by mixing the compound
according to the present invention or a salt thereof with a filler,
and if necessary, a binder, disintegrator, lubricant, coloring
agent, flavoring agent, and other components, and formulating the
mixture according to a conventional procedure into, for example, a
powder, subtle granules, granules, tablet, coated tablet or
capsules. 2) The tablets and granules can be appropriately coated
with, for example, sugar or gelatin according to necessity. 3) The
liquid formulations such as syrups, injection preparations or eye
drops can be prepared according to a conventional procedure by
adding a pH adjusting agent, solubilizer, and isotonizing agent,
and if necessary, a solubilizing agent, stabilizer, buffer,
suspending agent, antioxidant, and other components. The liquid
formulations can also be formed into freeze-dried products. The
injections can be administered intravenously, subcutaneously and/or
intramuscularly. Preferred examples of the suspending agents are
methylcellulose, polysorbate 80, hydroxyethyl cellulose, gum
arabic, powdered tragacanth, carboxymethylcellulose sodium and
polyoxyethylene sorbitan monolaurate; preferred examples of the
solubilizers are polyoxyethylene hydrogenated caster oil,
polysorbate 80, nicotinamide and polyoxyethylene sorbitan
monolaurate; preferred examples of the stabilizers are sodium
sulfite, sodium metasulfite and ether; preferred examples of the
preservatives are methyl p-hydroxybenzoate, ethyl
p-hydroxybenzoate, sorbic acid, phenol, cresol and
chlorocresol.
[0106] 4) The external preparations can be produced according to a
conventional procedure not specifically limited. Base materials for
use herein can be any raw materials generally used in, for example,
pharmaceutical preparations, quasi drugs and cosmetics. Such raw
materials include, for example, animal and vegetable oils, mineral
oils, ester oils, waxes, higher alcohols, fatty acids, silicone
oils, surfactants, phospholipids, alcohols, polyhydric alcohols,
water-soluble polymers, clay minerals, and purified water. Where
necessary, any of pH adjusting agents, antioxidants, chelating
agents, antiseptics and antimolds, coloring agents, flavors, and
others can be added. In addition, components having
differentiation-inducing action, blood-flow accelerators,
bactericides, anti-inflammatory agents, cell activators, vitamins,
amino acids, humectants, keratolytic agents, and other components
can be added according to necessity.
[0107] The dose of the pharmaceutical preparation according to the
present invention varies depending on the degree of symptom, age,
sex, body weight, administration mode, type of the salt, difference
in sensibility to the drug, concrete type of the disease and other
factors. Generally, the pharmaceutical preparation may be
administered to an adult in one to several divided doses at a daily
dose of about 30 .mu.g to about 10 g, preferably 100 .mu.g to 5 g,
and more preferably 100 .mu.g to 100 mg for oral administration, or
about 30 .mu.g to about 1 g, preferably 100 .mu.g to 500 mg, and
more preferably 100 .mu.g to 30 mg for injection
administration.
[0108] The present invention can provide a novel pyrimidine
compound. The compounds according to the present invention, salts
thereof or solvates of them have an excellent antagonism against an
adenosine receptor (adenosine A.sub.1, A.sub.2A, A.sub.2B or
A.sub.3 receptor) and are specifically excellent as an antagonist
against the adenosine A.sub.2 receptors, specifically against the
adenosine A.sub.2A and/or A.sub.2B receptor. They are useful as an
agent for treating or preventing a disease to which the adenosine
receptor (adenosine A.sub.1, A.sub.2A, A.sub.2B or A.sub.3
receptor) relates and a disease against which an antagonist of the
receptor is efficacious. They are useful as an agent for treating,
preventing or improving various constipations (functional
constipation, irritable bowel syndrome, constipation accompanying
irritable bowel syndrome, organic constipation, constipation
accompanying enteroparalytic ileus, constipation accompanying
congenital digestive tract dysfunction, constipation accompanying
ileus), as an agent for treating, preventing or improving diabetes
mellitus, diabetic complications, diabetic retinopathy, obesity or
asthma, and are also useful as, for example, a hypoglycemic agent,
agent for ameliorating glucose intolerance, insulin sensitizer,
antihypertensive drug, diuretic agent, antidepressant, agent for
treating osteoporosis, agent for treating Parkinson's disease,
agent for treating Alzheimer's disease, agent for treating an
inflammatory bowel disease or agent for treating Crohn's
disease.
EXAMPLES
[0109] The following Reference Examples, Examples and Test Examples
are illustrative, and the compounds of the present invention are
under no circumstances restricted by the following examples. Those
skilled in the art can modify not only the following Examples but
also the claims according to the present description in various
ways to exploit to the full of the present invention, and such
modifications and variations are also included within the scope of
the appended claims relating to the present description.
Reference Example 1
Ethyl (E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenoate
##STR00050##
[0111] A solution of ethyl 4-pyridylacetate (25.0 g, 0.151 mol) and
3-fluorobenzaldehyde (20.7 g, 0.167 mol) in a mixture of acetic
anhydride (100 mL) and triethylamine (20 mL) was heated under
reflux for 5.5 hours. After standing to cool, the reaction mixture
was concentrated. The residue was diluted with ethyl acetate and a
saturated aqueous sodium hydrogencarbonate solution, and the
aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with a saturated aqueous sodium
hydrogencarbonate solution twice and brine, dried over anhydrous
sodium sulfate and then concentrated. The residue was subjected to
silica gel column chromatography (eluent; hexane, hexane:ethyl
acetate=9:1), to give the title compound (25.5 g, 62%) as a
red-orange oil.
[0112] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 1.28 (3H, t,
J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 6.70-6.75 (1H, m), 6.80-6.84
(1H, m), 6.91-6.97 (1H, m), 7.12-7.18 (1H, m), 7.16 (2H, dd, J=1.6,
4.4 Hz), 7.85 (1H, s), 8.62 (2H, dd, J=1.6, 4.4 Hz).
Reference Example 2
Ethyl (E)-3-(2-furyl)-2-(4-pyridyl)-2-propenoate
##STR00051##
[0114] The title compound was synthesized in a similar manner to
Reference Example 1 using 2-furaldehyde.
[0115] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 1.20 (3H, t,
J=7.2 Hz), 4.18 (2H, q, J=7.2 Hz), 6.51 (1H, d, J=3.6 Hz), 6.54
(1H, dd, J=1.6, 3.6 Hz), 7.29 (2H, dd, J=1.6, 4.4 Hz), 7.66 (1H,
s), 7.69 (1H, d, J=1.6 Hz), 8.62 (2H, dd, J=1.6, 4.4 Hz).
Reference Example 3
(E)-4-(2-Furyl)-3-(4-pyridyl)-3-buten-2-one
##STR00052##
[0117] Under a nitrogen atmosphere, a 3.0M solution of
methylmagnesium bromide in diethyl ether (3.7 ml, 11.1 mmol) was
added dropwise over 5 minutes to a 1M solution of lithium
bis(trimethylsilyl)amide in tetrahydrofuran (22 ml, 22 mmol) at
-50.degree. C. (dry ice-acetone bath), followed by stirring as it
was for 1 hour. Then, a solution of ethyl
(E)-3-(2-furyl)-2-(4-pyridyl)-.degree. 2-propenoate (2.4 g, 9.87
mmol) in tetrahydrofuran (20 ml) was added dropwise therein to over
5 minutes. The reaction mixture was stirred for 30 minutes while
elevating to room temperature, and then the reaction was terminated
by adding hydrochloric acid. After diluting with a saturated
aqueous ammonium chloride solution, the mixture was extracted with
ethyl acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate and concentrated. The residue was
subjected to silica gel column chromatography (elution solvent;
hexane:ethyl acetate=1:1 to 4:1), to give the title compound (0.52
g, 23%).
[0118] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 2.36 (3H, s),
6.07 (1H, d, J=3.2 Hz), 6.34 (1H, dd, J=1.6, 3.2 Hz), 7.16 (2H, dd,
J=1.8, 4.4 Hz), 7.38 (1H, d, J=1.6 Hz), 7.55 (1H, s), 8.70 (2H, dd,
J=1.8, 4.4 Hz).
Reference Example 4
(E)-3-(3-Fluorophenyl)-2-(4-pyridyl)-2-propenenitrile
##STR00053##
[0120] Sodium (3.0 g, 130 mmol) was dissolved in ethanol (150 mL)
4-pyridylacetonitrile hydrochloride (10 g, 65 mmol) was added
thereto, and then the mixture was stirred at room temperature.
After 10 minutes, 3-fluorobenzaldehyde (8 g, 65 mmol) was added
thereto, followed by stirring as it was for 30 minutes. The
resulting precipitates were collected by filtration and washed with
a small portion of water, to give the title compound (8.2 g, 56%)
as a colorless solid.
[0121] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 7.40-7.46
(1H, m), 7.61-7.68 (1H, m>, 7.75 (2H, dd, J=1.6, 4.4 Hz),
7.77-7.86 (2H, m), 8.37 (1H, s), 8.73 (2H, dd, J=1.6, 4.4 Hz).
Reference Example 5
1-(2-Furyl)-2-(4-pyridyl)-1-ethanone
##STR00054##
[0123] To a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl
2-furancarboxylate (7.7 g, 54.9 mmol) in tetrahydrofuran (40 ml)
was dropwise added lithium bis(trimethylsilyl)amide (100 ml, 100
mmol) over 1 hour at 0.degree. C. under an atmosphere of nitrogen
gas, followed by stirring as it was for 2 hours. Hexane (140 ml)
was added to the reaction mixture, and the resulting crystals were
collected by filtration. The resulting crystals were dissolved in
ethyl acetate and a saturated aqueous ammonium chloride solution.
The organic layer was washed with a saturated aqueous ammonium
chloride solution twice and brine, dried over anhydrous sodium
sulfate and concentrated. Hexane was added to the residue, and the
resulting precipitates were collected by filtration and washed with
hexane, to give the title compound (6.5 g, 70%) as a pale yellow
solid.
[0124] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.26 (2 Hr
s), 6.77 (1H, dd, J=2.0, 3.6 Hz), 7.31 (2H, dd, J=1.6, 4.4 Hz),
7.65 (1H, dd, J=0.8, 3.6 Hz), 8.05 (1H, dd, J=0.8, 2.0 Hz), 8.51
(2H, dd, J=1.6, 4.4 Hz).
Reference Example 6
3-(Dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propen-1-one
##STR00055##
[0126] N,N-Dimethylformamide dimethyl acetal (5 ml) was added to
1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.0 g, 10.7 mmol) and the
mixture was stirred at 100.degree. C. for 2 hours. After cooling as
it was, the reaction mixture was diluted with ethyl acetate and a
saturated aqueous ammonium chloride solution. The aqueous layer was
extracted with ethyl acetate (.times.6). The combined organic
layers were dried over anhydrous sodium sulfate and then
concentrated, to give the title compound (2.5 g, 97%) as a reddish
brown oil.
[0127] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.80 (6H,
br s), 6.53 (1H, br), 6.60 (1H, br), 7.10 (2H, d, J=4.0 Hz), 7.65
(1H, br), 7.75 (1H, s), 8.44 (2H, d, J=4.0 Hz).
Reference Example 7
(6-Chloro-3-pyridyl)methanol
##STR00056##
[0129] To a solution of ethyl 6-chloronicotinate (25.8 g, 0.139
mol) in ethanol was added sodium borohydride (10.5 g, 0.278 mol),
followed by stirring under an atmosphere of nitrogen gas at room
temperature. After 41 hours, the reaction mixture was concentrated
and then the residue was diluted with a saturated aqueous ammonium
chloride solution and ethyl acetate. The organic layer was washed
with a saturated aqueous ammonium chloride solution, dried over
anhydrous sodium sulfate and concentrated. The residue was
subjected to silica gel column chromatography (elution solvent;
hexane, hexane:ethyl acetate=4:1, 2:1, and 3:2), to give the title
compound (11.7 g, 58%) as a pale yellow solid.
[0130] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.54 (2H,
d, J=5.6 Hz), 5.43 (1H, t, J=5.6 Hz), 7.48 (1H, d, J=8.4 Hz), 7.80
(1H, dd, J=2.4, 8.4 Hz), 8.35 (1H, d, J=2.4 Hz).
Reference Example 8
(6-Chloro-3-pyridyl)methyl methanesulfonate
##STR00057##
[0132] To a solution of (6-chloro-3-pyridyl)methanol (4.5 g, 31.3
mmol) and triethylamine (13.2 ml, 94.7 mmol) in dichloromethane (90
ml) was dropwise added methanesulfonyl chloride (3.6 ml, 46.5 mmol)
over 45 minutes at -9.degree. C. to 4.degree. C. under an
atmosphere of nitrogen gas, followed by stirring as it was. After 1
hour, the reaction mixture was elevated to room temperature. The
reaction mixture was washed with an aqueous saturated sodium
bicarbonate solution and a saturated aqueous ammonium chloride
solution, dried over anhydrous sodium sulfate and concentrated, to
give the title compound (6.14 g, 88%) as a pale brown solid.
[0133] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.30 (3H,
s), 5.34 (2H, s), 7.61 (1H, dd, J=0.6, 8.0 Hz), 7.97 (1H, dd,
J=2.4, 8.0 Hz), 8.53 (1H, dd, J=0.6, 2.4 Hz).
Reference Example 9
2-(6-Chloro-3-pyridyl)-1-(2-furyl)-1-ethanone
##STR00058##
[0135] To a mixture of 2-furaldehyde (7.9 g, 82.2 mmol) and zinc
(II) iodide (110 mg, 0.345 mmol) was dropwise added trimethylsilyl
cyanide (11.0 ml, 82.5 mmol) over 10 minutes at 0.degree. C. under
an atmosphere of nitrogen gas, followed by stirring as it was.
After 30 minutes, the reaction mixture was diluted with
tetrahydrofuran (200 ml) and then cooled to -78.degree. C. A 1.0M
solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (86
ml, 86 mmol) was added dropwise thereto over 1 hour and then a
solution of (6-chloro-3-pyridyl)methyl methanesulfonate (18.1 g,
81.7 mmol) in tetrahydrofuran (50 ml) was added dropwise over 1.5
hours thereto, followed by stirring while gradually elevated to
room temperature. After 12.5 hours, a 1.0M solution of
tetrabutylammonium fluoride in tetrahydrofuran (86 ml, 86 mmol) was
added thereto, followed by stirring as it was. After further 30
minutes, the reaction mixture was diluted with a saturated aqueous
ammonium chloride solution and ethyl acetate. The resulting organic
layer was washed with a saturated aqueous ammonium chloride
solution twice, dried over anhydrous sodium sulfate and
concentrated. The residue was subjected to silica gel column
chromatography (elution solvent; hexane, hexane:ethyl acetate=10:1,
4:1, 3:1, and 2:1) and then suspended in hexane. Subsequently, the
resulting precipitates were collected by filtration, to give the
title compound (11.9 g, 54%) as a pale brown solid.
[0136] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.31 (2H,
s), 6.78 (1H, dd, J=1.8, 3.4 Hz), 7.50 (1H, d, J=8.4 Hz), 7.64 (1H,
d, J=3.4 Hz), 7.77 (1H, dd, J=2.4, 8.4 Hz), 8.06 (1H, d, J=1.8 Hz),
8.33 (1H, d, J=2.4 Hz).
Reference Example 10
2-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(2-furyl)-2-propen-1-one
##STR00059##
[0138] The title compound was synthesized in a similar manner to
Reference Example 6 using
2-(6-chloro-3-pyridyl)-1-(2-furyl)-1-ethanone.
[0139] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.79 (6H,
br s), 6.55 (1H, dd, J=2.0, 3.4 Hz), 6.62 (1H, d, J=3.4 Hz), 7.45
(1H, d, J=8.0 Hz), 7.59 (1H, dd, J=2.4, 8.0 Hz), 7.77 (2H, d, J=2.0
Hz), 8.14 (1H, d, J=2.4 Hz).
Reference Example 11
(E)-3-(3-Fluorophenyl)-2-(6-methoxy-3-pyridyl)-2-propenenitrile
##STR00060##
[0141] To a suspension of sodium hydride (8.8 g, 0.220 mol) in
1,2-dimethoxyethane (300 ml) was added diethyl
cyanomethylphosphonate (19.7 g, 0.122 mol) little by little at room
temperature under an atmosphere of nitrogen gas. After stirring for
15 minutes, 5-bromo-2-methoxypyridine (20.0 g, 0.106 mol) and
tetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol) were
successively added thereto, followed by heating to 90.degree. C.
and stirring for 6 hours. The reaction mixture was cooled as it was
and further ice-cooled. 3-Fluorobenzaldehyde (13.7 g, 0.110 mol)
was added dropwise thereto over 1.5 hours at 1 to 4.degree. C.
under an atmosphere of nitrogen gas, followed by stirring further
for 2.5 hours while gradually elevating to room temperature. The
reaction mixture was diluted with a saturated aqueous ammonium
chloride solution and ethyl acetate, and then the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with a saturated aqueous ammonium chloride solution twice,
dried over anhydrous sodium sulfate and then concentrated. The
residue was suspended in methanol, and then the resulting solid was
collected by filtration and washed with diethyl ether and hexane,
to give the title compound (7.80 g, 29%) as a colorless solid.
[0142] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.92 (3H,
s), 7.00 (1H, d, J=8.8 Hz), 7.34-7.40 (1H, m), 7.57-7.64 (1H, m),
7.69-7.78 (2H, m), 8.03 (1H, s), 8.11 (1H, dd, J=2.6, 8.8 Hz), 8.53
(1H, d, J=2.6 Hz).
Reference Example 12
2-Amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone
##STR00061##
[0143] (Method 1)
[0144] Sodium (3.2 g, 139 mmol) was dissolved in ethanol (200 ml),
and then 4-pyridylacetonitrile (10.0 g, 64.7 mmol),
3-fluorobenzaldehyde (7.3 ml, 68.8 mmol) and guanidine
hydrochloride (7.0 g, 73.3 mmol) were successively added thereto,
followed by heating under reflux for 2 days. The insoluble matters
were filtered off and the filtrate was concentrated. The residue
was subjected to silica gel column chromatography (elution solvent;
dichloromethane, dichloromethane methanol=20:1, 10:1, 5:1), to give
a 5,6-dihydro product (13.6 g) of the title compound as a crude
product. Sulfur (26.4 g, 82.3 mmol as S) was added to the product,
followed by heating at 185.degree. C. for 2.5 hours. After cooling
as it was, the reaction mixture was suspended in methanol, and the
insoluble matters were filtered off and washed with 2N
hydrochloride. Methanol in the filtrate was concentrated and the
residue was washed with ethyl acetate twice. The aqueous layer was
adjusted to pH 11 with a 5N aqueous sodium hydroxide solution,
washed with ethyl acetate twice and then neutralized with 2N
hydrochloride. The resulting crystals were collected by filtration,
and washed with water and ethyl acetate, to give the title compound
(6.2 g, 34%) as a colorless solid. Furthermore, in this method, the
title compound was also obtained by isolating
(E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenenitrile and then
subjecting it to a cyclization reaction with guanidine in a similar
manner to Reference Example 4.
(Method 2)
[0145] Sodium (3.4 g, 147 mmol) was dissolved in ethanol (500 ml),
and then ethyl (E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenoate
(33 g, 121 mmol) and guanidine hydrochloride (13.9 g, 146 mmol)
were added thereto, followed by heating under reflux for 13 hours.
After cooling as it was, the solvent was removed. Tetrahydrofuran
(500 ml) was added to the residue, the insoluble matters were
filtered off, and the filtrate was concentrated. To a solution of
the residue in tetrahydrofuran (1500 ml)-methanol (100 ml) was
added active manganese dioxide (250 g), followed by heating under
reflux. After 2 hours, additional active manganese dioxide (100 g)
was added thereto, followed by heating under reflux further for 1
hour and 15 minutes. After cooling as it was, the manganese dioxide
was filtered off through Celite and washed with tetrahydrofuran and
methanol. The collected filtrate was concentrated and acetonitrile
was added to the residue. The resulting precipitates were collected
by filtration, to give the title compound (15 g, 44%) as a yellow
powder.
[0146] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.86 (2H,
br s), 6.96 (1H, d, J=7.6 Hz), 7.00-7.07 (3H, m), 7.00-7.15 (1H,
m), 7.20-7.28 (1H, m), 8.34 (2H, d, J=3.2 Hz); MS m/e (ESI) 283
(MH.sup.+).
Reference Example 13
2-Amino-6-(2-furyl)-5-(4-pirydyl)-3,4-dihydro-4-pyrimidinone
##STR00062##
[0148] The title compound was synthesized in a similar manner to
Method 1 of Reference Example 12 using 2-furaldehyde.
[0149] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.48 (1H,
dd, J=1.6, 3.6 Hz), 6.54 (1H, dd, J=0.8, 3.6 Hz), 6.91 (2H, br s),
7.21 (2H, dd, J=1.6, 4.6 Hz), 7.54 (1H, dd, J=0.8, 1.6 Hz), 8.52
(2H, dd, J=1.6, 4.6 Hz); MS m/e (ESI) 255 (MH.sup.+).
Reference Example 14
3-(Dimethylamino)-1-(2-furyl)-2-propen-1-one
##STR00063##
[0151] A mixture of 2-acetylfuran (25.0 g, 0.227 mol) and
N,N-dimethylformamide dimethylacetal (40 ml) was stirred at
100.degree. C. for 9 hours. After cooling as it was, the reaction
mixture was concentrated. To the residue were added diethyl ether
and hexane. The resulting solid was collected by filtration and
washed with hexane, to give the title compound (36.5 g, 97%) as a
brown solid.
[0152] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.88 (3H,
br s), 3.14 (3H, br s), 5.65 (1H, d, J=12.6 Hz), 6.60 (1H, dd,
J=2.0, 3.4 Hz), 7.10 (1H, dd, J=0.8, 3.4 Hz), 7.68 (1H, d, J=12.6
Hz), 7.79 (1H, dd, J=0.8, 2.0 Hz).
Reference Example 15
4-(2-Furyl)-2-pyrimidinylamine
##STR00064##
[0154] A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-one
(5.0 g, 30.3 mmol), guanidine hydrochloride (5.8 g, 60.7 mmol) and
potassium carbonate (8.4 g, 60.9 mmol) in N,N-dimethylformamide (50
ml) was stirred at 100.degree. C. for 21 hours. After cooling as it
was, the reaction mixture was diluted with ice water (250 ml). The
resulting solid was collected by filtration and washed with water,
to give the title compound (4.19 g, 86%) as a pale brown solid.
[0155] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.66 (2H,
br s), 6.68 (1H, dd, J=2.0, 3.2 Hz), 6.88 (1H, d, J=5.2 Hz), 7.17
(1H, dd, J=0.8, 3.2 Hz), 7.88 (1H, dd, J=0.8, 2.0 Hz), 8.28 (1H, d,
J=5.2 Hz); MS m/e (ESI) 162 (MH.sup.+).
Reference Example 16
5-bromo-4-(2-furyl)-2-pyrimidinylamine
##STR00065##
[0157] To a solution of 4-(2-furyl)-2-pyrimidinylamine (4.10 g,
25.4 mmol) in N,N-dimethylformamide (40 ml) was added
N-bromosuccinimide (4.53 g, 25.5 mmol) at 2.degree. C., followed by
stirring as it was. After 6 hours, the reaction mixture was diluted
with an aqueous saturated sodium bicarbonate solution (240 ml). The
mixture was ice-cooled, and then the crystals were collected by
filtration and washed with water, to give the title compound (5.10
g, 84%) as a pale brown solid.
[0158] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.73 (1H,
dd, J=1.6, 3.6 Hz) 6.96 (2H, br s), 7.50 (1H, dd, J=0.8, 3.6 Hz),
7.97 (1H, dd, J=0.8, 1.6 Hz), 8.41 (1H, s).
Reference Example 17
2-(Benzyloxy)-5-bromopyridine
##STR00066##
[0160] To a solution of benzyl alcohol (11.4 g, 0.105 mol) in
N,N-dimethylformamide (250 ml) was added 70% oily sodium hydride
(4.2 g, 0.123 mol) at 0.degree. C., followed by stirring as it was
for 1.5 hours. Then, 2,5-dibromopyridine (25 g, 0.106 mol) was
added thereto, followed by stirring at 70.degree. C. for 2 hours.
After cooling as it was, the reaction mixture was diluted with a
saturated aqueous ammonium chloride solution and extracted with
ethyl acetate. The resulting organic layer was washed with a
saturated aqueous ammonium chloride solution twice, dried over
anhydrous magnesium sulfate and concentrated, to give a crude
product of the title compound (29.5 g) as a pale yellow liquid.
[0161] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 5.33 (2H,
s), 6.90 (1H, d, J=9.0 Hz), 7.30-7.41 (3H, m), 7.41-7.46 (2H, m),
7.92 (1H, dd, J=2.8, 9.0 Hz), 8.30 (1H, d, J=2.8 Hz).
Reference Example 18
2-(Benzyloxy)-5-(1,1,1-tributylstanyl)pyridine
##STR00067##
[0163] To a suspension of the above crude product (29.5 g) of
2-(benzyloxy)-5-bromopyridine in diethyl ether (300 ml) was
dropwise added a 2.66 M solution of n-butyl lithium in hexane (40
ml, 0.106 mol) over 30 minutes at -76.degree. C. to -72.degree. C.
under an atmosphere of nitrogen gas. Subsequently, tetrahydrofuran
(170 ml) was added dropwise thereto, followed by stirring as it
was. After 1.5 hours, a solution of tributyltin chloride (35 g,
0.114 mol) in tetrahydrofuran (50 ml) was added dropwise thereto
over 1.5 hours. Then, the reaction mixture was stirred as it was
while gradually elevating to room temperature. After 6 hours, the
reaction mixture was diluted with a saturated aqueous ammonium
chloride solution and ethyl acetate. The resulting organic layer
was washed with a saturated aqueous ammonium chloride solution
twice, dried over anhydrous sodium sulfate and concentrated. The
residue was subjected to silica gel column chromatography (elution
solvent; hexane, hexane:ethyl acetate=20:1), to give the title
compound (47.0 g, 94%) as a colorless oil.
[0164] .sup.1H NMR (400 MHz, DMSO-d.sub.6).sub.6 ppm; 0.85 (9H, t,
J=7.6 Hz), 0.97-1.15 (6H, m), 1.29 (611, sex, J=7.6 Hz), 1.46-1.55
(6H, m), 5.33 (2H, s), 6.85-6.90 (1H, m), 7.29-7.41 (3H, m),
7.41-7.47 (2H, m), 7.66-7.78 (1H, m), 8.08-8.15 (1H, m).
Reference Example 19
2-(2-Fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone
##STR00068##
[0166] The title compound was synthesized in a similar manner to
Reference Example 5 using 2-fluoro-4-methylpyridine.
[0167] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.36 (2H,
s), 6.76 (1H, dd, J=1.6, 3.6 Hz), 7.11 (1H, br), 7.24-7.29 (1H, m),
7.63 (1H, dd, J=0.4, 3.6 Hz), 8.05 (m, dd, J=0.8, 1.6 Hz), 8.17
(1H, d, J=4.8 Hz).
Reference Example 20
2-(2-Bromo-4-pyridyl)-1-(2-furyl)-1-ethanone
##STR00069##
[0169] The title compound was synthesized in a similar manner to
Reference Example 5 using 2-bromo-4-methylpyridine.
[0170] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.31 (2H,
s), 6.77 (1H, dd, J=1.6, 3.6 Hz), 7.36 (1H, dd, J=1.6, 5.2 Hz),
7.60 (1H, dd, J=0.4, 1.6 Hz), 7.62 (1H, dd, J=0.8, 3.6 Hz), 8.05
(1H, dd, J=0.8, 1.6 Hz), 8.32 (1H, dd, J=0.4, 5.2 Hz).
Reference Example 21
4,6-Di(2-furyl)-2-pyrimidinamine
##STR00070##
[0172] The title compound was synthesized in a similar manner to
Reference Example 12 using 2-acetylfuran instead of
1-(2-furyl)-2-(4-pyridyl)-1-ethanone.
[0173] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.69 (2H,
dd, J=1.6, 3.6 Hz), 6.76 (2H, br s), 7.21 (1H, s), 7.21 (2H, dd,
J=0.8, 3.6 Hz), 7.90 (2H, dd, J=0.8, 1.6 Hz).
Reference Example 22
5-Bromo-4,6-di(2-furyl)-2-pyrimidinamine
##STR00071##
[0175] The title compound was synthesized in a similar manner to
Reference Example 16 using 4,6-di(2-furyl)-2-pyrimidinamine.
[0176] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.72 (2H,
dd, J=1.6, 3.6 Hz), 7.01 (2H, br s), 7.47 (2H, dd, J=0.8, 3.6 Hz),
7.95 (2H, dd, J=0.8, 1.6 Hz).
Reference Example 23
Alternative Synthetic Method of Reference Example 9
2-(6-Chloro-3-pyridyl)-1-(2-furyl)-1-ethanone
##STR00072##
[0178] The title compound was obtained in a similar manner to
Reference Example 9 using 2-chloro-5-(chloromethyl)pyridine instead
of (6-chloro-3-pyridyl)methyl methanesulfonate.
Reference Example 24
2-(6-Chloro-3-pyridyl)-1-(2-thienyl)-1-ethanone
##STR00073##
[0180] The title compound was obtained in a similar manner to
Reference Example 9 using 2-thiophenealdehyde.
[0181] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.46 (2H,
s), 7.31 (1H, dd, J=4.0, 4.8 Hz), 7.50 (1H, d, J=8.2 Hz), 7.78 (1H,
dd, J=2.4, 8.2 Hz), 8.07 (1H, dd, J=1.2, 4.8 Hz), 8.16 (1H, dd,
J=1.2, 4.0 Hz), 8.35 (1H, d, J=2.4 Hz).
Reference Example 25
2-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(2-thienyl)-2-propen-1-one
##STR00074##
[0183] The title compound was obtained in a similar manner to
Reference Example 6 using
2-(6-chloro-3-pyridyl)-1-(2-thienyl)-1-ethanone.
[0184] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.79 (6H,
br s), 7.06 (1H, dd, J=3.8, 5.0 Hz), 7.13 (1H, dd, J=1.0, 3.8 Hz),
7.47 (1H, d, J=8.0 Hz), 7.62 (1H, dd, J=2.4, 8.0 Hz), 7.69 (1H, s),
7.73 (1H, dd, J=1.0, 5.0 Hz), 8.16 (1H, d, J=2.4 Hz).
Reference Example 26
2-(6-Chloro-3-pyridyl)-1-phenyl-1-ethanone
##STR00075##
[0186] The title compound was obtained in a similar manner to
Reference Example 9 using benzaldehyde.
[0187] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.54 (2H,
s), 7.50 (1H, d, J=8.0 Hz), 7.55-7.61 (2H, m), 7.66-7.72 (1H, m),
7.76 (1H, dd, J=2.4, 8.0 Hz), 8.04-8.09 (2H, m), 8.32 (1H, d, J=2.4
Hz).
Reference Example 27
2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-phenyl-2-propen-1-one
##STR00076##
[0189] The title compound was obtained in a similar manner to
Reference Example 6 using
2-(6-chloro-3-pyridyl)-1-phenyl-1-ethanone.
[0190] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.73 (6H,
br s), 7.29 (1H, s), 7.36-7.45 (6H, m), 7.60 (1H, dd, J=2.2, 8.0
Hz), 8.14 (1H, d, J=2.2 Hz).
Reference Example 28
2-(6-Chloro-3-pyridyl)-1-(3-fluorophenyl)-1-ethanone
##STR00077##
[0192] The title compound was obtained in a similar manner to
Reference Example 9 using benzaldehyde.
[0193] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.55 (2H,
s), 7.51 (1H, d, J=8.2 Hz), 7.52-7.59 (1H, m), 7.61-7.68 (1H, m),
7.60 (1H, dd, J=2.4, 8.2 Hz), 7.82-7.87 (1H, m), 7.90-7.95 (1H, m),
8.31 (1H, d, J=2.4 Hz).
Reference Example 29
2-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(3-fluorophenyl)-2-propen-1-one
##STR00078##
[0195] The title compound was obtained in a similar manner to
Reference Example 6 using
2-(6-chloro-3-pyridyl)-1-(3-fluorophenyl)-1-ethanone.
[0196] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.74 (6H,
br s), 7.17-7.29 (3H, m), 7.31 (1H, s), 7.39-7.47 (2H, m), 7.61
(1H, dd, J=2.2, 8.0 Hz), 8.15 (1H, d, J=2.2 Hz).
Example 1
4-Chloro-6-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine
##STR00079##
[0198] A suspension of
2-amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone
(1.0 g, 3.54 mmol) in phosphorus oxychloride (15 ml) was stirred at
100.degree. C. for 30 minutes under an atmosphere of nitrogen gas.
After cooling as it was, the reaction mixture was concentrated and
the residue was dissolved in ethyl acetate and 2N sodium hydroxide.
The organic layer was washed with an aqueous saturated sodium
bicarbonate solution twice and brine, dried over anhydrous sodium
sulfate and concentrated. To the residue was added diethyl ether,
and the resulting precipitates were collected by filtration and
washed with diethyl ether, to give the title compound (513 mg, 48%)
as a colorless solid.
[0199] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 7.00-7.03
(1H, m), 7.05-7.10 (1H, m), 7.12-7.18 (1H, m), 7.24-7.31 (1H, m),
7.25 (2H, dd, J=1.6, 4.4 Hz), 8.51 (2H, dd, J=1.6, 4.4 Hz); MS m/e
(ESI) 301 (MH.sup.+).
Example 2
4-Chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine
##STR00080##
[0201] The title compound was synthesized in a similar manner to
Example 1 using
2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone.
[0202] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.27 (1H,
d, J=3.6 Hz), 6.48 (1H, dd, J=2.0, 3.6 Hz), 7.34 (2H, dd, J=1.6,
4.4 Hz), 7.35 (2H, br s), 7.67 (1H, dd, J=0.8, 2.0 Hz), 8.66 (2H,
dd, J=1.6, 4.4 Hz); MS m/e (ESI) 273 (MH.sup.+).
Example 3
4-(3-Fluorophenyl)-6-methoxy-5-(4-pyridyl)-2-pyrimidinylamine
##STR00081##
[0204] After sodium (20 mg, 0.870 mmol) was dissolved in methanol
(3 ml),
4-chloro-6-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine (50
mg, 0.166 mmol) was added thereto and the mixture was stirred under
an atmosphere of nitrogen gas at 60 to 65.degree. C. for 30
minutes. After cooling as it was, the reaction mixture was diluted
with ethyl acetate. Then, the mixture was washed with an aqueous
ammonium chloride solution thrice and brine, dried over anhydrous
sodium sulfate and concentrated. To the residue was added diethyl
ether, and the resulting precipitates were collected by filtration
and washed with diethyl ether, to give the title compound (16 mg,
32%) as a colorless solid.
[0205] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.83 (3H,
s), 6.90-7.16 (7H, m), 7.22-7.29 (1H, m), 8.40 (2H, d, J=4.8 Hz);
MS mie (ESI) 297 (MH.sup.+).
Example 4
4-Ethoxy-6-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine
##STR00082##
[0207] The title compound was synthesized in a similar manner to
Example 3 using ethanol.
[0208] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.23 (3H,
t, J=7.2 Hz), 4.33 (2 Hr q, J=7.2 Hz), 6.92 (2H, brs), 6.94-7.16
(5H, m), 7.22-7.29 (1H, m), 8.39 (2H, d, J=6.0 Hz); MS m/e (ESI)
311 (MH.sup.+).
Example 5
4-(3-Fluorophenyl)-6-propoxy-5-(4-pyridyl)-2-pyrimidinylamine
##STR00083##
[0210] The title compound was synthesized in a similar manner to
Example 3 using 1-propanol.
[0211] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 0.86 (3H,
t, J=7.2 Hz), 1.62 (2H, sex, J=7.2 Hz), 4.22 (2H, t, J=7.2 Hz),
6.92 (2H, br s), 6.96-7.00 (1H, m), 7.02-7.16 (2H, m), 7.08 (2H,
dd, J=1.6, 4.4 Hz), 7.23-7.29 (1H, m), 8.40 (2H, dd, J=1.6, 4.4
Hz); MS m/e (ESI) 325 (MH.sup.+).
Example 6
4-(3-Fluorophenyl)-6-isopropoxy-5-(4-pyridyl)-2-pyrimidinylamine
##STR00084##
[0213] The title compound was synthesized in a similar manner to
Example 3 using 2-propanol.
[0214] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.23 (6H,
d, J=6.0 Hz), 5.32 (1H, m), 6.89 (2H, br s), 6.92-7.16 (5H, m),
7.21-7.28 (1H, m), 8.38 (2H, br); MS m/e (ESI) 325 (MH.sup.+).
Example 7
4-Ethoxy-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine
##STR00085##
[0216] The title compound was synthesized in a similar manner to
Example 3 using
4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and
ethanol.
[0217] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.17 (3H,
t, J=6.8 Hz), 4.28 (2H, q, J=6.8 Hz), 6.36 (1H, dd, J=0.8, 3.6 Hz),
6.45 (1H, dd, J=1.6, 3.6 Hz), 6.81 (2H, br s), 7.19 (2H, d, J=4.4
Hz), 7.57 (1H, dd, J=0.8, 1.6 Hz), 8.54 (2H, d, J=4.4 Hz); MS m/e
(ESI) 283 (MH.sup.+).
Example 8
4-(2-Furyl)-6-propoxy-5-(4-pyridyl)-2-pyrimidinylamine
##STR00086##
[0219] The title compound was synthesized in a similar manner to
Example 3 using
4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and
1-propanol.
[0220] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 0.80 (3H,
t, J=7.2 Hz), 1.56 (2H, sex, J=7.2 Hz), 4.17 (2H, t, J=7.2 Hz),
6.38 (1H, dd, J=0.8, 3.6 Hz), 6.45 (1H, dd, J=1.6, 3.6 Hz), 6.80
(2H, br s), 7.19 (2H, dd, J=1.6, 4.4 Hz), 7.57 (1H, dd, J=0.8, 1.6
Hz), 8.54 (2H, dd, J=1.6, 4.4 Hz); MS m/e (ESI) 297 (MH.sup.+).
Example 9
4-(2-Furyl)-6-isopropoxy-5-(4-pyridyl)-2-pyrimidinylamine
##STR00087##
[0222] The title compound was synthesized in a similar manner to
Example 3 using
4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and
2-propanol.
[0223] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.17 (6H,
d, J=6.4 Hz), 5.28 (1H, sept, J=6.4 Hz), 6.35 (1H, dd, J=0.8, 3.6
Hz), 6.45 (1H, dd, J=1.6, 3.6 Hz), 6.78 (2H, br s), 7.17 (2H, dd,
J=1.6, 4.4 Hz), 7.56 (1H, dd, J=0.8, 1.6 Hz), 8.53 (2H, dd, J=1.6,
4.4 Hz); MS m/e (ESI) 297 (MH.sup.+).
Example 10
4-(Allyloxy)-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine
##STR00088##
[0225] The title compound was synthesized in a similar manner to
Example 3 using
4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and allyl
alcohol.
[0226] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.77 (2H,
dt, J=1.6, 5.2 Hz), 5.12 (1H, dq, J=1.6, 10.4 Hz), 5.14 (1H, dq,
J=1.6, 17.2 Hz), 5.93 (1H, ddt, J=5.2, 10.4, 17.2 Hz), 6.38 (1H,
dd, J=0.8, 3.4 Hz), 6.46 (1H, dd, J=1.6, 3.4 Hz), 6.84 (2H, br s),
7.21 (2H, dd, J=1.6, 4.4 Hz), 7.57 (1H, dd, J=0.8, 1.6 Hz), 8.55
(2H, dd, J=1.6, 4.4 Hz); MS m/e (FAB) 295 (MH.sup.+).
Example 11
4-(2-Furyl)-6-methyl-5-(4-pyridyl)-2-pyrimidinylamine
hydrochloride
##STR00089##
[0228] The title compound was synthesized in a similar manner to
Method 2 of Reference Example 10 using
(E)-4-(2-furyl)-3-(4-pyridyl)-3-buten-2-one.
[0229] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.09 (3H,
s), 6.53 (1H, dd, J=1.6, 3.6 Hz), 6.66 (1H, dd, J=0.8, 3.6 Hz),
7.63 (1H, dd, J=0.8, 1.6 Hz), 7.85 (2H, dd, J=1.2, 5.2 Hz), 8.90
(2H, dd, J=1.2, 5.2 Hz).
Example 12
4,6-Di(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine
##STR00090##
[0231] After dissolving sodium (540 mg, 23.5 mmol) in anhydrous
ethanol (200 ml), 1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.00 g,
10.7 mmol) and 2-furaldehyde (0.97 ml, 11.7 mmol) were successively
added thereto and the mixture was stirred at room temperature.
After 1.5 hours, guanidine hydrochloride (7.0 g, 73.3 mmol) was
added thereto, followed by heating under reflux for 14 hours. After
cooling as it was, the reaction mixture was concentrated and the
residue was suspended in tetrahydrofuran. Then, the insoluble
matters were filtered off and washed with tetrahydrofuran, and the
solvent of the filtrate was evaporated. To the residue were added
tetrahydrofuran (80 ml) and active manganese dioxide (30.0 g),
followed by heating under reflux for 2 hours. After cooling as it
was, the manganese dioxide was filtered off through Celite and
washed with tetrahydrofuran. The combined filtrates were
concentrated, and then methanol was added to the residue. The
resulting precipitates were collected by filtration and washed with
methanol, to give the title compound (1.32 g, 41%) as a pale brown
solid.
[0232] .sup.1H NR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.06 (2H,
dd, J=0.8, 3.4 Hz), 6.44 (2H, dd, J1.8, 3.4 Hz), 6.96 (2H, br s),
7.33 (2H, dd, J=1.6, 4.4 Hz), 7.65 (2H, dd, J=0.8, 1.8 Hz), 8.66
(2H, dd, J=1.6, 4.4 Hz).
Example 13
4-(2-Furyl)-6-phenyl-5-(4-pyridyl)-2-pyrimidinylamine
##STR00091##
[0234] The title compound was synthesized in a similar manner to
Example 12 using benzaldehyde.
[0235] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.19 (1H,
dd, J=0.8, 3.6 Hz), 6.46 (1H, dd, J=1.6, 3.6 Hz), 6.99 (2H, br s),
7.14 (2H, dd, J=1.6, 4.4 Hz), 7.17-7.27 (5H, m), 7.64 (1H, dd,
J=0.8, 1.6 Hz), 8.43 (2H, dd, J=1.6, 4.4 Hz).
Example 14
5-(6-Chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinylamine
##STR00092##
[0237] A suspension of
2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(2-furyl)-2-propen-1-one
(7.49 g, 27.1 mmol), guanidine hydrochloride (7.7 g, 81.0 mmol) and
potassium carbonate (22.4 g, 162 mmol) in N,N-dimethylformamide
(105 ml) was stirred at 70.degree. C. for 21 hours. After cooling
as it was, the reaction mixture was diluted with water. The
resulting crystals were collected by filtration and washed with
water, to give the title compound (5.48 g, 74%) as a pale yellow
solid.
[0238] H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.56 (1H, dd,
J=1.6, 3.6 Hz), 6.71 (1H, dd, J=0.8, 3.6 Hz), 6.96 (2H, br s), 7.55
(1H, dd, J=0.6, 8.4 Hz), 7.69 (1H, dd, J=0.8, 1.6 Hz), 7.77 (1H,
dd, J=2.8, 8.4 Hz), 8.22 (1H, s), 8.31 (1H, dd, J=0.6, 2.8 Hz).
Example 15
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
##STR00093##
[0240] After sodium (455 mg, 19.8 mmol) was dissolved in
4-methoxybenzyl alcohol (15 ml) at 90.degree. C. under an
atmosphere of nitrogen gas,
5-(6-chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinylamine (1.80 g, 6.60
mmol) was added thereto and the mixture was stirred as it was.
After 1.5 hours, the reaction mixture was cooled as it was and then
diluted with an aqueous saturated ammonium chloride solution and
ethyl acetate. The resulting organic layer was washed with an
aqueous saturated ammonium chloride solution, dried over anhydrous
sodium sulfate and concentrated. Trifluoroacetic acid (40 ml) was
added to the residue, followed by stirring at 65.degree. C. After
18 hours, the reaction mixture was cooled as it was and diluted
with dichloromethane, water and 5N hydrochloride. The resulting
aqueous layer was washed with ethyl acetate and adjusted to pH 6
with 5N sodium hydroxide. The resulting crystals were collected by
filtration and washed with water, to give crude crystals of the
title compound. The resulting crude crystals were suspended in
ethyl acetate, collected by filtration and washed with ethyl
acetate, to give the title compound (820 mg, 49%) as a colorless
solid.
[0241] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.33 (1H,
d, J=9.2 Hz), 6.58 (1H, dd, J=1.8, 3.6 Hz), 6.69 (1H, dd, J=0.8,
3.6 Hz), 6.79 (2H, br s), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.34 (1H,
d, J=2.8 Hz), 7.77 (1H, dd, J=0.8, 1.8 Hz), 8.12 (1H, s); MS m/e
(ESI) 255 (MH.sup.+).
Example 16
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone
##STR00094##
[0243] To a suspension of
5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (2.2
g, 8.65 mmol) in methanol (44 ml) was added sodium methoxide (940
mg, 17.4 mmol) at room temperature under an atmosphere of nitrogen
gas, followed by stirring. After 15 minutes, iodomethane (1.6 ml,
25.7 mmol) was added thereto, followed by stirring as it was for 22
hours. After concentrating the reaction mixture, water was added to
the residue. Then, the precipitates were collected by filtration
and washed with water, to give the crude crystals of the title
compound (1.98 g). The crude crystals were suspended in ethanol,
and then the precipitates were collected by filtration and washed
with ethanol, to give the title compound (1.54 g, 66%) as a pale
yellow solid.
[0244] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.46 (3H,
s), 6.38 (1H, d, J=9.2 Hz), 6.58 (1H, dd, J=1.6, 3.6 Hz), 6.73 (1H,
dd, J=0.8, 3.6 Hz), 6.81 (2H, br s), 7.21 (1H, dd, J=2.6, 9.2 Hz),
7.75 (1H, d, J=2.6 Hz), 7.77 (1H, dd, J=0.8, 1.6 Hz), 8.14 (1H, s);
MS m/e (ESI) 269 (MH.sup.+).
Example 17
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone
##STR00095##
[0246] The title compound was synthesized in a similar manner to
Example 16 using ethyl iodide.
[0247] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.24 (3H,
t, J=7.2 Hz), 3.93 (2H, q, J=7.2 Hz), 6.38 (1H, d, J=9.2 Hz), 6.58
(1H, dd, J=1.6, 3.2 Hz), 6.71 (1H, d, J=3.2 Hz), 6.82 (2H, br s),
7.23 (1H, dd, J=2.8, 9.2 Hz), 7.73 (1H, d, J=2.8 Hz), 7.78 (1H, d,
J=1.6 Hz), 8.17 (1H, s); MS m/e (ESI) 283 (MH.sup.+).
Example 18
1-Allyl-5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
##STR00096##
[0249] The title compound was synthesized in a similar manner to
Example 16 using allyl bromide.
[0250] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.53 (2H,
d, J=5.2 Hz), 5.10 (1H, dd, J=1.6, 17.2 Hz), 5.19 (1H, dd, J=1.6,
10.4 Hz), 5.97 (1H, ddt, J=5.2, 10.4, 17.2 Hz), 6.42 (1H, d, J=9.2
Hz), 6.58 (1H, dd, J=1.8, 3.6 Hz), 6.73 (1H, dd, J=0.8, 3.6 Hz),
6.82 (2H, br s), 7.27 (1H, dd, J=2.2, 9.2 Hz), 7.64 (1H, d, J=2.2
Hz), 7.76 (1H, dd, J=0.8, 1.8 Hz), 8.14 (1H, s).
Example 19
5-[2-Amino-4-(2-thienyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
##STR00097##
[0252] The title compound was synthesized in a similar manner to
Example 15 using
5-(6-chloro-3-pyridyl)-4-(2-thienyl)-2-pyrimidinylamine.
[0253] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.36 (1H,
d, J=9.2 Hz), 6.77 (2H, br s), 7.05 (1H, dd, J=3.6, 4.8 Hz), 7.13
(1H, dd, J=1.2, 3.6 Hz), 7.26 (1H, dd, J=2.4, 9.2 Hz), 7.39 (1H, d,
J=2.4 Hz), 7.68 (1H, dd, J=1.2, 4.8 Hz), 8.10 (1H, s).
Example 20
5-[2-Amino-4-(2-thienyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone
##STR00098##
[0255] The title compound was synthesized in a similar manner to
Example 16 using
5-[2-amino-4-(2-thienyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone-
.
[0256] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.46 (3H,
s), 6.41 (1H, d, J=9.2 Hz), 6.80 (2H, br s), 7.05 (1H, dd, J=3.8,
5.2 Hz), 7.16 (1H, dd, J=1.0, 3.8 Hz), 7.24 (1H, dd, J=2.8, 9.2
Hz), 7.68 (1H, dd, J=1.0, 5.2 Hz), 7.80 (1H, d, J=2.8 Hz), 8.12
(1H, s).
Example 21
5-[2-Amino-4-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
##STR00099##
[0258] The title compound was synthesized in a similar manner to
Example 15 using
5-(6-chloro-3-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine.
[0259] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.19 (1H,
d, J=9.6 Hz), 6.86 (2H, br s), 7.00 (1H, dd, J=2.8, 9.6 Hz),
7.15-7.30 (4H, m), 7.36-7.46 (1H, m), 8.26 (1H, s), 11.68 (1H, br
s); MS m/e (ESI) 283 (MH.sup.+).
Example 22
5-[2-Amino-4-(3-fluorophenyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridi-
none
##STR00100##
[0261] The title compound was synthesized in a similar manner to
Example 16 using
5-[2-amino-4-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyrid-
inone.
[0262] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.42 (3H,
s), 6.21 (1H, d, J=9.6 Hz), 6.87 (1H, dd, J=2.8, 9.6 Hz), 6.89 (2H,
brs), 7.20-7.29 (3H, m), 7.37-7.44 (1H, m), 7.75 (1H, d, J=2.8 Hz),
8.28 (1H, s).
Example 23
5-(2-Amino-4-phenyl-5-pyrimidinyl)-1,2-dihydro-2-pyridinone
##STR00101##
[0264] The title compound was synthesized in a similar manner to
Example 15 using
5-(6-chloro-3-pyridyl)-4-phenyl-2-pyrimidinylamine.
[0265] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.16 (1H,
d, J=9.6 Hz), 6.80 (2H, br s), 6.96 (1H, dd, J=2.6, 9.6 Hz), 7.23
(1H, d, J=2.6 Hz), 7.34-7.44 (5H, m), 8.23 (1H, s).
Example 24
5-(2-Amino-4-phenyl-5-pyrimidinyl)-1-methyl-1,2-dihydro-2-pyridinone
##STR00102##
[0267] The title compound was synthesized in a similar manner to
Example 16 using
5-(2-amino-4-phenyl-5-pyrimidinyl)-1,2-dihydro-2-pyridinone.
[0268] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.42 (3H,
s), 6.18 (1H, d, J=9.2 Hz), 6.82 (1H, dd, J=2.4, 9.2 Hz), 6.83 (2H,
brs), 7.32-7.47 (5H, m), 7.74 (1H, d, J=2.4 Hz), 8.25 (1H, s).
Example 25
5-(6-Chloro-3-pyridyl)-4,6-di(2-furyl)-2-pyrimidinylamine
##STR00103##
[0270] The title compound was synthesized in a similar manner to
Example 12 using 2-(6-chloro-3-pyridyl)-1-(2-furyl)-1-ethanone.
[0271] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.21 (2H,
dd, J=0.6, 3.4 Hz), 6.49 (2H, dd, J=1.8, 3.4 Hz), 6.97 (2H, br s),
7.62 (1H, d, J=8.4 Hz), 7.67 (2H, dd, J=0.6, 1.8 Hz), 7.80 (1H, dd,
J=2.4, 8.4 Hz), 8.28 (1H, d, J=2.4 Hz).
Example 26
5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
##STR00104##
[0273] The title compound was synthesized in a similar manner to
Example 15 using
5-(6-chloro-3-pyridyl)-4,6-di(2-furyl)-2-pyrimidinylamine.
[0274] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.36 (2H,
dd, J=0.8, 3.6 Hz), 6.46 (1H, d, J=9.2 Hz), 6.55 (2H, dd, J=1.6,
3.6 Hz), 6.67 (2H, br s), 7.24 (1H, d, J=2.2 Hz), 7.31 (1H, dd,
J=2.2, 9.2 Hz), 7.78 (2H, dd, J=0.8, 1.6 Hz), 11.76 (1H, s); MS m/e
(ESI) 321 (MH.sup.+).
Example 27
5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinon-
e
##STR00105##
[0276] The title compound was synthesized in a similar manner to
Example 16 using
5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridino-
ne.
[0277] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.43 (3H,
s), 6.39 (2H, dd, J=0.8, 3.6 Hz), 6.52 (1H, d, J=9.2 Hz), 6.54 (2H,
dd, J=1.8, 3.6 Hz), 6.88 (2H, br s), 7.32 (1H, dd, J=2.6, 9.2 Hz),
7.64 (1H, d, J=2.6 Hz), 7.77 (2H, dd, J=0.8, 1.8 Hz); MS m/e (ESI)
335 (MH.sup.+).
Example 28
6-(3-Fluorophenyl)-5-(6-methoxy-3-pyridyl)-2,4-pyrimidinediamine
##STR00106##
[0279] The title compound was synthesized in a similar manner to
Method 2 of Reference Example 12 using
(E)-3-(3-fluorophenyl)-2-(6-methoxy-3-pyridyl)-2-propenenitrile.
[0280] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.81 (3H,
s), 5.96 (2H, br s), 6.12 (2H, br s), 6.74 (1H, d, J=8.6 Hz),
6.92-7.06 (3H, m), 7.18-7.24 (1H, m), 7.41 (1H, dd, J=2.4, 8.6 Hz),
7.80 (1H, d, J=2.4 Hz).
Example 29
5-[2,4-Diamino-6-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
##STR00107##
[0282] A solution of
6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-2,4-pyrimidinediamine
(5.00 g, 16.1 mmol) in acetic acid (30 ml)/concentrated hydrobromic
acid (50 ml) was stirred at 100.degree. C. for 1.5 hours. After
cooling as it was, the reaction mixture was adjusted to pH 12 to 13
with 5N sodium hydroxide and washed with ethylacetate. The aqueous
layer was neutralized with 5N hydrochloric acid. The resulting
solid was collected by filtration, to give the title compound (3.36
g, 70%) as a colorless solid.
[0283] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.06 (2H,
br s), 6.07 (2H, br s), 6.21 (1H, d, J=9.2 Hz), 6.97 (1H, d, J=2.4
Hz), 7.01-7.09 (4H, m), 7.23-7.30 (1H, m); MS m/e (ESI) 298
(MH.sup.+).
Example 30
5-[2,4-Diamino-6-(3-fluorophenyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-py-
ridinone
##STR00108##
[0285] The title compound was synthesized in a similar manner to
Example 16 using
5-[2,4-diamino-6-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-p-
yridinone.
[0286] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.32 (3H,
s), 6.07 (2H, br s), 6.17 (2H, br s), 6.23 (1H, d, J=9.4 Hz), 6.94
(1H, dd, J=2.6, 9.4 Hz), 7.02-7.12 (3H, m), 7.23-7.30 (1H, m), 7.46
(1H, d, J=2.6 Hz); MS m/e (ESI) 312 (MH.sup.+).
Example 31
5-[6-(Benzyloxy)-3-pyridyl]-4-(2-furyl)-2-pyrimidinylamine
##STR00109##
[0288] A solution of 5-bromo-4-(2-furyl)-2-pyrimidinylamine (10.5
g, 43.9 mmol), 2-(benzyloxy)-5-(1,1,1-tributylstanyl)-pyridine
(41.7 g, 87.9 mmol) and dichlorobis-(triphenylphosphine)palladium
(11) (1.6 g, 2.28 mmol) in N,N-dimethylformamide (100 ml) was
stirred at 100.degree. C. for 25 hours under an atmosphere of
nitrogen gas. After cooling as it was, the reaction mixture was
diluted with ethyl acetate and an aqueous saturated ammonium
chloride solution. The insoluble matters were filtered off, and
then the organic layer in the filtrate was washed with an aqueous
saturated ammonium chloride solution twice, dried over anhydrous
magnesium sulfate and concentrated. The residue was suspended in
hexane, and then the solid was collected by filtration and washed
with hexane. The obtained solid was suspended in ethyl acetate, and
then collected by filtration and washed with ethyl acetate, to give
the title compound (8.35 g, 55%) as a pale orange solid.
[0289] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 5.36 (2H,
s), 6.50 (1H, dd, J=0.8, 3.4 Hz), 6.52 (1H, dd, J=1.8, 3.4 Hz),
6.82 (2H, br s), 6.90 (1H, dd, J=0.6, 8.4 Hz), 7.30-7.35 (1H, m),
7.36-7.41 (2H, m), 7.44-7.49 (2H, m), 7.59 (1H, dd, J=2.6, 8.4 Hz),
6.68 (1H, dd, J=0.8, 1.8 Hz), 8.06 (1H, dd, J=0.6, 2.6 Hz), 8.14
(1H, s).
Example 32
Alternative Synthetic Method of Example 15
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
[0290] A suspension of
5-[6-(benzyloxy)-3-pyridyl]-4-(2-furyl)-2-pyrimidinylamine (8.35 g,
24.2 mmol) in concentrated hydrochloric acid (40 ml)-water (40 ml)
was stirred at 80.degree. C. for 1 hour. After cooling as it was,
the reaction mixture was washed with ethyl acetate twice. The
aqueous layer was neutralized with an aqueous 5N sodium hydroxide
solution. The resulting solid was collected by filtration, washed
with water and dried at 50.degree. C. for 14 hours, to give the
title compound (5.54 g, 90%) as a pale brown solid.
Example 33
5-[6-(Benzyloxy)-3-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine
##STR00110##
[0292] The title compound was synthesized in a similar manner to
Example 31 using 5-bromo-4,6-di(2-furyl)-2-pyrimidinamine.
[0293] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 5.42 (2H,
s), 5.93 (2H, dd, J=0.4, 3.6 Hz), 6.44 (2H, dd, J=1.6, 3.6 Hz),
6.88 (2H, br s), 7.01 (1H, dd, J=0.4, 8.8 Hz), 7.30-7.51 (5H, m)
7.62 (1H, dd, J=2.4, 8.8 Hz), 7.67 (2H, dd, J=0.4, 1.6 Hz), 7.97
(1H, d, J=2.4 Hz).
Example 34
5-(2-Fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine
##STR00111##
[0295] The title compound was synthesized in a similar manner to
Example 12 using 2-(2-fluoro-4-pyridyl) 1-(2-furyl)-1-ethanone.
[0296] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.33 (2H,
dd, J=0.8, 3.6 Hz), 6.48 (2H, dd, J=1.6, 3.6 Hz), 6.99 (2H, br s),
7.21 (1H, br), 7.28-7.32 (1H, m), 7.65 (2H, dd, J=0.8, 1.6 Hz),
8.31 (1H, d, J=5.2 Hz).
Example 35
5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(3-furyl)-2-pyrimidinamine
##STR00112##
[0298] The title compound was synthesized in a similar manner to
Example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and
3-furaldehyde.
[0299] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.31 (1H,
dd, J=0.8, 2.0 Hz) 6.37 (1H, dd, J=0.8, 3.6 Hz), 6.47 (1H, dd,
J=1.6, 3.6 Hz), 6.91 (2H, br s), 7.17-7.18 (2H, m), 7.26-7.30 (1H,
m), 7.58 (1H, dd, J=1.6, 2.0 Hz), 7.62 (1H, dd, J=0.8, 1.6 Hz),
8.30 (1H, d, J=4.8 Hz).
Example 36
5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(2-thienyl)-2-pyrimidinamine
##STR00113##
[0301] The title compound was synthesized in a similar manner to
Example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and
2-thiophenecarboxyaldehyde.
[0302] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.35 (1H,
d, J=3.6 Hz), 6.42 (1H, dd, J=0.8, 3.6 Hz), 6.48 (1H, dd, J=1.6,
3.6 Hz), 6.91 (1H, dd, J=3.6, 5.2 Hz), 6.95 (2H, brs), 7.27 (1H,
br) 7.34-7.38 (1H, m), 7.61-7.66 (2H, m), 8.34 (1H, d, J=4.8
Hz).
Example 37
5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(3-thienyl)-2-pyrimidinamine
##STR00114##
[0304] The title compound was synthesized in a similar manner to
Example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and
3-thiophenecarboxyaldehyde.
[0305] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.39 (1H,
dd, J=0.8, 3.6 Hz), 6.48 (1H, dd, J=1.6, 3.6 Hz), 6.94-6.97 (3H,
m), 7.07 (1H, br), 7.18-7.20 (1H, m), 7.27 (1H, dd, J=1.2, 2.8 Hz),
7.40 (1H, dd, J=2.8, 5.2 Hz), 7.62 (1H, dd, J=0.8, 1.6 Hz), 8.20
(1H, d, J=5.2 Hz).
Example 38
5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(2-pyridyl)-2-pyrimidinamine
##STR00115##
[0307] The title compound was synthesized in a similar manner to
Example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and
2-pyridinecarboxyaldehyde.
[0308] .sup.1H NMR (400 Hz, DMSO-d.sub.6) .delta. ppm; 6.43 (1H,
dd, J=0.8, 3.6 Hz), 6.50 (1H, dd, J=2.0, 3.6 Hz), 6.89 (1H, br),
7.02-7.04 (1H, m), 7.09 (2H, br s), 7.27 (1H, ddd, J=1.2, 4.8, 7.6
Hz), 7.60 (1H, ddd, J=0.8, 1.2, 7.6 Hz), 7.65 (1H, dd, J=0.8, 2.0
Hz), 7.79 (1H, ddd, J=1.6, 7.6, 7.6 Hz), 8.03 (1H, d, J=5.2 Hz),
8.27 (1H, ddd, J=0.8, 1.6, 4.8 Hz).
Example 39
5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(3-pyridyl)-2-pyrimidinamine
##STR00116##
[0310] The title compound was synthesized in a similar manner to
Example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and
3-pyridinecarboxyaldehyde.
[0311] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.48 (1H,
d, J=3.6 Hz), 6.51 (1H, dd, J=1.6, 3.6 Hz), 7.05 (1H, br), 7.12
(2H, brs), 7.14-7.18 (1H, m), 7.28 (1H, dd, J=5.2, 8.0 Hz), 7.60
(1H, ddd, J=1.6, 2.0, 8.0 Hz), 7.65 (1H, dd, J=0.8, 1.6 Hz), 8.10
(1H, d, J=4.8 Hz), 8.39 (1H, d, J=2.0 Hz), 8.45 (1H, dd, J=1.6, 5.2
Hz).
Example 40
5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(4-pyridyl)-2-pyrimidinamine
##STR00117##
[0313] The title compound was synthesized in a similar manner to
Example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and
4-pyridinecarboxyaldehyde.
[0314] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.48 (1H,
d, J=3.6 Hz), 6.51 (1H, dd, J=2.0, 3.6 Hz), 7.05 (1H, s), 7.12-7.18
(1H, m), 7.15 (2H, br s), 7.19 (2H, dd, J=1.6, 4.4 Hz), 7.63-7.67
(1H, m), 8.10 (1H, d, J=5.6 Hz), 8.46 (2H, dd, J=1.6, 4.4 Hz).
Example 41
5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-phenyl-2-pyrimidinamine
##STR00118##
[0316] The title compound was synthesized in a similar manner to
Example 12 using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and
benzaldehyde.
[0317] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.44 (1H,
d, J=3.2 Hz), 6.49 (1H, dd, J=1.6, 3.2 Hz), 6.97 (1H, br), 7.02
(2H, brs), 7.07-7.12 (1H, m), 7.16-7.29 (5H, m), 7.60-7.64 (1H, m),
8.07 (1H, d, J=5.2 Hz).
Example 42
5-(2-Bromo-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine
##STR00119##
[0319] The title compound was synthesized in a similar manner to
Example 12 using 2-(2-bromo-4-pyridyl)-1-(2-furyl)-1-ethanone.
[0320] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.33 (2H,
dd, J=0.8, 3.6 Hz), 6.49 (2H, dd, J=1.6, 3.6 Hz), 6.97 (2H, br s),
7.40 (1H, dd, J=1.6, 4.8 Hz), 7.63 (1H, dd, J=0.8, 1.6 Hz), 7.64
(2H, dd, J=0.8, 1.6 Hz), 8.44 (1H, dd, J=0.8, 4.8 Hz).
Example 43
5-[2-(Dimethylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine
##STR00120##
[0322] In an autoclave,
5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (200 mg,
0.621 mmol) was suspended in 1,2-dimethoxyethane (10 ml) and then a
50% dimethylamine aqueous solution (5 ml) was added thereto,
followed by stirring at 70.degree. C. After 11 hours, the reaction
mixture was extracted with ethyl acetate, and the extract was
washed with water and brine, dried over anhydrous sodium sulfate
and then the filtrate was concentrated. The resulting solid was
suspended in ethanol, collected by filtration and washed with
ethanol, to give the title compound (92 mg, 43%) as a pale yellow
solid.
[0323] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.99 (6H,
s), 6.02 (2H, d, J=3.2 Hz), 6.44 (2H, dd, J=1.6, 3.2 Hz), 6.49 (1H,
dd, J=1.2, 4.8 Hz), 6.54 (1H, s), 6.86 (2H, br s), 7.70 (2H, d,
J=1.6 Hz), 8.17 (1H, d, J=4.8 Hz).
Example 44
4,6-Di(furyl)-5-[2-(methylamino)-4-pyridyl]-2-pyridinamine
##STR00121##
[0325] The title compound was synthesized in a similar manner to
Example 43 at 70 to 80.degree. C. using a 40% methylamine aqueous
solution.
[0326] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.78 (3H,
d, J=5.2 Hz), 6.07 (2H, d, J=3.6 Hz), 6.30 (1H, s), 6.41 (1H, dd,
J=1.2, 5.2 Hz) 6.46 (2H, dd, J=2.0, 3.6 Hz), 6.51 (1H, q, J=5.2
Hz), 6.86 (2H, br s), 7.71 (2H, d, J=2.0 Hz), 8.08 (1H, d, J=5.2
Hz).
Example 45
5-[2-(Ethylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine
##STR00122##
[0328] The title compound was synthesized in a similar manner to
Example 43 at 80.degree. C. from a 70% ethylamine aqueous
solution.
[0329] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.12 (3H,
t, J=7.2 Hz), 3.23-3.30 (2H, m), 6.07 (2H, dd, J=0.8, 3.2 Hz), 6.30
(1H, dd, J=0.8, 1.2 Hz), 6.41 (1H, dd, J=1.2, 4.8 Hz), 6.46 (2H,
dd, J=1.6, 3.2 Hz), 6.47 (1H, t, J=3.2 Hz), 6.86 (2H, br s), 7.72
(2H, dd, J=0.8, 1.6 Hz), 8.07 (1H, dd, J=0.8, 4.8 Hz).
Example 46
4,6-Di(2-furyl)-5-[2-(propylamino)-4-pyridyl]-2-pyrimidinamine
##STR00123##
[0331] In a reaction vessel,
5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (200 mg,
0.621 mmol) and n-propylamine (5 ml) were mixed together and the
mixture was stirred at 120 (C. After 18 hours, the reaction mixture
was extracted with ethyl acetate, and the extract was washed with
water and brine, dried over anhydrous sodium sulfate and then the
filtrate was concentrated. The resulting solid was suspended in
ethanol, collected by filtration and washed with ethanol, to give
the title compound (64%, 72 mg) as a pale yellow solid.
[0332] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 0.89 (3H,
t, J=7.2 Hz), 1.47-1.57 (2H, m), 3.18-3.23 (2H, m), 6.07 (2H, dd,
J=0.8, 3.2 Hz), 6.31-6.32 (1H, m), 6.39 (1H, dd, J=1.2, 5.2 Hz),
6.46 (2H, dd, J=1.6, 3.2 Hz), 6.51 (1H, t, T=5.6 Hz), 6.86 (2H, br
s), 7.72 (2H, dd, J=0.8, 1.6 Hz), 8.06 (1H, dd, J=0.8, 5.2 Hz).
Example 47
5-[2-(Butylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine
##STR00124##
[0334] The title compound was synthesized in a similar manner to
Example 46 at 80 to 120.degree. C. using n-butylamine.
[0335] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 0.89 (3H,
t, J=7.2 Hz), 1.28-1.37 (2H, m), 1.45-1.53 (2H, m), 3.21-3.26 (2H,
m), 6.07 (2H, dd, J=0.8, 3.6 Hz), 6.29-6.30 (1H, m), 6.39 (1H, dd,
J=1.2, 5.2 Hz), 6.46 (2H, dd, J=1.6, 3.6 Hz), 6.48 (1H, t, J=5.2
Hz), 6.86 (2H, br s), 7.71 (2H, dd, J=0.8, 1.6 Hz), 8.06 (1H, dd,
J=0.8, 5.2 Hz).
Example 48
4,6-Di(2-furyl)-5-[2-(isopropylamino)-4-pyridyl]-2-pyrimidinamine
##STR00125##
[0337] The title compound was synthesized in a similar manner to
Example 46 at 120 to 200.degree. C. using i-propylamine.
[0338] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.13 (6H,
d, J=6.8 Hz), 3.97-4.05 (1H, m), 6.07 (2H, dd, J=0.8, 3.2 Hz), 6.28
(1H, s), 6.31 (1H, d, J=7.2 Hz), 6.39 (1H, dd, J=1.2, 5.2 Hz), 6.46
(2H, dd, J=1.6, 3.2 Hz), 6.86 (2H, br s), 7.72 (2H, dd, J=0.8, 1.6
Hz), 8.07 (1H, d, J=5.2 Hz).
Example 49
5-(2-Amino-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine
##STR00126##
[0340] The title compound was synthesized in a similar manner to
Example 43 at 80 to 120.degree. C. using 28% aqueous ammonia.
[0341] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm, 5.98 (2H,
br s), 6.08 (2H, d, J=3.2 Hz), 6.29 (1H, br), 6.42 (1H, d, J=5.2
Hz), 6.46 (2H, dd, J=1.6, 3.2 Hz), 6.86 (2H, br s), 7.72 (2H, hr),
8.01 (1H, d, J=5.2 Hz).
Example 50
2-(4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridylamino)-1-ethanol
##STR00127##
[0343] The title compound was synthesized in a similar manner to
Example 46 at 120.degree. C. using ethanolamine.
[0344] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 3.57 (2H, td,
J=4.4, 5.2 Hz), 3.84 (2H, t, J=4.4 Hz), 4.88 (1H, t, J=5.2 Hz),
5.28 (2H, br s), 6.08 (2H, dd, J=0.4, 3.6 Hz), 6.33 (2H, dd, J=1.6,
3.6 Hz), 6.38 (1H, br), 6.59 (1H, dd, J=1.2, 5.2 Hz), 7.48 (2H, d,
J=1.6 Hz), 8.18 (1H, d, J=5.2 Hz).
Example 51
5-[2-(Benzylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine
##STR00128##
[0346] The title compound was synthesized in a similar manner to
Example 46 at 120.degree. C. using benzylamine.
[0347] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.52 (2H,
d, J=6.0 Hz), 6.05 (2H, dd, J=0.8, 3.6 Hz), 6.39 (1H, br), 6.43
(1H, dd, J=1.6, 5.2 Hz), 6.46 (2H, dd, J=1.6, 3.6 Hz), 6.86 (2H, br
s), 7.07 (1H, t, J=6.0 Hz), 7.17-7.21 (1H, m), 7.26-7.31 (4H, m),
7.71 (2H, dd, J=0.8, 1.6 Hz), 8.06 (1H, dd, J=0.8, 5.2 Hz).
Example 52
1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinol
##STR00129##
[0349] The title compound was synthesized in a similar manner to
Example 46 at 120.degree. C. using 4-hydroxypiperidine in
1-methyl-2-pyrrolidinone.
[0350] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.25-1.33
(2H, m), 1.69-1.72 (2H, m), 3.03-3.09 (2H, m), 3.67 (1H, br),
3.96-3.99 (2H, m), 4.67 (1H, br d, J=3.2 Hz), 6.03 (2H, dd, J=0.8,
3.2 Hz), 6.44 (2H, dd, J=1.6, 3.2 Hz), 6.51 (1H, dd, J=1.2, 5.2
Hz), 6.76 (1H, br), 6.86 (2H, br s), 7.70 (2H, dd, J=0.8, 1.6 Hz),
8.18 (1H, d, J=5.2 Hz).
Example 53
Ethyl
1-{4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidine-
carboxylate
##STR00130##
[0352] The title compound was synthesized in a similar manner to
Example 46 at 120.degree. C. using ethyl isonipecotate.
[0353] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.17 (3H,
t, J=7.2 Hz), 1.44-1.53 (2H, m), 1.78-1.80 (2H, m), 2.56-2.62 (1H,
m), 2.90-2.96 (2H, m), 4.06 (2H, t, J=7.2 Hz), 4.16-4.19 (2H, m),
6.04 (2H, d, J=3.2 Hz), 6.43 (2H, dd, J=1.2, 3.2 Hz), 6.54 (1H, dd,
J=0.8, 4.8 Hz), 6.78 (1H, br), 6.87 (2H, br s), 7.69 (2H, d, J=1.2
Hz), 8.19 (1H, d, J=4.8 Hz).
Example 54
N1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-1,2-ethanediamine
##STR00131##
[0355] The title compound was synthesized in a similar manner to
Example 46 using ethylenediamine under reflux.
[0356] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 2.93 (2H, t,
J=5.6 Hz), 3.36 (2H, td, J=5.6, 5.6 Hz), 4.96 (1H, br t, J=5.6 Hz),
5.30 (2H, br s), 6.06 (2H, dd, J=0.8, 3.6 Hz), 6.31 (2H, dd, J=2.0,
3.6 Hz), 6.34-6.35 (1H, m), 6.55 (1H, dd, J=1.6, 5.2 Hz), 7.49 (2H,
dd, J=0.8, 2.0 Hz), 8.22 (1H, dd, J=0.8, 5.2 Hz).
Example 55
N1-(4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl)-1,3-propanediamin-
e
##STR00132##
[0358] The title compound was synthesized in a similar manner to
Example 46 at 120.degree. C. using 1,3-diaminopropane.
[0359] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 1.74 (2H, tt,
J=6.8, 6.8 Hz), 2.83 (2H, t, J=6.8 Hz), 3.37 (2H, dt, J=5.2, 6.8
Hz), 5.08 (1H, br t, J=5.2 Hz), 5.28 (2H, br s), 6.06 (2H, dd,
J=0.8, 3.6 Hz), 6.30-6.32 (1H, m), 6.31 (2H, dd, J=1.6, 3.6 Hz),
6.53 (1H, dd, J=1.6, 5.2 Hz), 7.49 (2H, dd, J=0.8, 1.6 Hz), 8.21
(1H, dd, J=0.8, 5.2 Hz).
Example 56
N1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-1,4-butanediamine
##STR00133##
[0361] The title compound was synthesized in a similar manner to
Example 46 at 120.degree. C. using 1,4-diaminobutane.
[0362] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 1.49-1.68
(4H, m), 2.71 (2H, t, J=6.8 Hz), 3.27 (2H, t, J=6.4 Hz), 4.77 (1H,
br), 5.29 (2H, br s), 6.06 (2H, dd, J=0.8, 3.6 Hz), 6.30-6.32 (1H,
m), 6.31 (2H, dd, J=1.6, 3.6 Hz) 6.54 (1H, dd, J=1.2, 5.2 Hz), 7.49
(2H, dd, J=0.8, 1.6 Hz), 8.21 (1H, dd, J=0.8, 5.2 Hz).
Example 57
5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(3-furyl)-2-pyrimidinamine
##STR00134##
[0364] The title compound was synthesized in a similar manner to
Example 43 at 80.degree. C. using
5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(3-furyl)-2-pyrimidinamine.
[0365] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.99 (6H,
s), 6.07 (1H, d, J=3.6 Hz), 6.44-6.46 (2H, m), 6.48 (1H, dd, J=1.2,
4.8 Hz), 6.53 (1H, s), 6.76 (2H, br s), 7.14 (1H, s), 7.58 (1H, dd,
J=1.2, 1.2 Hz), 7.70 (1H, d, J=1.6 Hz), 8.17 (1H, d, J=5.2 Hz).
Example 58
5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(2-thienyl)-2-pyrimidinamine
##STR00135##
[0367] The title compound was synthesized in a similar manner to
Example 43 at 80.degree. C. using
5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(2-thienyl)-2-pyrimidinamine.
[0368] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.00 (6H,
s), 6.02 (1H, dd, J=0.8, 3.6 Hz), 6.45 (1H, dd, J=2.0, 3.6 Hz),
6.52 (1H, dd, J=1.2, 5.2 Hz), 6.59 (1H, s), 6.62 (1H, dd, J=1.2,
4.0 Hz), 6.81 (2H, br s), 6.91 (1H, dd, J=4.0, 5.2 Hz), 7.59 (1H,
dd, J=1.2, 5.2 Hz), 7.71 (1H, dd, J=0.8, 2.0 Hz), 8.20 (1H, dd,
J=0.8, 5.2 Hz).
Example 59
5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(3-thienyl)-2-pyrimidinamine
##STR00136##
[0370] The title compound was synthesized in a similar manner to
Example 43 at 80.degree. C. using
5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(3-thienyl)-2-pyrimidinamine.
[0371] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.94 (6H,
s), 6.06 (1H, d, J=3.2 Hz), 6.39-6.46 (3H, m), 6.78 (2H, br s),
7.05 (1H, dd, J=1.2, 4.8 Hz), 7.34-7.39 (2H, m), 7.68 (1H, d, J=1.2
Hz), 8.07 (1H, d, J=4.8 Hz).
Example 60
5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(2-pyridyl)-2-pyrimidinamine
##STR00137##
[0373] The title compound was synthesized in a similar manner to
Example 43 at 80.degree. C. using
5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(2-pyridyl)-2-pyrimidinamine.
[0374] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.84 (6H,
s), 6.19 (1H, dd, J=0.8, 3.2 Hz), 6.26 (1H, br), 6.28 (1H, dd,
J=1.2, 5.2 Hz), 6.46 (1H, dd, J=1.6, 3.2 Hz), 6.95 (2H, br s), 7.25
(1H, ddd, J=1.2, 4.8, 7.6 Hz), 7.38-7.40 (1H, m), 7.68-7.73 (2H,
m), 7.87 (1H, dd, J=0.4, 5.2 Hz), 8.36-8.38 (1H, m).
Example 61
5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(3-pyridyl)-2-pyrimidinamine
##STR00138##
[0376] The title compound was synthesized in a similar manner to
Example 43 at 80.degree. C. using
5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(3-pyridyl)-2-pyrimidinamine.
[0377] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.87 (6H,
s), 6.17 (1H, dd, J=0.8, 3.6 Hz), 6.36 (1H, dd, J=1.2, 5.2 Hz),
6.39 (1H, br), 6.46 (1H, dd, J=1.6, 3.6 Hz), 6.96 (2H, br s), 7.27
(1H, ddd, J=0.8, 5.2, 8.0 Hz), 7.67 (1H, dt, J=2.0, 8.0 Hz), 7.70
(1H, dd, J=0.8, 1.6 Hz), 7.94 (1H, d, J=5.2 Hz), 8.41-8.45 (2H,
m).
Example 62
5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(4-pyridyl)-2-pyrimidinamine
##STR00139##
[0379] The title compound was synthesized in a similar manner to
Example 43 at 80.degree. C. using
5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(4-pyridyl)-2-pyrimidinamine.
[0380] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.88 (6H,
s), 6.17 (1H, d, J=3.6 Hz), 6.36 (1H, d, J=5.2 Hz), 6.39 (1H, s),
6.47 (1H, dd, J=1.6, 3.6 Hz), 7.01 (2H, br s), 7.24 (2H, d, J=5.6
Hz), 7.72 (1H, s), 7.95 (1H, d, J=5.2 Hz), 8.44 (2H, d, J=5.6
Hz).
Example 63
5-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-phenyl-2-pyrimidinamine
##STR00140##
[0382] The title compound was synthesized in a similar manner to
Example 43 at 80.degree. C. using
5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-phenyl-2-pyrimidinamine.
[0383] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 2.84 (6H,
s), 6.12 (1H, d, J=3.2 Hz), 6.31 (1H, br), 6.32 (1H, br), 6.44 (1H,
dd, J=1.6, 3.2 Hz), 6.85 (2H, br s), 7.19-7.26 (5H, m), 7.67-7.68
(1H, m), 7.91 (1H, d, J=5.6 Hz).
Example 64
5-(2-Butoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine
##STR00141##
[0385] In a reaction vessel, sodium (21 mg, 0.931 mmol) was
dissolved in n-butanol (4 ml) and then
5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (100 mg,
0.310 mmol) was added thereto, followed by stirring under reflux
for 5 hours under an atmosphere of nitrogen gas. The reaction was
terminated by adding water thereto. Then, the reaction mixture was
extracted with ethyl acetate, washed with water and brine, dried
over anhydrous sodium sulfate and then the filtrate was
concentrated. The resulting solid was suspended in ethanol,
collected by filtration and washed with ethanol, to give the title
compound (63 mg, 54%) as a pale yellow solid.
[0386] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 0.92 (3H,
t, J=7.2 Hz), 1.36-1.45 (2H, m), 1.66-1.73 (2H, m), 4.29 (2H, t,
J=6.8 Hz), 6.09 (2H, dd, J=0.8, 3.6 Hz), 6.45 (2H, dd, J=1.6, 3.6
Hz), 6.69 (1H, dd, J=0.8, 1.6 Hz), 6.90 (1H, dd, J=1.6, 5.2 Hz),
6.91 (2H, br s), 7.66 (2H, dd, J=0.8, 1.6 Hz), 8.22 (1H, dd, J=0.8,
5.2 Hz).
Example 65
2-({4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}oxy)-1-ethanol
##STR00142##
[0388] In a reaction vessel, sodium hydride (15 mg, 0.372 mmol) was
suspended in N,N-dimethylformamide (4 ml) and ethylene glycol (23
mg, 0.372 mmol) was added thereto, followed by stirring at
80.degree. C. for 30 minutes under an atmosphere of nitrogen gas.
Subsequently,
5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (100 mg,
0.310 mmol) was added thereto, followed by stirring for 14 hours
under the same conditions. Then, the reaction was terminated by
adding water thereto. The reaction mixture was extracted with ethyl
acetate, washed with water and brine, dried over anhydrous sodium
sulfate and then the filtrate was concentrated. The resulting crude
product was purified by silica gel column chromatography, to give
the title compound (41 mg, 36%) as a pale yellow solid.
[0389] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.71 (2H,
td, J=5.2, 5.2 Hz), 4.30 (2H, t, J=5.2 Hz), 4.84 (1H, t, J=5.2 Hz),
6.09 (2H, d, j=3.2 Hz), 6.45 (2H, dd, J=1.6, 3.2 Hz), 6.71 (1H,
br), 6.91-6.92 (3H, m), 7.66 (2H, d, j=1.6 Hz), 8.22 (1H, d, J=5.2
Hz).
Example 66
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone
##STR00143##
[0391] In a reaction vessel,
5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (100
mg, 0.393 mmol) and potassium carbonate (109 mg, 0.787 mmol) were
suspended in methanol (2 ml). Then, propyl iodide (134 mg, 0.787
mmol) was added thereto, followed by stirring at 50.degree. C. for
17 hours. After the reaction was terminated, the mixture was
concentrated and suspended in dimethylsulfoxide. The insoluble
matters were removed by filtration and the resulting filtrate was
purified by HPLC, to give the title compound (48 mg, 41%) as a pale
yellow solid.
[0392] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 0.86 (3H,
t, J=7.2 Hz), 1.67 (2H, tq, J=7.2, 7.2 Hz), 3.85 (2H, t, J=7.2 Hz),
6.37 (1H, dd, J=0.4, 9.6 Hz), 6.57 (1H, dd, J=1.6, 3.2 Hz), 6.68
(1H, dd, J=0.8, 3.2 Hz), 6.79 (2H, br s), 7.22 (1H, dd, J=2.4, 9.6
Hz), 7.68 (1H, dd, J=0.4, 2.4 Hz), 7.75 (1H, dd, J=0.8, 1.6 Hz),
8.13 (1H, s).
Example 67
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-butyl-1,2-dihydro-2-pyridinone
##STR00144##
[0394] The title compound was synthesized in a similar manner to
Example 66 using butyl iodide.
[0395] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 0.89 (3H,
t, J=7.2 Hz), 1.28 (2H, tq, J=7.2, 7.2 Hz), 1.63 (2H, dt, J=7.2,
7.2 Hz), 3.88 (2H, t, J=7.2 Hz), 6.37 (1H, d, J=9.2 Hz), 6.57 (1H,
dd, J=1.6, 3.6 Hz), 6.68 (1H, d, J=3.6 Hz), 6.79 (2H, br s), 7.22
(1H, dd, J=2.4, 9.2 Hz), 7.68 (1H, d, J=2.4 Hz), 7.73-7.75 (1H, m),
8.13 (1H, s).
Example 68
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-fluoroethyl)-1,2-dihydro-2-pyri-
dinone
##STR00145##
[0397] The title compound was synthesized in a similar manner to
Example 66 using 1-iodo-2-fluoroethane.
[0398] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.24 (2H,
dt, J=4.8, 26.0 Hz), 4.70 (2H, dt, J=4.8, 47.2 Hz), 6.42 (1H, d,
J=9.2 Hz), 6.57 (1H, dd, J=1.6, 3.6 Hz), 6.70 (1H, dd, J=0.8, 3.6
Hz), 6.81 (2H, br s), 7.27 (1H, dd, J=2.8, 9.2 Hz), 7.68 (1H, d,
J=2.8 Hz), 7.74-7.76 (1H, m), 8.11 (1H, s).
Example 69
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(8-hydroxyoctyl)-1,2-dihydro-2-pyr-
idinone
##STR00146##
[0400] The title compound was synthesized in a similar manner to
Example 66 using 8-bromo-1-octanol.
[0401] .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm; 1.20-1.31
(8H, m), 1.37-1.45 (2H, m), 1.62-1.71 (2H, m), 3.42 (2H, t, J=6.8
Hz), 3.92 (2H, t, J=7.2 Hz), 6.42 (1H, dd, J=2.0, 3.6 Hz), 6.46
(1H, d, J=9.2 Hz), 6.75 (1H, d, J=3.6 Hz), 7.27 (1H, dd, J=2.4, 9.2
Hz), 7.46-7.48 (1H, m), 7.53 (1H, d, J=2.4 Hz), 8.03 (1H, s).
Example 70
Methyl
4-{5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridi-
nyl}butanoate
##STR00147##
[0403] The title compound was synthesized in a similar manner to
Example 66 using ethyl 4-bromobutylate.
[0404] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 2.12 (2H, tt,
J=7.2, 7.2 Hz), 2.41 (2H, t, J=7.2 Hz), 3.67 (3H, s), 4.04 (2H, t,
J=7.2 Hz), 5.45 (2H, br s), 6.44 (1H, dd, J=1.6, 3.6 Hz), 6.60 (1H,
d, J=9.2 Hz), 6.71 (1H, d, J=3.6 Hz), 7.20 (1H, dd, J=2.8, 9.2 Hz),
7.24 (1H, d, J=2.8 Hz), 7.49 (1H, dd, J=0.8, 1.6 Hz), 8.14 (1H,
s).
Example 71
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-propynyl)-1,2-dihydro-2-pyridin-
one
##STR00148##
[0406] The title compound was synthesized in a similar manner to
Example 66 using propargyl bromide.
[0407] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 2.49 (1H, t,
J=2.8 Hz), 4.82 (2H, d, J=2.8 Hz), 5.31 (2H, br s), 6.45 (1H, dd,
J=1.6, 3.6 Hz), 6.61 (1H, dd, J=0.4, 9.2 Hz), 6.74 (1H, dd, J=0.8,
3.6 Hz), 7.23 (1H, dd, J=2.4, 9.2 Hz), 7.49 (1H, dd, J=0.8, 1.6
Hz), 7.59 (1H, dd, J=0.4, 2.4 Hz), 8.16 (1H, s).
Example 72
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isobutyl-1,2-dihydro-2-pyridinone
##STR00149##
[0409] The title compound was synthesized in a similar manner to
Example 66 using 1-iodo-2-methylpropane.
[0410] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 0.96 (6H, t,
J=7.2 Hz), 2.16-2.27 (1H, m), 3.78 (2H, d, J=7.6 Hz), 5.26 (2H, br
s), 6.43 (1H, dd, J=1.6, 3.6 Hz), 6.61 (1H, d, J=9.6 Hz), 6.68 (1H,
dd, J=0.8, 3.6 Hz), 7.14 (1H, dd, J=0.4, 2.4 Hz), 7.19 (1H, dd,
J=2.4, 9.6 Hz), 7.48 (1H, dd, J=0.8, 1.6 Hz), 8.12 (1H, s).
Example 73
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-butynyl)-1,2-dihydro-2-pyridino-
ne
##STR00150##
[0412] The title compound was synthesized in a similar manner to
Example 66 using 1-bromo-2-butyne.
[0413] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.80 (3H,
s), 4.67 (2H, d, J=2.0 Hz), 6.41 (1H, d, J=9.2 Hz), 6.56-6.59 (1H,
m), 6.74 (1H, d, J=3.2 Hz), 6.80 (2H, br s), 7.26 (1H, dd, J=2.0,
9.2 Hz), 7.72 (1H, d, J=2.0 Hz), 7.74 (1H, br), 8.13 (1H, s).
Example 74
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-benzyl-1,2-dihydro-2-pyridinone
##STR00151##
[0415] The title compound was synthesized in a similar manner to
Example 66 using benzyl chloride.
[0416] .sup.1H NR (400 MHz, CDCl.sub.3) .delta. ppm; 5.14 (2H, br),
5.18 (2H, s), 6.39 (1H, dd, J=1.6, 3.6 Hz), 6.64-6.68 (2H, m),
7.18-7.23 (2H, m), 7.27-7.36 (5H, m), 7.41 (1H, dd, J=0.8, 1.6 Hz),
8.07 (1H, s).
Example 75
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isopentyl-1,2-dihydro-2-pyridinone
##STR00152##
[0418] The title compound was synthesized in a similar manner to
Example 66 using 1-iodo-3-methylbutane. .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. ppm; 0.98 (6H, d, J=6.0 Hz), 1.60-1.70 (3H,
m), 4.05 (2H, t, J=7.2 Hz), 6.53 (1H, dd, J=1.6, 3.6 Hz), 6.57 (1H,
d, J=9.2 Hz), 6.86 (1H, dd, J=0.4, 3.6 Hz), 7.38 (1H, dd, J=2.8,
9.2 Hz), 7.58 (1H, dd, J=0.4, 1.6 Hz), 7.65 (1H, d, J=2.8 Hz), 8.14
(1H, s).
Example 76
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methylbutyl)-1,2-dihydro-2-pyri-
dinone
##STR00153##
[0420] The title compound was synthesized in a similar manner to
Example 66 using 1-iodo-2-methylbutane.
[0421] .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm; 0.91 (3H,
d, J=6.8 Hz), 0.96 (3H, t, J=7.6 Hz), 1.17-1.28 (1H, m), 1.38-1.50
(1H, m), 1.93-2.04 (1H, m), 3.79 (1H, dd, J=8.4, 12.8 Hz), 3.99
(1H, dd, J=6.8, 12.8 Hz), 6.53 (1H, dd, J=1.6, 3.6 Hz), 6.58 (1H,
d, J=9.2 Hz), 6.87 (1H, d, J=3.6 Hz), 7.39 (1H, dd, J=2.4, 9.2 Hz),
7.57 (1H, br), 7.60 (1H, d, J=2.4 Hz), 8.12 (1H, s).
Example 77
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-octyl-1,2-dihydro-2-pyridinone
##STR00154##
[0423] The title compound was synthesized in a similar manner to
Example 66 using octyl bromide.
[0424] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 0.87 (3H, t,
J=7.2 Hz), 1.18-1.42 (10H, m), 1.72-1.81 (2H, m), 3.95 (2H, d,
J=7.6 Hz) 5.17 (2H, br s), 6.43 (1H, dd, J=1.6, 3.6 Hz), 6.60 (1H,
d, J=10.4 Hz), 6.66 (1H, dd, J=0.8, 3.6 Hz), 7.16-7.22 (2H, m),
7.48-7.51 (1H, m), 8.13 (1H, s).
Example 78
2-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}eth-
ylcyanide
##STR00155##
[0426] The title compound was synthesized in a similar manner to
Example 66 using 3-bromopropionitrile.
[0427] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 2.99 (2H, t,
j=6.0 Hz), 4.20 (2H, t, J=6.0 Hz), 5.18 (2H, br s), 6.45 (1H, dd,
J=1.6, 3.6 Hz), 6.62 (1H, d, J=9.6 Hz), 6.78 (1H, d, J=3.6 Hz),
7.22-7.33 (2H, m), 7.48-7.51 (1H, m), 8.16 (1H, s).
Example 79
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-fluoropropyl)-1,2-dihydro-2-pyr-
idinone
##STR00156##
[0429] The title compound was synthesized in a similar manner to
Example 66 using 1-bromo-3-fluoropropane.
[0430] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 2.21 (2H,
dtt, J=6.0, 6.8, 27.2 Hz), 4.12 (2H, t, J=6.8 Hz), 4.51 (2H, dt,
J=6.0, 46.8 Hz), 5.42 (2H, br s), 6.46 (1H, dd, J=1.6, 3.6 Hz),
6.60 (1H, dd, J=0.8, 9.2 Hz), 6.75 (1H, d, J=3.6 Hz), 7.20-7.26
(2H, m), 7.48-7.52 (1H, m), 8.11 (1H, s).
Example 80
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-hydroxyethyl)-1,2-dihydro-2-pyr-
idinone
##STR00157##
[0432] The title compound was synthesized in a similar manner to
Example 66 using 2-iodoethanol.
[0433] MS m/e (ESI) 299 (MH.sup.+).
Example 81
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-hydroxypropyl)-1,2-dihydro-2-py-
ridinone
##STR00158##
[0435] The title compound was synthesized in a similar manner to
Example 66 using 3-iodopropanol.
[0436] .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm; 1.98 (2H,
dt, J=6.4, 6.4 Hz), 3.60 (2H, t, J=6.4 Hz), 4.14 (2H, t, J=6.4 Hz),
6.54 (1H, dd, J=2.0, 3.6 Hz), 6.58 (1H, d, J=9.2 Hz), 6.89 (1H, d,
J=3.6 Hz), 7.39 (1H, dd, J=2.4, 9.2 Hz), 7.58-7.60 (1H, m), 7.66
(1H, d, J=2.4 Hz), 8.15 (1H, s).
Example 82
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methoxyethyl)-1,2-dihydro-2-pyr-
idinone
##STR00159##
[0438] The title compound was synthesized in a similar manner to
Example 66 using 2-bromoethyl methyl ether.
[0439] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 3.30 (3H, s),
3.70 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 5.23 (2H, br s),
6.40-6.46 (1H, m), 6.60 (1H, d, J=9.2 Hz), 6.65 (1H, d, J=3.2 Hz),
7.20 (1H, dd, J=2.4, 9.2 Hz), 7.31 (1H, d, J=1.6 Hz), 7.50 (1H,
br), 8.14 (1H, s).
Example 83
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-[2-(1H-1-pyrrolyl)ethyl]-1,2-dihyd-
ro-2-pyridinone
##STR00160##
[0441] The title compound was synthesized in a similar manner to
Example 66 using 1-(2-bromoethyl)pyrrole.
[0442] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 4.21-4.26
(2H, m), 4.28-4.33 (2H, m), 5.12 (2H, br s), 6.12 (2H, dd, J=2.0,
2.0 Hz), 6.37 (1H, d, J=2.4 Hz), 6.43 (1H, dd, J=1.6, 3.6 Hz), 6.52
(2H, dd, J=2.0, 2.0 Hz), 6.57 (1H, d, J=9.6 Hz), 6.66 (1H, dd,
J=0.8, 3.6 Hz), 7.15 (1H, dd, J=2.4, 9.6 Hz), 7.47 (1H, dd, J=0.8,
1.6 Hz), 7.84 (1H, s).
Example 84
2-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}ace-
tamide
##STR00161##
[0444] The title compound was synthesized in a similar manner to
Example 66 using 2-bromoacetamide.
[0445] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.52 (2H,
s), 6.38 (1H, d, J=9.2 Hz), 6.56 (1H, dd, J=1.6, 3.6 Hz), 6.73 (1H,
d, J=3.6 Hz), 6.80 (2H, br s), 7.19 (1H, br s), 7.24 (1H, dd,
J=2.4, 9.2 Hz), 7.62 (1H, br s), 7.63 (1H, d, J=2.4 Hz), 7.77 (m,
br), 8.10 (1H, s).
Example 85
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(cyclopropylmethyl)-1,2-dihydro-2--
pyridinone
##STR00162##
[0447] The title compound was synthesized in a similar manner to
Example 66 using cyclopropylmethyl bromide.
[0448] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 0.36-0.41
(2H, m), 0.58-0.65 (2H, m), 1.22-1.33 (1H, m), 3.84 (2H, d, J=7.2
Hz), 5.16 (2H, br s), 6.44 (1H, dd, J=1.6, 3.6 Hz), 6.62 (1H, d,
J=9.2 Hz), 6.68 (1H d, J=3.6 Hz), 7.21 (1H, dd, J=2.4, 9.2 Hz),
7.32 (1H, d, J=2.4 Hz), 7.48-7.52 (1H, m), 8.15 (1H, s).
Example 86
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-[2-(2-methoxyethoxy)ethyl]-1,2-dih-
ydro-2-pyridinone
##STR00163##
[0450] The title compound was synthesized in a similar manner to
Example 66 using 1-bromo-2-(2-methoxyethoxy)ethane.
[0451] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 3.27 (3H, s),
3.39-3.46 (2H, m), 3.53-3.61 (2H, m), 3.81 (2H, t, J=4.8 Hz), 4.19
(2H, t, J=4.8 Hz), 5.50 (2H, br s), 6.43 (1H, dd, J=1.6, 3.2 Hz),
6.59 (1H, d, J=9.2 Hz), 6.66 (1H, d, J=3.2 Hz), 7.19 (1H, dd,
J=2.4, 9.2 Hz), 7.41 (1H, d, J=2.4 Hz), 7.50 (1H, d, J=1.6 Hz),
8.15 (1H, s).
Example 87
5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone
##STR00164##
[0453] The title compound was synthesized in a similar manner to
Example 66 using
5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyr idinone
and ethyl iodide.
[0454] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.15 (3H,
t, J=7.2 Hz), 3.89 (2H, q, J=7.2 Hz), 6.37 (2H, dd, J=0.8, 3.6 Hz),
6.48 (1H, dd, J=0.4, 9.2 Hz), 6.53 (2H, dd, J=1.6, 3.6 Hz), 6.87
(2H, br s), 7.27 (1H, dd, J=2.4, 9.2 Hz), 7.61 (1H, d, J=2.4 Hz),
7.75 (2H, dd, J=0.8, 1.6 Hz).
Example 88
5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-allyl-1,2-dihydro-2-pyridinone
##STR00165##
[0456] The title compound was synthesized in a similar manner to
Example 66 using
5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyr idinone
and allyl bromide.
[0457] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.50 (2H,
d, J=5.2 Hz), 4.95 (1H, dd, J=1.2, 17.2 Hz), 5.08 (1H, dd, J=1.2,
10.0 Hz), 5.88 (1H, ddt, J=5.2, 10.0, 17.2 Hz), 6.43 (2H, dd,
J=0.8, 3.6 Hz), 6.52 (1H, dd, J=0.8, 9.2 Hz), 6.53 (2H, dd, J=1.6,
3.6 Hz), 6.86 (2H, br s), 7.32 (1H, dd, J=2.4, 9.2 Hz), 7.50 (1H,
dd, J=0.8, 2.4 Hz), 7.74 (2H, dd, J=0.8, 1.6 Hz).
Example 89
5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinon-
e
##STR00166##
[0459] The title compound was synthesized in a similar manner to
Example 66 using
5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridino-
ne and propyl iodide.
[0460] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 0.90 (3H, t,
J=7.2 Hz), 1.76 (2H, tq, J=7.2, 7.2 Hz), 3.93 (2H, t, J=7.2 Hz),
6.12 (2H, br s), 6.44 (2H, dd, J=1.6, 3.6 Hz), 6.57 (2H, d, J=3.6
Hz), 6.78 (1H, d, J=9.2 Hz), 7.11 (1H, d, J=2.4 Hz), 7.24 (1H, dd,
J=2.4, 9.2 Hz), 7.53 (2H, dd, J=0.8, 1.6 Hz).
Example 90
5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-butyl-1,2-dihydro-2-pyridinone
##STR00167##
[0462] The title compound was synthesized in a similar manner to
Example 66 using
5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridino-
ne and butyl iodide.
[0463] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm; 0.90 (3H, t,
J=7.2 Hz), 1.23-1.34 (2H, m), 1.65-1.74 (2H, m), 3.98 (2H, t, J=7.2
Hz), 6.50 (2H, dd, J=1.6, 3.6 Hz), 6.75 (2H, d, J=3.6 Hz), 6.81
(1H, d, J=9.2 Hz), 7.04 (2H, br s), 7.14 (1H, d, J=2.4 Hz),
7.22-7.30 (1H, m), 7.56 (2H, d, J=1.6 HZ).
Example 91
5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-(2-butynyl)-1,2-dihydro-2-pyri-
dinone
##STR00168##
[0465] The title compound was synthesized in a similar manner to
Example 66 using
5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridino-
ne and 1-bromo-2-butyne.
[0466] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.74 (3H,
t, J=2.4 Hz), 4.65 (2H, q, J=2.4 Hz), 6.41 (2H, dd, J=0.8, 3.6 Hz),
6.52 (1H, dd, J=0.4, 9.2 Hz), 6.54 (2H, dd, J=2.0, 3.6 Hz), 6.88
(2H, br s), 7.30 (1H, dd, J=2.4, 9.2 Hz), 7.62 (1H, dd, J=0.4, 2.4
Hz), 7.75 (2H, dd, J=0.8, 2.0 Hz).
Example 92
5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-(2-fluoroethyl)-1,2-dihydro-2--
pyridinone
##STR00169##
[0468] The title compound was synthesized in a similar manner to
Example 66 using
5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridino-
ne and 1-iodo-2-fluoroethane
[0469] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 4.22 (2H,
dt, J=4.8, 26.0 Hz), 4.64 (2H, dt, J=4.8, 47.6 Hz), 6.38 (2H, dd,
J=0.8, 3.6 Hz), 6.52 (2H, dd, J=1.6, 3.6 Hz), 6.52 (1H, d, J=9.2
Hz), 6.87 (2H, br s), 7.30 (1H, dd, J=2.8, 9.2 Hz), 7.59 (1H, d,
J=2.8 Hz), 7.74 (2H, dd, J=0.8, 1.6 Hz).
Example 93
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-thienyl)-1,2-dihydro-2-pyridino-
ne
##STR00170##
[0471] In a reaction vessel,
5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (50
mg, 0.197 mmol), thiophene-3-boronic acid (50 mg, 0.393 mmol), and
copper acetate (4 mg, 0.0197 mmol) were suspended in
N,N-dimethylformamide (3 ml). Pyridine (31 mg, 0.393 mmol) was
added thereto, followed by stirring at room temperature for 14.5
hours in the air. After the reaction was terminated, the mixture
was concentrated and suspended in dimethylsulfoxide. Subsequently,
the insoluble matters were removed by filtration and the resulting
filtrate was purified by HPLC, to give the title compound (34 mg,
51%) as a pale yellow solid.
[0472] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.47 (1H,
dd, J=0.8, 9.6 Hz), 6.59 (1H, dd, J=1.6, 3.2 Hz), 6.78 (2H, br s),
6.82 (1H, dd, J=0.8, 3.2 Hz), 7.28 (1H, dd, J=2.4, 9.6 Hz), 7.35
(1H, dd, J=1.6, 5.2 Hz), 7.61 (1H, dd, J=3.2, 5.2 Hz), 7.71 (1H,
dd, J=0.8, 2.4 Hz), 7.78-7.81 (2H, m), 8.23 (1H, s).
Example 94
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-phenyl-1,2-dihydro-2-pyridinone
##STR00171##
[0474] The title compound was synthesized in a similar manner to
Example 93 using phenylboronic acid.
[0475] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.47 (1H,
dd, J=0.8, 9.2 Hz), 6.60 (1H, dd, J=1.6, 3.6 Hz), 6.77 (2H, br s),
6.82 (1H, dd, J=0.8, 3.6 Hz), 7.32 (1H, dd, J=2.4, 9.2 Hz),
7.40-7.52 (5H, m), 7.62 (1H, d, J=2.4 Hz), 7.81 (1H, dd, J=0.8, 1.6
Hz), 8.21 (1H, s).
Example 95
5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-[(E)-2-phenyl-1-ethenyl]-1,2-dihyd-
ro-2-pyridinone
##STR00172##
[0477] The title compound was synthesized in a similar manner to
Example 93 using E-phenylethenylboronic acid.
[0478] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.48 (1H,
d, J=9.2 Hz), 6.59 (1H, dd, J=1.6, 3.2 Hz), 6.79-6.84 (3H, m), 7.15
(1H, d, J=15.2 Hz), 7.27 (1H, dd, J=2.4, 9.6 Hz), 7.29 (1H, d,
J=7.6 Hz), 7.37 (2H, t, J=7.6 Hz), 7.51 (2H, d, J=7.6 Hz), 7.78
(1H, dd, J=0.8, 1.6 Hz), 7.93 (1H, d, J=15.2 Hz), 8.06 (1H, d,
J=2.4 Hz), 8.25 (1H, s).
Example 96
1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinecarbox-
ylic acid
##STR00173##
[0480] In a reaction vessel, ethyl
1-{4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinecarbo-
xylate (59 mg, 0.128 mmol) was suspended in methanol (0.8 ml). A 5N
aqueous sodium hydroxide solution (0.2 ml) was added thereto,
followed by stirring at room temperature for 15 hours. After the
reaction was terminated, the reaction mixture was extracted with
ethyl acetate, washed with water and brine, dried over anhydrous
sodium sulfate and then the filtrate was concentrated, to give the
title compound (20 mg, 36%) as a white solid.
[0481] .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm; 1.60-1.73
(2H, m), 1.88-1.96 (2H, m), 2.50-2.60 (1H, m), 2.96-3.05 (2H, m),
4.17-4.25 (2H, m), 6.25 (2H, dd, J=0.8, 3.6 Hz), 6.40 (2H, dd,
J=2.0, 3.6 Hz), 6.58 (1H, dd, J=1.2, 5.2 Hz), 6.78 (1H, br), 7.55
(2H, dd, J 0.8, 2.0 Hz), 8.20 (1H, dd, J=0.8, 5.2 Hz).
Example 97
4-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}but-
yric acid
##STR00174##
[0483] The title compound was synthesized in a similar manner to
Example 96 using methyl
4-{5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}bu-
tanoate
[0484] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.89 (2H,
tt, J=7.2, 7.2 Hz) 2.21 (2H, t, J=7.2 Hz), 3.91 (2H, t, J=7.2 Hz),
6.37 (1H, d, J=9.2 Hz), 6.56 (1H, dd, J=1.6, 3.6 Hz), 6.70 (1H, d,
J=3.6 Hz), 6.79 (2H, br s), 7.22 (1H, dd, J=2.4, 9.2 Hz), 7.65 (1H,
d, J=2.4 Hz), 7.74-7.76 (1H, m), 8.15 (1H, s).
Example 98
5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine
##STR00175##
[0486] The title compound was synthesized in a similar manner to
Reference Example 6 and Example 14 using
2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone.
[0487] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.59 (1H,
dd, J=1.8, 3.6 Hz), 6.81 (1H, dd, J=0.8, 3.6 Hz), 7.06 (2H, br s,
2H), 7.13 (1H, s), 7.18-7.22 (1H, m), 7.70 (1H, dd, J=0.8, 1.8 Hz),
8.21 (1H, d, J=5.2 Hz), 8.27 (1H, s).
Example 99
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
##STR00176##
[0489] A suspension of
5-(2-fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine (3.00 g,
11.70 mmol) in concentrated hydrochloric acid (15 ml)-water (15 ml)
was stirred at 100.degree. C. for 2 hours. After cooling as it was,
the reaction mixture was neutralized with a 5N aqueous sodium
hydroxide solution. The resulting solid was collected by
filtration, washed with water and dried at 60.degree. C. for 22
hours, to give the title compound (2.19 g, 70%) as a pale brown
solid.
[0490] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 5.93 (1H,
dd, J=1.8, 6.8 Hz), 6.26 (1H, d, J=1.8 Hz), 6.59 (1H, dd, J=1.8,
3.4 Hz), 6.82 (1H, dd, J=0.8, 3.4 Hz), 6.96 (2H, br s), 7.31 (1H,
d, J=6.8 Hz), 7.78 (1H, dd, J=0.8, 1.8 Hz), 8.19 (1H, s).
[0491] The compounds of Examples 100 to 142 below were synthesized
in a similar manner to Examples 16, 66, and/or 96 using
4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridin
one.
Example 100
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-benzyl-1,2-dihydro-2-pyridinone
##STR00177##
[0493] MS m/e (ESI) 345 (MH.sup.+).
Example 101
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-phenethyl-1,2-dihydro-2-pyridinone
##STR00178##
[0495] MS m/e (ESI) 359 (MH.sup.+).
Example 102
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-phenylpropyl)-1,2-dihydro-2-pyr-
idinone
##STR00179##
[0497] MS m/e (ESI) 373 (MH.sup.+).
Example 103
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-fluorobenzyl)-1,2-dihydro-2-pyr-
idinone
##STR00180##
[0499] MS m/e (ESI) 363 (MH.sup.+).
Example 104
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-fluorobenzyl)-1,2-dihydro-2-pyr-
idinone
##STR00181##
[0501] MS m/e (ESI) 363 (MH.sup.+).
Example 105
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-fluorobenzyl)-1,2-dihydro-2-pyr-
idinone
##STR00182##
[0503] MS m/e (ESI) 363 (MH.sup.+).
Example 106
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,4-difluorobenzyl)-1,2-dihydro-2-
-pyridinone
##STR00183##
[0505] MS m/e (ESI) 381 (MH.sup.+).
Example 107
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,5-difluorobenzyl)-1,2-dihydro-2-
-pyridinone
##STR00184##
[0507] MS m/e (ESI) 381 (MH.sup.+).
Example 108
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-trifluoromethylbenzyl)-1,2-dihy-
dro-2-pyridinone
##STR00185##
[0509] MS m/e (ESI) 413 (MH.sup.+).
Example 109
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-trifluoromethylbenzyl)-1,2-dihy-
dro-2-pyridinone
##STR00186##
[0511] MS m/e (ESI) 413 (MH.sup.+).
Example 110
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone
##STR00187##
[0513] MS m/e (ESI) 269 (MH.sup.+).
Example 111
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone
##STR00188##
[0515] MS m/e (ESI) 283 (MH.sup.+).
Example 112
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone
##STR00189##
[0517] MS m/e (ESI) 297 (MH.sup.+).
Example 113
1-Allyl-4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
##STR00190##
[0519] MS m/e (ESI) 295 (MH.sup.+).
Example 114
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-butenyl)-1,2-dihydro-2-pyridino-
ne
##STR00191##
[0521] MS m/e (ESI) 309 (MH.sup.+).
Example 115
7-{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}hep-
tanenitrile
##STR00192##
[0523] MS m/e (ESI) 364 (MH.sup.+).
Example 116
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-cyclobutylmethyl-1,2-dihydro-2-pyr-
idinone
##STR00193##
[0525] MS m/e (ESI) 323 (MH.sup.+).
Example 117
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-fluoropropyl)-1,2-dihydro-2-pyr-
idinone
##STR00194##
[0527] MS m/e (ESI) 315 (MH.sup.+).
Example 118
4-{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}but-
yronitrile
##STR00195##
[0529] MS m/e (ESI) 322 (MH.sup.+).
Example 119
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(6-chloro-3-pyridylmethyl)-1,2-dih-
ydro-2-pyridinone
##STR00196##
[0531] MS m/e (ESI) 380 (MH.sup.+).
Example 120
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-pyridylmethyl)-1,2-dihydro-2-py-
ridinone
##STR00197##
[0533] MS m/e (ESI) 346 (MH.sup.+).
Example 121
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-pyridylmethyl)-1,2-dihydro-2-py-
ridinone
##STR00198##
[0535] MS m/e (ESI) 346 (MH.sup.+).
Example 122
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-pyridylmethyl)-1,2-dihydro-2-py-
ridinone
##STR00199##
[0537] MS m/e (ESI) 346 (MH.sup.+).
Example 123
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-butynyl)-1,2-dihydro-2-pyridino-
ne
##STR00200##
[0539] MS m/e (ESI) 307 (MH.sup.+).
Example 124
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4,4,4-trifluorobutyl)-1,2-dihydro-
-2-pyridinone
##STR00201##
[0541] MS m/e (ESI) 365 (MH.sup.+).
Example 125
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methoxyethyl)-1,2-dihydro-2-pyr-
idinone
##STR00202##
[0543] MS m/e (ESI) 313 (MH.sup.+).
Example 126
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-pentynyl-1,2-dihydro-2-pyridino-
ne
##STR00203##
[0545] MS m/e (ESI) 321 (MH.sup.+).
Example 127
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methylallyl)-1,2-dihydro-2-pyri-
dinone
##STR00204##
[0547] MS m/e (ESI) 309 (MH.sup.+).
Example 128
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isobutyl-1,2-dihydro-2-pyridinone
##STR00205##
[0549] MS m/e (ESI) 311 (MH.sup.+).
Example 129
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-pentenyl)-1,2-dihydro-2-pyridin-
one
##STR00206##
[0551] MS m/e (ESI) 323 (MH.sup.+).
Example 130
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-methyl-2-butenyl)-1,2-dihydro-2-
-pyridinone
##STR00207##
[0553] MS m/e (ESI) 323 (MH.sup.+).
Example 131
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-methylbutyl)-1,2-dihydro-2-pyri-
dinone
##STR00208##
[0555] MS m/e (ESI) 325 (MH.sup.+).
Example 132
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-methyl-3-pentenyl)-1,2-dihydro--
2-pyridinone
##STR00209##
[0557] MS m/e (ESI) 337 (MH.sup.+).
Example 133
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-propynyl)-1,2-dihydro-2-pyridin-
one
##STR00210##
[0559] MS m/e (ESI) 293 (MH.sup.+).
Example 134
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-diethylaminoethyl)-1,2-dihydro--
2-pyridinone
##STR00211##
[0561] MS m/e (ESI) 354 (MH.sup.+).
Example 135
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,2,2-trifluoroethyl)-1,2-dihydro-
-2-pyridinone
##STR00212##
[0563] MS m/e (ESI) 337 (MH.sup.+).
Example 136
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-fluoroethyl)-1,2-dihydro-2-pyri-
dinone
##STR00213##
[0565] MS m/e (ESI) 301 (MH.sup.+).
Example 137
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(1,2,2,2-tetrafluoroethyl)-1,2-dih-
ydro-2-pyridinone
##STR00214##
[0567] MS m/e (ESI) 355 (MH.sup.+).
Example 138
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,2-difluoroethyl)-1,2-dihydro-2--
pyridinone
##STR00215##
[0569] MS m/e (ESI) 319 (MH.sup.+).
Example 139
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-ethoxyethyl)-1,2-dihydro-2-pyri-
dinone
##STR00216##
[0571] MS m/e (ESI) 327 (MH.sup.+).
Example 140
Methyl
{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridiny-
l}acetate
##STR00217##
[0573] MS m/e (ESI) 327 (MH.sup.+).
Example 141
{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}aceti-
c acid
##STR00218##
[0575] MS m/e (ESI) 313 (MH.sup.+).
Example 142
4-{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}but-
yric acid
##STR00219##
[0577] MS m/e (ESI) 341 (MH.sup.+).
Example 143
N1,N1-Diethyl-2-{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-
-pyridinyl}acetamide
##STR00220##
[0579] A suspension of
{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acet-
ic acid (10 mg, 32 .mu.mol), 1-hydroxybenzotriazole (15 mg, 98
.mu.mol), 3-(3'-dimethylaminopropyl)-1-ethylcarbodiimide (15 mg, 96
mmol), diethylamine hydrochloride (18 mg, 164 .mu.mol) and
triethylamine (22 .mu.l, 160 .mu.mol) in N,N-dimethylformamide (1.0
ml) was stirred at room temperature for 17 hours. The reaction
mixture was diluted with water and then extracted with ethyl
acetate. The organic layer was concentrated and then purified by
HPLC, to give the title compound (0.73 mg, 6%).
[0580] MS m/e (ESI) 368 (MH.sup.+).
Example 144
N1-Phenyl-2-{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyr-
idinyl}acetamide
##STR00221##
[0582] The title compound was synthesized in a similar manner to
Example 143 using aniline.
[0583] MS m/e (ESI) 388 (MH.sup.+).
Example 145
4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone
##STR00222##
[0585] The title compound was synthesized in a similar manner to
Example 99 using
5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinylamine.
[0586] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.13 (1H,
dd, J=1.6, 6.8 Hz), 6.19 (1H, d, J=1.6 Hz), 6.51-6.56 (4H, m), 6.91
(2H, br s), 7.48 (1H, d, J=6.8 Hz), 7.74-7.78 (2H, m).
[0587] The compounds of Examples 146 to 148 below were synthesized
in a similar manner to Examples 16 or 66 using
4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.
Example 146
4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinon-
e
##STR00223##
[0589] MS m/e (ESI) 335 (MH.sup.+).
Example 147
4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone
##STR00224##
[0591] MS m/e (ESI) 349 (MH.sup.+).
Example 148
4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinon-
e
##STR00225##
[0593] MS m/e (ESI) 363 (MH.sup.+).
Example 149
5-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-(3-hydroxypropyl)-1,2-dihydro--
2-pyridinone
##STR00226##
[0595] The title compound was synthesized in a similar manner to
Example 66 using
5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyr idinone
and 3-iodopropanol.
[0596] MS m/e (ESI) 379 (MH.sup.+).
Example 150
4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-pyridinecarboxyamide
##STR00227##
[0598] A suspension of
5-(2-fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine (300 mg, 1.17
mmol) and sodium cyanide in dimethylsulfoxide (3 ml) was stirred at
150.degree. C. for 46 hours. After cooling as it was, the reaction
mixture was diluted with ethyl acetate and washed with an aqueous
solution of saturated ammonium chloride twice. The resulting
organic layer was dried over anhydrous sodium sulfate and
concentrated. The residue was subjected to silica gel plate
(developing solvent; dichloromethane:methanol=10:1) and then washed
with diethyl ether, to give the title compound (10 mg, 3%) as a
colorless solid.
[0599] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.40 (1H,
dd, J=1.2, 5.2 Hz), 6.51 (1H, d, J=1.2 Hz), 6.54 (1H, dd, J=1.6,
3.4 Hz), 6.60 (1H, dd, J=0.8, 3.4 Hz), 6.89 (2H, br s), 7.72 (1H,
dd, J=0.8, 1.6 Hz), 8.04 (1H, d, J=5.2 Hz), 8.18 (1H, s).
Example 151
5-(2-Methoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine
##STR00228##
[0601] The title compound was synthesized in a similar manner to
Example 64 using methanol.
[0602] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 3.88 (3H,
s), 6.08 (2H, d, J=3.6 Hz), 6.44 (2H, dd, J=1.6, 3.6 Hz), 6.73 (1H,
br), 6.87-6.94 (3H, m), 7.65 (2H, d, j=1.6 Hz), 8.23 (1H, d, J=5.2
Hz).
Example 152
5-(2-Ethoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine
##STR00229##
[0604] The title compound was synthesized in a similar manner to
Example 64 using ethanol.
[0605] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 1.32 (3H,
t, J=7.2 Hz), 4.34 (2H, q, J=7.2 Hz), 6.09 (2H, dd, J=0.8, 3.6 Hz),
6.45 (2H, dd, J=1.6, 3.6 Hz), 6.70 (1H, dd, J=0.8, 1.2 Hz),
6.88-6.94 (3H, m), 7.67 (2H, dd, J=0.8, 1.6 Hz), 8.22 (1H, dd,
J=0.8, 5.2 Hz).
Example 153
5-(2-Propoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine
##STR00230##
[0607] The title compound was synthesized in a similar manner to
Example 64 using n-propanol.
[0608] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 0.95 (3H,
t, J=7.2 Hz), 1.72 (2H, tq, J=7.2, 7.2 Hz), 4.25 (2H, t, J=7.2 Hz),
6.09 (2H, dd, J=0.8, 3.6 Hz), 6.45 (2H, dd, J=1.6, 3.6 Hz), 6.70
(1H, dd, J=0.8, 1.2 Hz), 6.89-6.94 (3H, m), 7.67 (2H, dd, J=0.8,
1.6 Hz), 8.22 (1H, dd, J=0.8, 5.2 Hz).
Example 154
5-(6-Chloro-3-pyridyl)-4-(2-thienyl)-2-pyrimidinylamine
##STR00231##
[0610] The title compound was obtained in a similar manner to
Example 14 using
2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(2-thienyl)-2-propen-1-o-
ne.
[0611] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 6.73 (1H,
dd, J=1.2, 4.0 Hz), 6.94 (2H, br s), 6.98 (1H, dd, J=4.0, 5.0 Hz),
7.59 (1H, dd, J=0.8, 8.2 Hz), 7.67 (1H, dd, J=1.2, 5.0 Hz), 7.83
(1H, dd, J=2.4, 8.2 Hz), 8.17 (1H, s), 8.36 (1H, dd, J=0.8,
2.4).
Example 155
5-(6-Chloro-3-pyridyl)-4-phenyl-2-pyrimidinylamine
##STR00232##
[0613] The title compound was obtained in a similar manner to
Example 14 using
2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-phenyl-2-propen-1-one.
[0614] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm; 7.01 (2H,
br s), 7.27-7.40 (5H, m), 7.42 (1H, dd, J=0.8, 8.2 Hz), 7.55 (1H,
dd, J=2.8, 8.2 Hz), 8.14 (1H, dd, J=0.8, 2.8 Hz), 8.35 (1H, s).
Example 156
5-(6-Chloro-3-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine
##STR00233##
[0616] The title compound was obtained in a similar manner to
Example 14 using
2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(3-fluorophenyl)-2-prope-
n-1-one.
[0617] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm, 7.00-7.06
(1H, m), 7.07 (2H, br s), 7.15-7.25 (2H, m), 7.33-7.39 (1H, m),
7.44 (1H, dd, J=0.6, 8.2 Hz), 7.58 (1H, dd, J=2.6, 8.2 Hz), 8.18
(1H, dd, J=0.6, 2.6 Hz), 8.38 (1H, s).
[0618] The compounds represented by the above formula (I) according
to the present invention are useful as an adenosine receptor
(A.sub.1, A.sub.2A, A.sub.2B or A.sub.3 receptor) antagonist and
are specifically useful as an A.sub.2B receptor antagonist. Test
examples demonstrating the efficacy of the compounds of the present
invention as a medicament will be described below.
Test Example 1
Measurement of the Binding Affinity to Adenosine A.sub.1
Receptor
[0619] A human adenosine A.sub.1 receptor cDNA was expressed in
excess in CHOK1 cells, and this membrane sample was suspended at a
protein concentration of 66.7 .mu.g/ml in 20 mM HEPES buffer, pH
7.4 (10 mM MgCl.sub.2, 100 mM NaCl). To 0.45 ml of this membrane
sample suspension were added 0.025 ml of 60 nM tritium-labeled
chlorocyclopentyl adenosine (.sup.3H-CCPA, from NEN Ltd.) and 0.025
ml of test compound. This mixture was left at 30.degree. C. for 120
minutes, filtered rapidly under suction through a glass fiber
filter (GF/B, from Whatman), and immediately washed twice with 5 ml
of 50 mM water-cooled Tris-HCl buffer. Thereafter, the glass fiber
filter was transferred to a vial, scintillator was added thereto,
and the radioactivity on the filter was measured by a liquid
scintillation counter. The inhibition of binding of .sup.3H-CCPA to
A.sub.1 receptor by the test compound was determined using the
following formula, and from this value, 50% inhibition
concentration (IC.sub.50) was calculated. Inhibition
(%)=[1-{binding in the presence of the test compound-nonspecific
binding)/(total binding-nonspecific binding)}].times.100
[0620] In the above formula, the total binding means
.sup.3H-CCPA-bound radioactivity in the absence of the test
compound; the nonspecific binding means .sup.3H-CCPA-bound
radioactivity in the presence of 100 .mu.M CPA
([R]-[1-methyl-2-phenylethyl]adenosine); and the binding in the
presence of the test compound means .sup.3H-CCPA-bound
radioactivity in the presence of the test compound at predetermined
concentrations. The inhibition constant (Ki value) in the table was
determined from the formula of Cheng-Prusoff.
Test Example 2
Measurement of the Binding Ability to Adenosine A.sub.2A
Receptor
[0621] An experiment of inhibition of binding to adenosine A.sub.2A
receptor was conducted using a membrane sample (Receptor Biology
Inc.) where an adenosine A.sub.2A receptor cDNA was expressed in
excess. This membrane sample was suspended at a protein
concentration of 22.2 .mu.g/ml in 20 mM HEPES buffer, pH 7.4 (10 mM
MgCl.sub.2 and 100 mM NaCl). To 0.45 ml of this membrane sample
suspension were added 0.025 ml of 500 nM tritium-labeled
2-p-[2-carboxyethyl]phenetylamino-5'-N-ethylarboxyamide adenosine
(.sup.3H-CGS21680, from NEN) and 0.025 ml of test compound. This
mixture was left at 25.degree. C. for 90 minutes, filtered rapidly
under suction through a glass fiber filter (GF/B, from Whatman),
and immediately washed twice with 5 ml of 50 m Mice-cooled Tris-HCl
buffer. Thereafter, the glass fiber filter was transferred to a
vial, scintillator was added thereto, and the radioactivity on the
filter was measured by a liquid scintillation counter. The
inhibition of binding of .sup.3H-CGS21680 to A.sub.2A receptor by
the test compound was determined using the following formula, and
from this inhibition, 50% inhibition concentration (IC.sub.50) was
calculated.
Inhibition (%)=[1-{[(binding in the presence of the test
compound)-(nonspecific binding)]/[(total binding)-(nonspecific
binding)]}].times.100
[0622] Here, the total binding means .sup.3H-CGS21680-bound
radioactivity in the absence of the test compound; the nonspecific
binding means .sup.3H--CGS21680-bound radioactivity in the presence
of 100 .mu.M RPIA; and the binding in the presence of the test
compound means .sup.3H-CGS21680-bound radioactivity in the presence
of the test compound at predetermined concentrations.
[0623] The inhibition constant (Ki value) in the table was
determined from the formula of Cheng-Prusoff.
Test Example 3
Experiment of Inhibition of NECA-Stimulated Production of cAMP in
Adenosine A.sub.2B Receptor-Expressing Cells
[0624] CHOK1 cells where human adenosine A.sub.2B receptor had been
expressed in excess were plated onto a 24-well plate at a density
of 1.5.times.10.sup.5 cells/well, cultured overnight, and used in
the experiment. The degree of inhibitory effect of the test
compound on the amount of cAMP produced by stimulation with 30 nM
5'-N-ethylcarboxyamide adenosine (NECA from Sigma) was evaluated in
terms of affinity for A.sub.2B receptor. That is, the adhering
cells were washed twice with 2 ml/well Krebs-Ringer buffer solution
(containing 0.1% BSA; pH 7.4) and pre-incubated for 30 minutes in a
volume of 0.5 ml/well. Then, a mixed solution containing NECA and
the test compound was added in a volume of 0.1 ml/well in the
presence of a phosphodiesterase inhibitor Ro-20-1724 (a product of
RBI. After pre-incubation for 15 minutes, the reaction was
terminated with 0.1 N HCl in a volume of 300 .mu.l/well.
Measurement of intracellular cAMP was carried out using a cAMP
enzyme immunoassay kit produced by Amersham. The inhibition of
NECA-stimulated production of CAMP by the test compound was
determined using the following equation:
Inhibition (%)=[1-{(amount of cAMP in the coexistence of NECA and
the test compound-amount of cAMP in only the Krebs-Ringer buffer
solution)/(amount of cAMP upon stimulation with NECA only-amount of
cAMP in only the Krebs-Ringer buffer solution)}].times.100
[0625] The ability of the compound according to the present
invention to bind to or the ability to antagonize adenosine
receptor are as follows.
TABLE-US-00001 TABLE 1 Ki (nM) Ki (nM) IC.sub.50 (nM) Test Compound
A.sub.1 A.sub.2A A.sub.2B Ex 16 175 6 29 Ex 17 289 3 25 Ex 18 114 2
26
[0626] The compounds according to the present invention, salts
thereof or solvates of them have an excellent inhibitory action
against the adenosine receptors.
Test Example 4
Evaluation of Defecation-Promoting Action
[0627] The defecation-promoting action of the adenosine A.sub.2B
receptor-inhibiting compound which was identified by measuring the
binding affinity or antagonistic activity thereof to the adenosine
receptor in Test Examples 1 to 3, a salt thereof, a solvate of
them, or a pharmaceutical composition containing it can be
evaluated on the basis of the following method. That is, SD IGS
rats (6 weeks-old, from Charles River) were placed in cages (3
animals/cage) and preliminarily allowed food and water ad libitum
and raised for 1 week. Then, a tared water-absorbing sheet was
placed below each cage, and the animals were fasted but allowed
water ad libitum throughout the experiment. After 1.5 hours, the
fecal pellets were collected from each cage and observed for
abnormality before the experiment. The compound suspended or
dissolved in 0.5% (w/v) methyl cellulose (MC) was orally
administered in a volume of 5 ml/kg. On one hand, 0.5% (w/v) MC
only was orally given to the control group. After administration of
the compound, the rats were returned to the cage provided with a
new water-absorbing sheet, and 90 minutes after the administration,
the fecal pellets on the water-absorbing sheet were collected from
each cage, and the external appearance was observed, and then
counted and weighed. The number of fecal pellets is expressed per
each cage.
TABLE-US-00002 TABLE 2 Number of fecal pellets Test Compound Dose
Mean .+-. S.E. Control -- 1.25 .+-. 0.63 Ex 16 3 mg/kg 12.50 .+-.
0.96 Ex 17 3 mg/kg 15.50 .+-. 3.18 Ex 18 3 mg/kg 14.50 .+-.
1.26
[0628] The compounds according to the present invention, a salt
thereof or solvates of them have an excellent defecation-promoting
action.
Test Example 5
Evaluation of Effects on Haloperidol-Induced Catalepsy
[0629] Parkinson's disease is a disease caused by the degeneration
or cell death of nigrostriatal dopaminergic neurons. The
administration of haloperidol (dopamine D.sub.1/D.sub.2 receptor
antagonist) blocks postsynaptic D.sub.2 receptors to induce
catalepsy. The haloperidol-induced catalepsy has been known as a
classic model that mimics Parkinson's disease by drug
administration (Eur. J. Pharmacol., 182, 327-334 (1990)).
[0630] The adenosine A.sub.2A receptor antagonist compounds
identified by measuring on their binding abilities to the receptors
in Test Examples 1 to 3, the salts thereof, solvates of them, or
pharmaceutical compositions containing those were evaluated for
effect on haloperidol-induced catalepsy by the method described
below. That is, the experiment was conducted by eight 5-week-old
male ICR mice (available from Charles River) per group. Haloperidol
(manufactured by Sigma Co., Ltd.) was dissolved in a 6.1% tartaric
acid solution and the resulting solution in a dose of 1 mg/kg was
then intraperitoneally administered to the mice. The test compound
was used as a 0.5% MC suspension. 1.5 hours after the
intraperitoneal administration of haloperidol, each of the
suspension with the test compound and the suspension without the
test compound (control) was orally administered to the mice (0.1 ml
per 10 g of mouse body weight). 1 hour after the administration of
the test compound, the degree of catalepsy was measured with
respect to each of the mice such that a pair of only forelimbs and
a pair of only hindlimbs of each mouse were placed by turns on a
stand 4.5 cm in height and 10 cm in width. 0.1 mg/kg and 0.3 mg/kg
of each of the test compounds were orally administered. Catalepsy
scores and criterions are as follows.
Score Duration of Catalepsy
[0631] 0: When the pair of only forelimbs and the pair of only hind
limbs are independently placed on the stand, the duration of such a
posture of each pair for less than 5 seconds. 1: The duration of
the posture in which the forelimbs were being placed on the stand
was 5 or more seconds but less than 10 seconds, and the duration of
such a posture of the hindlimbs was less than 5 seconds. 2: The
duration of the posture in which the forelimbs were being placed on
the stand was 10 or more seconds, and the duration of such a
posture of the pair hindlimbs was less than 5 seconds. 3: The
duration of the posture in which both the forelimbs and hindlimbs
were being placed on the stand was 5 or more seconds but less than
10 seconds; or the duration of the posture in which the forelimbs
were being placed on the stand was less than 5 seconds and the
duration of such a posture of the hindlimbs was 5 or more seconds.
4: The duration of the posture in which the forelimbs were being
placed on the stand was 10 or more seconds and the duration of such
a posture of the hindlimbs was 5 or more seconds but less than 10
seconds; or the duration of the posture in which the forelimbs were
being placed on the stand was 5 or more seconds but less than 10
seconds and the duration of such a posture of the hindlimbs was 10
or more seconds. 5: The duration of the posture in which both the
forelimbs and hindlimbs were being placed on the stand was 10 or
more seconds.
[0632] The effects of the compound were determined by making a
comparison between the score of the control group and the score of
the test group in which the test compound was administered. A
significant difference was analyzed by Dunnett's-test. The results
are shown in Table 3.
TABLE-US-00003 TABLE 3 Dose of Test Catalepsy score Name of group
Administered content Compound (Mean .+-. S.E.) Control Haloperidol
5.00 .+-. 0.00 Example 16 Haloperidol + Test 0.1 mg/kg 4.63 .+-.
0.38 compound Example 16 Haloperidol + Test 1.0 mg/kg 0.88 .+-.
0.64** compound Example 17 Haloperidol + Test 0.1 mg/kg 3.38 .+-.
0.53** compound Example 17 Haloperidol + Test 1.0 mg/kg 1.13 .+-.
0.67** compound **p < 0.01 (comparison with Control group)
* * * * *