U.S. patent application number 16/921338 was filed with the patent office on 2020-10-29 for 1-substituted 1,2,3,4-tetrahydro-1,7-naphthyridin-8-amine derivatives and their use as ep4 receptor antagonists.
The applicant listed for this patent is TAKEDA PHARMACEUTICAL COMPANY LIMITED. Invention is credited to Dinesh BARAWKAR, Anil M DESHPANDE, Dilip JADHAV, Bheemashankar KULKARNI, Anil PANMAND, Santosh PATIL, Yogesh WAMAN.
Application Number | 20200339577 16/921338 |
Document ID | / |
Family ID | 1000004944625 |
Filed Date | 2020-10-29 |
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United States Patent
Application |
20200339577 |
Kind Code |
A1 |
BARAWKAR; Dinesh ; et
al. |
October 29, 2020 |
1-SUBSTITUTED 1,2,3,4-TETRAHYDRO-1,7-NAPHTHYRIDIN-8-AMINE
DERIVATIVES AND THEIR USE AS EP4 RECEPTOR ANTAGONISTS
Abstract
The present invention provides a compound represented by the
formula (I): ##STR00001## wherein each symbol is as defined in the
specification, or a salt thereof has an EP4 receptor antagonistic
action, and is useful as an agent for the prophylaxis or treatment
of EP4 receptor associated diseases (e.g., rheumatoid arthritis,
aortic aneurysm (e.g. abdominal aortic aneurysm, thoracic aortic
aneurysm, thoracoabdominal aortic aneurysm etc.), endometriosis,
ankylosing spondylitis, inflammatory breast cancer etc.) and the
like.
Inventors: |
BARAWKAR; Dinesh;
(Maharashtra, IN) ; DESHPANDE; Anil M;
(Maharashtra, IN) ; PATIL; Santosh; (Maharashtra,
IN) ; WAMAN; Yogesh; (Maharashtra, IN) ;
PANMAND; Anil; (Maharashtra, IN) ; JADHAV; Dilip;
(Maharashtra, IN) ; KULKARNI; Bheemashankar;
(Karnataka, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TAKEDA PHARMACEUTICAL COMPANY LIMITED |
Osaka-shi |
|
JP |
|
|
Family ID: |
1000004944625 |
Appl. No.: |
16/921338 |
Filed: |
July 6, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15746828 |
Jan 23, 2018 |
10745397 |
|
|
PCT/JP2016/072244 |
Jul 22, 2016 |
|
|
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16921338 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 513/04 20130101; A61P 19/02 20180101; C07D 498/04
20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 498/04 20060101 C07D498/04; C07D 513/04 20060101
C07D513/04; A61P 19/02 20060101 A61P019/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 23, 2015 |
IN |
2244/DEL/2015 |
Claims
1. A compound represented by the formula (I) ##STR00146## wherein
G.sup.1 is a carbon atom or a nitrogen atom, G.sup.2 is a carbon
atom or a nitrogen atom, Ring A is an optionally further
substituted 6-membered nitrogen-containing heterocycle, G.sup.3 is
an oxygen atom, an optionally substituted methylene, NR', a sulfur
atom, S(O) or S(O).sub.2, R.sup.1 is a hydrogen atom or a
substituent, X is an optionally substituted ethylene, R.sup.2 and
R.sup.3 are each independently a hydrogen atom or an optionally
substituted C.sub.1-6 alkyl group, or R.sup.2 and R.sup.3 are
joined together to form a cycloalkane or a heterocycle, each of
which is optionally substituted, R.sup.4 is a hydrogen atom or a
substituent, Ring B is an optionally further substituted ring, Ring
C is an optionally further substituted ring, and W is a bond, or a
spacer in which the number of atoms in the main chain is 1 to 4, or
a salt thereof.
2. The compound or salt of claim 1, wherein G.sup.1 is a carbon
atom, G.sup.2 is a carbon atom or a nitrogen atom, Ring A is
pyridine or pyrimidine, each of which is optionally further
substituted by 1 to 2 substituents selected from the group
consisting of (a) a halogen atom, (b) a C.sub.1-6 alkyl group, and
(c) a C.sub.3-10 cycloalkyl group, G.sup.3 is an oxygen atom,
NR.sup.1 wherein R.sup.1 is a C.sub.1-6 alkyl group, methylene or a
sulfur atom, X is ethylene optionally substituted by an oxo group,
R.sup.2 and R.sup.3 are each a hydrogen atom or a C.sub.1-6 alkyl
group, or R.sup.2 and R.sup.3 are joined together to form a
C.sub.3-10 cycloalkane, R.sup.4 is a hydrogen atom, Ring B is (1) a
C.sub.6-14 aromatic hydrocarbon ring optionally further substituted
by 1 to 3 substituents selected from the group consisting of (a) a
carboxy group, (b) a C.sub.1-6 alkoxy-carbonyl group, (c) a cyano
group, (d) a carbamoyl group, (e) a mono- or di-C.sub.1-6
alkyl-carbamoyl group, (f) a mono- or di-C.sub.1-6 alkoxy-carbamoyl
group, (g) a mono- or di-C.sub.7-16 aralkyloxy-carbamoyl group, (h)
5-tetrazolyl, and (i) a C.sub.1-6 alkoxy group, (2) a C.sub.3-10
cycloalkane, or (3) a 5- to 10-membered aromatic heterocycle
optionally further substituted by 1 to 3 C.sub.1-6 alkyl groups,
Ring C is a C.sub.6-14 aromatic hydrocarbon ring, a C.sub.3-10
cycloalkane or a 5- to 14-membered aromatic heterocycle, each of
which is optionally further substituted by 1 to 3 substituents
selected from the group consisting of (1) a halogen atom, (2) an
optionally halogenated C.sub.1-6 alkyl group, (3) a C.sub.1-6
alkoxy group, and (4) a C.sub.6-14 aryl group, and W is (1) a
C.sub.1-4 alkylene group optionally substituted by an oxo group, or
(2) --(CH.sub.2).sub.m1--O-- wherein m1 is an integer of 0 to
3.
3.
4-[(1S)-1-[[4-[(3-Chlorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]ox-
azin-5-yl]amino]ethyl]benzoic acid or a salt thereof.
4.
4-[1-[[4-[(3,4-Difluorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxa-
zin-5-yl]amino]cyclopropyl]benzoic acid or a salt thereof.
5.
4-[(1S)-1-[[4-[(4-Methoxyphenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]o-
xazin-5-yl]amino]ethyl]benzoic acid or a salt thereof.
6. A medicament comprising the compound or salt according to claim
1.
7. The medicament according to claim 6, which is an EP4 receptor
antagonist.
8. The medicament according to claim 6, which is an agent for the
prophylaxis or treatment of EP4 receptor associated diseases.
9. The medicament according to claim 8, wherein the EP4 receptor
associated diseases are selected from rheumatoid arthritis, aortic
aneurysm, endometriosis, ankylosing spondylitis and inflammatory
breast cancer.
10. The compound or salt of claim 1 for use in the prophylaxis or
treatment of EP4 receptor associated diseases.
11. The compound or salt of claim 10, wherein the EP4 receptor
associated diseases are selected from rheumatoid arthritis, aortic
aneurysm, endometriosis, ankylosing spondylitis and inflammatory
breast cancer.
12. A method of inhibiting EP4 receptor in a mammal, which
comprises administering an effective amount of the compound or salt
of claim 1 to the mammal.
13. A method for the prophylaxis or treatment of EP4 receptor
associated diseases in a mammal, which comprises administering an
effective amount of the compound or salt of claim 1 to the
mammal.
14. The method of claim 13, wherein the EP4 receptor associated
diseases are selected from rheumatoid arthritis, aortic aneurysm,
endometriosis, ankylosing spondylitis and inflammatory breast
cancer.
15. Use of the compound or salt of claim 1 for the production of an
agent for the prophylaxis or treatment of EP4 receptor associated
diseases.
16. Use of claim 15, wherein the EP4 receptor associated diseases
are selected from rheumatoid arthritis, aortic aneurysm,
endometriosis, ankylosing spondylitis and inflammatory breast
cancer.
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel heterocyclic
compound having an EP4 receptor antagonistic action, and may be
useful an agent for the prophylaxis or treatment of EP4 receptor
associated diseases (e.g., rheumatoid arthritis, aortic aneurysm
(e.g. abdominal aortic aneurysm, thoracic aortic aneurysm,
thoracoabdominal aortic aneurysm etc.), endometriosis, ankylosing
spondylitis, inflammatory breast cancer etc.) and the like.
BACKGROUND OF THE INVENTION
[0002] Prostaglandin E2 (PGE2) is one of the most broadly
distributed prostanoids throughout animal species and widely
produced within the body by the actions of cyclooxygenases (COX) on
arachidonic acid. PGE2 is involved in a number of physiological and
pathophysiological responses such as fever, pain, inflammation
(non-patent document 1) and elicits its biological functions
through four receptor subtypes EP1-4, all G-protein-coupled
receptor.
[0003] Emerging biology has revealed important roles of EP4
receptors in immune system (non-patent documents 2 and 3). For
example, EP4 receptor activation stimulates dendritic cells and
promotes IL-23 production synergistically with CD40 and Toll-like
receptor signaling. PGE2 then enhances the expansion of Th17 cells
with IL-23. EP4 receptor activation promotes the differentiation of
Th1 from naive T cells synergistically with IL-12. PGE2
synergistically induces IL-6 and IL-1.beta. expression with LPS via
EP4 receptors in macrophages. Th1, Th17 and macrophage cells play
key roles in the development of autoimmune/inflammatory diseases.
Thus, a selective EP4 receptor antagonist is expected to inhibit
IL-23 & IL-6 production and suppression of Th1 & Th17
function (non-patent documents 4 and 5), reduce inflammatory pain
and offers an attractive therapeutic approach for rheumatoid
arthritis (RA), inflammatory bowel diseases and other
autoimmune/inflammatory diseases.
[0004] Non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2
inhibitors are clinically proven to relieve inflammation and pain
by inhibiting the synthesis of arachidonic acid pathway metabolites
including PGE2. However, their use is associated with adverse
effects due to pleiotropic function of arachidonic acid pathway
metabolites and imbalance in their levels. An imbalance between
TXA2 and PGI2, for example, has been implicated in the vasospasm,
hyperaggregability and thromboembolism that are associated with
many cardiovascular diseases (non-patent document 6). As EP4
selective antagonists specifically block PGE2 function through only
EP4 receptor, leaving functions through other receptors intact, it
is expected that they will not exhibit the adverse effects similar
to that of NSAIDs and COX-2 inhibitors (non-patent document 7).
Further, compared to other targeted therapies (e.g. JAK,
TNF.alpha., IL-6) for RA, EP4 antagonist has been shown to improve
both joint damage and inflammatory pain in animal models. Thus,
this mechanism has potential to "complete symptom management" for
RA in clinic (non-patent document 8).
[0005] In addition to autoimmune diseases, endometriosis, aortic
aneurysm (e.g. abdominal aortic aneurysm, thoracic aortic aneurysm,
thoracoabdominal aortic aneurysm etc.) and ankylosing spondylitis
are other indications for EP4 antagonist. Endometriosis (EM) is a
chronic, estrogen-dependent inflammatory disease and defined as the
presence of functional endometrial tissue at ectopic sites. It is a
common disease that 10-20% of women of reproductive age are
affected. The most common symptom is a dysmenorrhea. Chronic pelvic
pain, dyspareunia, dyschezia (pain on defecation), loin pain, lower
abdominal pain or back pain, pain on micturition, pain on exercise
are also part of the symptoms of EM (non-patent document 9).
Current treatments include surgical intervention, pharmacotherapies
using NSAIDs, COX-2 inhibitors and hormonal therapies, or a
combination of both. NSAIDs or COX-2 inhibitors are effective in
relieving pelvic pain, but can cause severe side effects including
gastrointestinal injury, nephropathy, and increase cardiovascular
risk (non-patent document 10). Hormonal therapy controls disease
conditions, but has side effect such as pseudomenopause and
decreased bone density due to suppression of estrogen production
(non-patent document 11). Development of a safer, but equally
efficacious treatment is highly demanded. EP4 receptor proteins
were abundantly expressed in human endometriosis tissues (ectopic
and eutopic endometrium) during the proliferative phase of the
menstrual cycle (non-patent document 12). In human immortalized
endometriotic epithelial and stromal cells selective inhibition of
EP4 induced apoptosis (non-patent document 12), inhibited
proliferation (non-patent document 13), inhibited migration and
invasion (non-patent document 14) and inhibited adhesion
(non-patent document 15). These studies suggest that inhibition of
EP4 signaling is a potential therapeutic option for women with EM
(non-patent document 15).
[0006] Abdominal aortic aneurysm (AAA) is a common, progressive,
and life-threatening degenerative vascular disease (non-patent
documents 16 and 17). It is an inflammatory disorder characterized
by localized connective tissue degeneration and smooth muscle cell
apoptosis, leading to aortic dilatation and rupture (non-patent
documents 18-20). After rupture occurs, the probability of
mortality is greater than 60% (non-patent document 21). No
pharmacotherapy has been found to be effective at decreasing the
growth rate or rupture rate of AAAs except. In aneurysm walls,
COX-2 is widely expressed in macrophages and smooth muscle cells,
along with locally synthetized PGE2 (non-patent document 22). EP4
expression is increased in the aneurysm areas of human AAA tissues,
both in human aortic aneurysm smooth muscle cell as well as in
macrophages in the lesion (non-patent documents 23 and 24). EP4
receptor antagonist or global gene deletion of the EP4 receptor
significantly decreased MMP-2 activation and IL-6 production in
human AAA tissues and the rate of AAA formation in preclinical
mouse models (non-patent document 23 and 25).
[0007] Ankylosing spondylitis is the prototypic
spondyloarthropathy, one of a group of conditions which also
includes psoriatic arthritis, reactive arthritis and arthritis
complicating inflammatory bowel disease. Ankylosing spondylitis is
highly heritable (non-patent documents 26 and 27) and familial
(non-patent document 28). Men are affected 2-3 times more
frequently than women. The disease is known to be strongly
associated with HLA-B27. Since association between EP4 receptor
gene (PTGER4) and ankylosing spondylitis has been also demonstrated
(non-patent document 29), EP4 receptor is likely to be involved in
disease pathogenesis. There is no cure for ankylosing spondylitis
as yet, but the patient's back pain and stiffness usually show good
symptomatic response to NSAIDs. Since EP4 antagonists are known to
possess analgesic activity at least in animal models (non-patent
documents 30 and 31), a safe and chronically-treatable EP4
antagonist may be an alternative symptom-relieving pharmacotherapy
for ankylosing spondylitis.
[0008] Examples of the compound having a structure similar to the
compound described in the present specification include the
following compounds.
[0009] (1) Patent document 1 describes a compound represented by
the formula:
##STR00002##
wherein each symbol is as defined in the specification, which is
useful as an agent for the prophylaxis or treatment of metabolic
disease, cerebrovascular disease and the like.
[0010] (2) Patent document 2 describes a compound represented by
the formula:
##STR00003##
wherein each symbol is as defined in the specification, as a proton
pump inhibitor (PPI), which is useful as an agent for the
prophylaxis or treatment of peptic ulcer and the like.
[0011] (3) Patent document 3 describes a compound represented by
the formula:
##STR00004##
wherein each symbol is as defined in the specification, as a
corticotropin releasing factor (CRF), which is useful as an agent
for the prophylaxis or treatment of anxiety, depression, other
psychiatric and neurological disorders, and the like.
[0012] (4) Patent document 4 describes a compound represented by
the formula:
##STR00005##
wherein each symbol is as defined in the specification, as a RAF
kinase inhibitor, which is useful as an agent for the prophylaxis
or treatment of cancer.
[0013] (5) Patent document 5 describes a compound represented by
the formula:
##STR00006##
wherein each symbol is as defined in the specification, as a mGluR1
antagonist, which is useful an agent for the prophylaxis or
treatment of pain.
DOCUMENT LIST
Patent Document
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Document 2] WO 2006/011670 A1 [0016] [Patent Document 3] WO
97/44038 A1 [0017] [Patent Document 4] WO 2006/065703 A1 [0018]
[Patent Document 5] WO 2001/032632 A2
Non-Patent Document
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[0034] [Non-Patent Document 16] Arterioscler. Thromb. Vasc. Biol.,
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[0039] [Non-Patent Document 21] World J. Surg., 2008. 32(6): p.
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p. 48-54 [0041] [Non-Patent Document 23] PLoS One, 2012. 7(5): p.
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[Non-Patent Document 29] Nature Genetics, 2011. 43: p. 761-767
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2010. 15: p. 3760-3
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0050] The present invention aims to provide a novel heterocyclic
compound having an EP4 receptor antagonistic action, and useful as
an agent for the prophylaxis or treatment of EP4 receptor
associated diseases (e.g., rheumatoid arthritis, aortic aneurysm
(e.g. abdominal aortic aneurysm, thoracic aortic aneurysm,
thoracoabdominal aortic aneurysm etc.), endometriosis, ankylosing
spondylitis, inflammatory breast cancer etc.) and the like.
Means of Solving the Problems
[0051] The present inventors have conducted intensive studies, and
have found that a compound represented by the below-mentioned
formula (I) unexpectedly has an EP4 receptor antagonistic action,
and therefore, may be useful as an agent for the prophylaxis or
treatment of EP4 receptor associated diseases (e.g., rheumatoid
arthritis, aortic aneurysm (e.g. abdominal aortic aneurysm,
thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.),
endometriosis, ankylosing spondylitis, inflammatory breast cancer
etc.) and the like, and completed the present invention based on
these findings.
[0052] Accordingly, the present invention provides the following.
[1] A compound represented by the formula (I):
##STR00007##
wherein G.sup.1 is a carbon atom or a nitrogen atom, G.sup.2 is a
carbon atom or a nitrogen atom, Ring A is an optionally further
substituted 6-membered nitrogen-containing heterocycle, G.sup.3 is
an oxygen atom, an optionally substituted methylene, NR.sup.1, a
sulfur atom, S(O) or S(O).sub.2, R.sup.1 is a hydrogen atom or a
substituent, X is an optionally substituted ethylene, R.sup.2 and
R.sup.3 are each independently a hydrogen atom or an optionally
substituted C.sub.1-6 alkyl group, or R.sup.2 and R.sup.3 are
joined together to form a cycloalkane or a heterocycle, each of
which is optionally substituted, R.sup.4 is a hydrogen atom or a
substituent, Ring B is an optionally further substituted ring, Ring
C is an optionally further substituted ring, and W is a bond, or a
spacer in which the number of atoms in the main chain is 1 to 4, or
a salt thereof (hereinafter to be referred to as compound (I). [2]
The compound or salt of the above-mentioned [1], wherein
[0053] G.sup.1 is a carbon atom,
[0054] G.sup.2 is a carbon atom or a nitrogen atom,
[0055] Ring A is pyridine or pyrimidine, each of which is
optionally further substituted by 1 to 2 substituents selected from
the group consisting of
[0056] (a) a halogen atom,
[0057] (b) a C.sub.1-6 alkyl group, and
[0058] (c) a C.sub.3-10 cycloalkyl group,
[0059] G.sup.3 is an oxygen atom, NR.sup.1 wherein R.sup.1 is a
C.sub.1-6 alkyl group, methylene or a sulfur atom,
[0060] X is ethylene optionally substituted by an oxo group,
[0061] R.sup.2 and R.sup.3 are each a hydrogen atom or a C.sub.1-6
alkyl group, or R.sup.2 and R.sup.3 are joined together to form a
C.sub.3-10 cycloalkane,
[0062] R.sup.4 is a hydrogen atom,
[0063] Ring B is
(1) a C.sub.6-14 aromatic hydrocarbon ring optionally further
substituted by 1 to 3 substituents selected from the group
consisting of
[0064] (a) a carboxy group,
[0065] (b) a C.sub.1-6 alkoxy-carbonyl group,
[0066] (c) a cyano group,
[0067] (d) a carbamoyl group,
[0068] (e) a mono- or di-C.sub.1-6 alkyl-carbamoyl group,
[0069] (f) a mono- or di-C.sub.1-6 alkoxy-carbamoyl group,
[0070] (g) a mono- or di-C.sub.7-16 aralkyloxy-carbamoyl group,
[0071] (h) 5-tetrazolyl, and
[0072] (i) a C.sub.1-6 alkoxy group,
(2) a C.sub.3-10 cycloalkane, or (3) a 5- to 10-membered aromatic
heterocycle optionally further substituted by 1 to 3 C.sub.1-6
alkyl groups,
[0073] Ring C is a C.sub.6-14 aromatic hydrocarbon ring, a
C.sub.3-10 cycloalkane or a 5- to 14-membered aromatic heterocycle,
each of which is optionally further substituted by 1 to 3
substituents selected from the group consisting of
[0074] (1) a halogen atom,
[0075] (2) an optionally halogenated C.sub.1-6 alkyl group,
[0076] (3) a C.sub.1-6 alkoxy group, and
[0077] (4) a C.sub.6-14 aryl group, and
[0078] W is
(1) a C.sub.1-4 alkylene group optionally substituted by an oxo
group, or (2) --(CH.sub.2).sub.m1--O-- wherein m1 is an integer of
0 to 3. [3]
4-[(1S)-1-[[4-[(3-Chlorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazi-
n-5-yl]amino]ethyl]benzoic acid or a salt thereof. [4]
4-[1-[[4-[(3,4-Difluorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazin-
-5-yl]amino]cyclopropyl]benzoic acid or a salt thereof. [5]
4-[(1S)-1-[[4-[(4-Methoxyphenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxaz-
in-5-yl]amino]ethyl]benzoic acid or a salt thereof. [6] A
medicament comprising the compound or salt of the above-mentioned
[1]. [7] The medicament according to the above-mentioned [6], which
is an EP4 receptor antagonist. [8] The medicament according to the
above-mentioned [6], which is an agent for the prophylaxis or
treatment of EP4 receptor associated diseases. [9] The medicament
according to the above-mentioned [8], wherein the EP4 receptor
associated diseases are selected from rheumatoid arthritis, aortic
aneurysm, endometriosis, ankylosing spondylitis and inflammatory
breast cancer. [10] The compound or salt of the above-mentioned [1]
for use in the prophylaxis or treatment of EP4 receptor associated
diseases. [11] The compound or salt of the above-mentioned [10],
wherein the EP4 receptor associated diseases are selected from
rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing
spondylitis and inflammatory breast cancer. [12] A method of
inhibiting EP4 receptor in a mammal, which comprises administering
an effective amount of the compound or salt of the above-mentioned
[1] to the mammal. [13] A method for the prophylaxis or treatment
of EP4 receptor associated diseases in a mammal, which comprises
administering an effective amount of the compound or salt of the
above-mentioned [1] to the mammal. [14] The method of the
above-mentioned [13], wherein the EP4 receptor associated diseases
are selected from rheumatoid arthritis, aortic aneurysm,
endometriosis, ankylosing spondylitis and inflammatory breast
cancer. [15] Use of the compound or salt of the above-mentioned [1]
for the production of an agent for the prophylaxis or treatment of
EP4 receptor associated diseases. [16] Use of the above-mentioned
[15], wherein the EP4 receptor associated diseases are selected
from rheumatoid arthritis, aortic aneurysm, endometriosis,
ankylosing spondylitis and inflammatory breast cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0079] FIG. 1 shows suppression of arthritis development in
adjuvant induced arthritis model when treated with the compound of
Example B2.
[0080] FIG. 2 shows suppression of arthritis development in
adjuvant induced arthritis model when treated with the compound of
Example B4.
EFFECT OF THE INVENTION
[0081] Compound (I) has a superior EP4 receptor antagonistic
action, which may be useful as an agent for the prophylaxis or
treatment of EP4 receptor associated diseases (e.g., rheumatoid
arthritis, aortic aneurysm (e.g. abdominal aortic aneurysm,
thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.),
endometriosis, ankylosing spondylitis, inflammatory breast cancer
etc.) and the like.
DETAILED DESCRIPTION OF THE INVENTION
[0082] The definition of each substituent used in the present
specification is described in detail in the following. Unless
otherwise specified, each substituent has the following
definition.
[0083] In the present specification, examples of the "halogen atom"
include fluorine, chlorine, bromine and iodine.
[0084] In the present specification, examples of the "C.sub.1-6
alkyl group" include methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,
2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
[0085] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkyl group" include a C.sub.1-6 alkyl group
optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,
pentafluoroethyl, propyl, 2,2-difluoropropyl,
3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.
[0086] In the present specification, examples of the "C.sub.2-6
alkenyl group" include ethenyl, 1-propenyl, 2-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
[0087] In the present specification, examples of the "C.sub.2-6
alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,
4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl
and 4-methyl-2-pentynyl.
[0088] In the present specification, examples of the "C.sub.3-10
cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.
[0089] In the present specification, examples of the "optionally
halogenated C.sub.3-10 cycloalkyl group" include a C.sub.3-10
cycloalkyl group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include cyclopropyl,
2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl,
difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
[0090] In the present specification, examples of the "C.sub.3-10
cycloalkenyl group" include cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
[0091] In the present specification, examples of the "C.sub.6-14
aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl,
2-anthryl and 9-anthryl.
[0092] In the present specification, examples of the "C.sub.7-16
aralkyl group" include benzyl, phenethyl, naphthylmethyl and
phenylpropyl.
[0093] In the present specification, examples of the "C.sub.1-6
alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
[0094] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkoxy group" include a C.sub.1-6 alkoxy
group optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy,
isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy,
pentyloxy and hexyloxy.
[0095] In the present specification, examples of the "C.sub.3-10
cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and
cyclooctyloxy.
[0096] In the present specification, examples of the "C.sub.1-6
alkylthio group" include methylthio, ethylthio, propylthio,
isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio
and hexylthio.
[0097] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkylthio group" include a C.sub.1-6
alkylthio group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and
hexylthio.
[0098] In the present specification, examples of the "C.sub.1-6
alkyl-carbonyl group" include acetyl, propanoyl, butanoyl,
2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl,
2,2-dimethylpropanoyl, hexanoyl and heptanoyl.
[0099] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkyl-carbonyl group" include a C.sub.1-6
alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include acetyl,
chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl,
butanoyl, pentanoyl and hexanoyl.
[0100] In the present specification, examples of the "C.sub.1-6
alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,
pentyloxycarbonyl and hexyloxycarbonyl.
[0101] In the present specification, examples of the "C.sub.6-14
aryl-carbonyl group" include benzoyl, 1-naphthoyl and
2-naphthoyl.
[0102] In the present specification, examples of the "C.sub.7-16
aralkyl-carbonyl group" include phenylacetyl and
phenylpropionyl.
[0103] In the present specification, examples of the "5- to
14-membered aromatic heterocyclylcarbonyl group" include
nicotinoyl, isonicotinoyl, thenoyl and furoyl.
[0104] In the present specification, examples of the "3- to
14-membered non-aromatic heterocyclylcarbonyl group" include
morpholinylcarbonyl, piperidinylcarbonyl and
pyrrolidinylcarbonyl.
[0105] In the present specification, examples of the "mono- or
di-C.sub.1-6 alkyl-carbamoyl group" include methylcarbamoyl,
ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and
N-ethyl-N-methylcarbamoyl.
[0106] In the present specification, examples of the "mono- or
di-C.sub.7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and
phenethylcarbamoyl.
[0107] In the present specification, examples of the "C.sub.1-6
alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl
and tert-butylsulfonyl.
[0108] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkylsulfonyl group" include a C.sub.1-6
alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include methylsulfonyl,
difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.
[0109] In the present specification, examples of the "C.sub.6-14
arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and
2-naphthylsulfonyl.
[0110] In the present specification, examples of the "substituent"
include a halogen atom, a cyano group, a nitro group, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an acyl group, an optionally substituted amino
group, an optionally substituted carbamoyl group, an optionally
substituted thiocarbamoyl group, an optionally substituted
sulfamoyl group, an optionally substituted hydroxy group, an
optionally substituted sulfanyl (SH) group and an optionally
substituted silyl group.
[0111] In the present specification, examples of the "hydrocarbon
group" (including "hydrocarbon group" of "optionally substituted
hydrocarbon group") include a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-10 cycloalkyl
group, a C.sub.3-10 cycloalkenyl group, a C.sub.6-14 aryl group and
a C.sub.7-16 aralkyl group.
[0112] In the present specification, examples of the "optionally
substituted hydrocarbon group" include a hydrocarbon group
optionally having substituent(s) selected from the following
substituent group A.
[substituent group A] (1) a halogen atom, (2) a nitro group, (3) a
cyano group, (4) an oxo group, (5) a hydroxy group, (6) an
optionally halogenated C.sub.1-6 alkoxy group, (7) a C.sub.6-14
aryloxy group (e.g., phenoxy, naphthoxy), (8) a C.sub.7-16
aralkyloxy group (e.g., benzyloxy), (9) a 5- to 14-membered
aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) a 3- to
14-membered non-aromatic heterocyclyloxy group (e.g.,
morpholinyloxy, piperidinyloxy), (11) a C.sub.1-6 alkyl-carbonyloxy
group (e.g., acetoxy, propanoyloxy), (12) a C.sub.6-14
aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,
2-naphthoyloxy), (13) a C.sub.1-6 alkoxy-carbonyloxy group (e.g.,
methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
butoxycarbonyloxy), (14) a mono- or di-C.sub.1-6 alkyl-carbamoyloxy
group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy,
dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) a C.sub.6-14
aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,
naphthylcarbamoyloxy), (16) a 5- to 14-membered aromatic
heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to
14-membered non-aromatic heterocyclylcarbonyloxy group (e.g.,
morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) an optionally
halogenated C.sub.1-6 alkylsulfonyloxy group (e.g.,
methylsulfonyloxy, trifluoromethylsulfonyloxy), (19) a C.sub.6-14
arylsulfonyloxy group optionally substituted by a C.sub.1-6 alkyl
group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) an
optionally halogenated C.sub.1-6 alkylthio group, (21) a 5- to
14-membered aromatic heterocyclic group, (22) a 3- to 14-membered
non-aromatic heterocyclic group, (23) a formyl group, (24) a
carboxy group, (25) an optionally halogenated C.sub.1-6
alkyl-carbonyl group, (26) a C.sub.6-14 aryl-carbonyl group, (27) a
5- to 14-membered aromatic heterocyclylcarbonyl group, (28) a 3- to
14-membered non-aromatic heterocyclylcarbonyl group, (29) a
C.sub.1-6 alkoxy-carbonyl group, (30) a C.sub.6-14 aryloxy-carbonyl
group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl,
2-naphthyloxycarbonyl), (31) a C.sub.7-16 aralkyloxy-carbonyl group
(e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl
group, (33) a thiocarbamoyl group, (34) a mono- or di-C.sub.1-6
alkyl-carbamoyl group, (35) a C.sub.6-14 aryl-carbamoyl group
(e.g., phenylcarbamoyl), (36) a 5- to 14-membered aromatic
heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl,
thienylcarbamoyl), (37) a 3- to 14-membered non-aromatic
heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl,
piperidinylcarbamoyl), (38) an optionally halogenated C.sub.1-6
alkylsulfonyl group, (39) a C.sub.6-14 arylsulfonyl group, (40) a
5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,
pyridylsulfonyl, thienylsulfonyl), (41) an optionally halogenated
C.sub.1-6 alkylsulfinyl group, (42) a C.sub.6-14 arylsulfinyl group
(e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),
(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,
pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) a
mono- or di-C.sub.1-6 alkylamino group (e.g., methylamino,
ethylamino, propylamino, isopropylamino, butylamino, dimethylamino,
diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),
(46) a mono- or di-C.sub.6-14 arylamino group (e.g., phenylamino),
(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,
pyridylamino), (48) a C.sub.7-16 aralkylamino group (e.g.,
benzylamino), (49) a formylamino group, (50) a C.sub.1-6
alkyl-carbonylamino group (e.g., acetylamino, propanoylamino,
butanoylamino), (51) a (C.sub.1-6 alkyl) (C.sub.1-6
alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (52) a
C.sub.6-14 aryl-carbonylamino group (e.g., phenylcarbonylamino,
naphthylcarbonylamino), (53) a C.sub.1-6 alkoxy-carbonylamino group
(e.g., methoxycarbonylamino, ethoxycarbonylamino,
propoxycarbonylamino, butoxycarbonylamino,
tert-butoxycarbonylamino), (54) a C.sub.7-16
aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)
a C.sub.1-6 alkylsulfonylamino group (e.g., methylsulfonylamino,
ethylsulfonylamino), (56) a C.sub.6-14 arylsulfonylamino group
optionally substituted by a C.sub.1-6 alkyl group (e.g.,
phenylsulfonylamino, toluenesulfonylamino), (57) an optionally
halogenated C.sub.1-6 alkyl group, (58) a C.sub.2-6 alkenyl group,
(59) a C.sub.2-6 alkynyl group, (60) a C.sub.3-10 cycloalkyl group,
(61) a C.sub.3-10 cycloalkenyl group and (62) a C.sub.6-14 aryl
group.
[0113] The number of the above-mentioned substituents in the
"optionally substituted hydrocarbon group" is, for example, 1 to 5,
preferably 1 to 3. When the number of the substituents is two or
more, the respective substituents may be the same or different.
[0114] In the present specification, examples of the "heterocyclic
group" (including "heterocyclic group" of "optionally substituted
heterocyclic group") include (i) an aromatic heterocyclic group,
(ii) a non-aromatic heterocyclic group and (iii) a 7- to
10-membered bridged heterocyclic group, each containing, as a
ring-constituting atom besides carbon atom, 1 to 4 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
[0115] In the present specification, examples of the "aromatic
heterocyclic group" (including "5- to 14-membered aromatic
heterocyclic group") include a 5- to 14-membered (preferably 5- to
10-membered) aromatic heterocyclic group containing, as a
ring-constituting atom besides carbon atom, 1 to 4 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
[0116] Preferable examples of the "aromatic heterocyclic group"
include 5- or 6-membered monocyclic aromatic heterocyclic groups
such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,
isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl,
triazinyl and the like; and 8- to 14-membered fused polycyclic
(preferably bi or tricyclic) aromatic heterocyclic groups such as
benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl,
imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl,
pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl,
imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl,
furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,
oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl,
naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl,
1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl
.beta.-carbolinyl, phenanthridinyl, acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl and the like.
[0117] In the present specification, examples of the "non-aromatic
heterocyclic group" (including "3- to 14-membered non-aromatic
heterocyclic group") include a 3- to 14-membered (preferably 4- to
10-membered) non-aromatic heterocyclic group containing, as a
ring-constituting atom besides carbon atom, 1 to 4 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
[0118] Preferable examples of the "non-aromatic heterocyclic group"
include 3- to 8-membered monocyclic non-aromatic heterocyclic
groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl,
oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl,
pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl,
oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl,
thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl,
tetrahydroisooxazolyl, piperidinyl, piperazinyl,
tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,
tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,
tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl,
thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl,
azocanyl, diazocanyl and the like; and 9- to 14-membered fused
polycyclic (preferably bi or tricyclic) non-aromatic heterocyclic
groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl,
dihydrobenzoxazolyl, dihydrobenzothiazolyl,
dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,
tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl,
indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl,
tetrahydrobenzazepinyl, tetrahydroquinoxalinyl,
tetrahydrophenanthridinyl, hexahydrophenothiazinyl,
hexahydrophenoxazinyl, tetrahydrophthalazinyl,
tetrahydronaphthyridinyl, tetrahydroquinazolinyl,
tetrahydrocinnolinyl, tetrahydrocarbazolyl,
tetrahydro-.beta.-carbolinyl, tetrahydroacrydinyl,
tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl
and the like.
[0119] In the present specification, preferable examples of the "7-
to 10-membered bridged heterocyclic group" include quinuclidinyl
and 7-azabicyclo[2.2.1]heptanyl.
[0120] In the present specification, examples of the
"nitrogen-containing heterocyclic group" include a "heterocyclic
group" containing at least one nitrogen atom as a ring-constituting
atom.
[0121] In the present specification, examples of the "optionally
substituted heterocyclic group" include a heterocyclic group
optionally having substituent(s) selected from the aforementioned
substituent group A.
[0122] The number of the substituents in the "optionally
substituted heterocyclic group" is, for example, 1 to 3. When the
number of the substituents is two or more, the respective
substituents may be the same or different.
[0123] In the present specification, examples of the "acyl group"
include a formyl group, a carboxy group, a carbamoyl group, a
thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl
group and a phosphono group, each optionally having "1 or 2
substituents selected from a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.3-10 cycloalkyl group, a C.sub.3-10
cycloalkenyl group, a C.sub.6-14 aryl group, a C.sub.7-16 aralkyl
group, a 5- to 14-membered aromatic heterocyclic group and a 3- to
14-membered non-aromatic heterocyclic group, each of which
optionally has 1 to 3 substituents selected from a halogen atom, an
optionally halogenated C.sub.1-6 alkoxy group, a hydroxy group, a
nitro group, a cyano group, an amino group and a carbamoyl
group".
[0124] Examples of the "acyl group" also include a
hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a
hydrocarbon-sulfinyl group and a heterocyclylsulfinyl group.
[0125] Here, the hydrocarbon-sulfonyl group means a hydrocarbon
group-bonded sulfonyl group, the heterocyclylsulfonyl group means a
heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl
group means a hydrocarbon group-bonded sulfinyl group and the
heterocyclylsulfinyl group means a heterocyclic group-bonded
sulfinyl group.
[0126] Preferable examples of the "acyl group" include a formyl
group, a carboxy group, a C.sub.1-6 alkyl-carbonyl group, a
C.sub.2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C.sub.3-10
cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl,
cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a
C.sub.3-10 cycloalkenyl-carbonyl group (e.g.,
2-cyclohexenecarbonyl), a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a
C.sub.6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl,
naphthyloxycarbonyl), a C.sub.7-16 aralkyloxy-carbonyl group (e.g.,
benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group, a mono- or
di-C.sub.2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a
mono- or di-C.sub.3-10 cycloalkyl-carbamoyl group (e.g.,
cyclopropylcarbamoyl), a mono- or di-C.sub.6-14 aryl-carbamoyl
group (e.g., phenylcarbamoyl), a mono- or di-C.sub.7-16
aralkyl-carbamoyl group, a 5- to 14-membered aromatic
heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a
thiocarbamoyl group, a mono- or di-C.sub.1-6 alkyl-thiocarbamoyl
group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a
mono- or di-C.sub.2-6 alkenyl-thiocarbamoyl group (e.g.,
diallylthiocarbamoyl), a mono- or di-C.sub.3-10
cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,
cyclohexylthiocarbamoyl), a mono- or di-C.sub.6-14
aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or
di-C.sub.7-16 aralkyl-thiocarbamoyl group (e.g.,
benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to 14-membered
aromatic heterocyclylthiocarbamoyl group (e.g.,
pyridylthiocarbamoyl), a sulfino group, a C.sub.1-6 alkylsulfinyl
group (e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a
C.sub.1-6 alkylsulfonyl group, a C.sub.6-14 arylsulfonyl group, a
phosphono group and a mono- or di-C.sub.1-6 alkylphosphono group
(e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono,
dibutylphosphono).
[0127] In the present specification, examples of the "optionally
substituted amino group" include an amino group optionally having
"1 or 2 substituents selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group, a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, a C.sub.1-6 alkylsulfonyl
group and a C.sub.6-14 arylsulfonyl group, each of which optionally
has 1 to 3 substituents selected from substituent group A".
[0128] Preferable examples of the optionally substituted amino
group include an amino group, a mono- or di-(optionally halogenated
C.sub.1-6 alkyl)amino group (e.g., methylamino,
trifluoromethylamino, dimethylamino, ethylamino, diethylamino,
propylamino, dibutylamino), a mono- or di-C.sub.2-6 alkenylamino
group (e.g., diallylamino), a mono- or di-C.sub.3-10
cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a
mono- or di-C.sub.6-14 arylamino group (e.g., phenylamino), a mono-
or di-C.sub.7-16 aralkylamino group (e.g., benzylamino,
dibenzylamino), a mono- or di-(optionally halogenated C.sub.1-6
alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), a
mono- or di-C.sub.6-14 aryl-carbonylamino group (e.g.,
benzoylamino), a mono- or di-C.sub.7-16 aralkyl-carbonylamino group
(e.g., benzylcarbonylamino), a mono- or di-5- to 14-membered
aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,
isonicotinoylamino), a mono- or di-3- to 14-membered non-aromatic
heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), a
mono- or di-C.sub.1-6 alkoxy-carbonylamino group (e.g.,
tert-butoxycarbonylamino), a 5- to 14-membered aromatic
heterocyclylamino group (e.g., pyridylamino), a carbamoylamino
group, a (mono- or di-C.sub.1-6 alkyl-carbamoyl) amino group (e.g.,
methylcarbamoylamino), a (mono- or di-C.sub.7-16
aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), a
C.sub.1-6 alkylsulfonylamino group (e.g., methylsulfonylamino,
ethylsulfonylamino), a C.sub.6-14 arylsulfonylamino group (e.g.,
phenylsulfonylamino), a (C.sub.1-6 alkyl) (C.sub.1-6
alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a
(C.sub.1-6 alkyl) (C.sub.6-14 aryl-carbonyl) amino group (e.g.,
N-benzoyl-N-methylamino).
[0129] In the present specification, examples of the "optionally
substituted carbamoyl group" include a carbamoyl group optionally
having "1 or 2 substituents selected from a C.sub.1-6 alkyl group,
a C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group and a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, each of which optionally has
1 to 3 substituents selected from substituent group A".
[0130] Preferable examples of the optionally substituted carbamoyl
group include a carbamoyl group, a mono- or di-C.sub.1-6
alkyl-carbamoyl group, a mono- or di-C.sub.2-6 alkenyl-carbamoyl
group (e.g., diallylcarbamoyl), a mono- or di-C.sub.3-10
cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl,
cyclohexylcarbamoyl), a mono- or di-C.sub.6-14 aryl-carbamoyl group
(e.g., phenylcarbamoyl), a mono- or di-C.sub.7-16 aralkyl-carbamoyl
group, a mono- or di-C.sub.1-6 alkyl-carbonyl-carbamoyl group
(e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or
di-C.sub.6-14 aryl-carbonyl-carbamoyl group (e.g.,
benzoylcarbamoyl) and a 5- to 14-membered aromatic
heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl).
[0131] In the present specification, examples of the "optionally
substituted thiocarbamoyl group" include a thiocarbamoyl group
optionally having "1 or 2 substituents selected from a C.sub.1-6
alkyl group, a C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl
group, a C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a
C.sub.1-6 alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group and a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, each of which optionally has
1 to 3 substituents selected from substituent group A".
[0132] Preferable examples of the optionally substituted
thiocarbamoyl group include a thiocarbamoyl group, a mono- or
di-C.sub.1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,
ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl,
N-ethyl-N-methylthiocarbamoyl), a mono- or di-C.sub.2-6
alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono-
or di-C.sub.3-10 cycloalkyl-thiocarbamoyl group (e.g.,
cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or
di-C.sub.6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl),
a mono- or di-C.sub.7-16 aralkyl-thiocarbamoyl group (e.g.,
benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or
di-C.sub.1-6 alkyl-carbonyl-thiocarbamoyl group (e.g.,
acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or
di-C.sub.6-14 aryl-carbonyl-thiocarbamoyl group (e.g.,
benzoylthiocarbamoyl) and a 5- to 14-membered aromatic
heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).
[0133] In the present specification, examples of the "optionally
substituted sulfamoyl group" include a sulfamoyl group optionally
having "1 or 2 substituents selected from a C.sub.1-6 alkyl group,
a C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group and a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, each of which optionally has
1 to 3 substituents selected from substituent group A".
[0134] Preferable examples of the optionally substituted sulfamoyl
group include a sulfamoyl group, a mono- or di-C.sub.1-6
alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl,
dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a
mono- or di-C.sub.2-6 alkenyl-sulfamoyl group (e.g.,
diallylsulfamoyl), a mono- or di-C.sub.3-10 cycloalkyl-sulfamoyl
group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or
di-C.sub.6-14 aryl-sulfamoyl group (e.g., phenylsulfamoyl), a mono-
or di-C.sub.7-16 aralkyl-sulfamoyl group (e.g., benzylsulfamoyl,
phenethylsulfamoyl), a mono- or di-C.sub.1-6
alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,
propionylsulfamoyl), a mono- or di-C.sub.6-14
aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to
14-membered aromatic heterocyclylsulfamoyl group (e.g.,
pyridylsulfamoyl).
[0135] In the present specification, examples of the "optionally
substituted hydroxy group" include a hydroxyl group optionally
having "a substituent selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group, a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, a C.sub.1-6 alkylsulfonyl
group and a C.sub.6-14 arylsulfonyl group, each of which optionally
has 1 to 3 substituents selected from substituent group A".
[0136] Preferable examples of the optionally substituted hydroxy
group include a hydroxy group, a C.sub.1-6 alkoxy group, a
C.sub.2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy,
2-pentenyloxy, 3-hexenyloxy), a C.sub.3-10 cycloalkyloxy group
(e.g., cyclohexyloxy), a C.sub.6-14 aryloxy group (e.g., phenoxy,
naphthyloxy), a C.sub.7-16 aralkyloxy group (e.g., benzyloxy,
phenethyloxy), a C.sub.1-6 alkyl-carbonyloxy group (e.g.,
acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a
C.sub.6-14 aryl-carbonyloxy group (e.g., benzoyloxy), a C.sub.7-16
aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), a 5- to
14-membered aromatic heterocyclylcarbonyloxy group (e.g.,
nicotinoyloxy), a 3- to 14-membered non-aromatic
heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), a
C.sub.1-6 alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy),
a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,
pyridyloxy), a carbamoyloxy group, a C.sub.1-6 alkyl-carbamoyloxy
group (e.g., methylcarbamoyloxy), a C.sub.7-16 aralkyl-carbamoyloxy
group (e.g., benzylcarbamoyloxy), a C.sub.1-6 alkylsulfonyloxy
group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a C.sub.6-14
arylsulfonyloxy group (e.g., phenylsulfonyloxy).
[0137] In the present specification, examples of the "optionally
substituted sulfanyl group" include a sulfanyl group optionally
having "a substituent selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group and a 5- to
14-membered aromatic heterocyclic group, each of which optionally
has 1 to 3 substituents selected from substituent group A" and a
halogenated sulfanyl group.
[0138] Preferable examples of the optionally substituted sulfanyl
group include a sulfanyl (--SH) group, a C.sub.1-6 alkylthio group,
a C.sub.2-6 alkenylthio group (e.g., allylthio, 2-butenylthio,
2-pentenylthio, 3-hexenylthio), a C.sub.3-10 cycloalkylthio group
(e.g., cyclohexylthio), a C.sub.6-14 arylthio group (e.g.,
phenylthio, naphthylthio), a C.sub.7-16 aralkylthio group (e.g.,
benzylthio, phenethylthio), a C.sub.1-6 alkyl-carbonylthio group
(e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio,
pivaloylthio), a C.sub.6-14 aryl-carbonylthio group (e.g.,
benzoylthio), a 5- to 14-membered aromatic heterocyclylthio group
(e.g., pyridylthio) and a halogenated thio group (e.g.,
pentafluorothio).
[0139] In the present specification, examples of the "optionally
substituted silyl group" include a silyl group optionally having "1
to 3 substituents selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group and a C.sub.7-16 aralkyl group, each of which
optionally has 1 to 3 substituents selected from substituent group
A".
[0140] Preferable examples of the optionally substituted silyl
group include a tri-C.sub.1-6 alkylsilyl group (e.g.,
trimethylsilyl, tert-butyl(dimethyl)silyl).
[0141] In the present specification, examples of the "hydrocarbon
ring" include a C.sub.6-14 aromatic hydrocarbon ring, C.sub.3-10
cycloalkane and C.sub.3-10 cycloalkene.
[0142] In the present specification, examples of the "C.sub.6-14
aromatic hydrocarbon ring" include benzene and naphthalene.
[0143] In the present specification, examples of the "C.sub.3-10
cycloalkane" include cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane and cyclooctane.
[0144] In the present specification, examples of the "C.sub.3-10
cycloalkene" include cyclopropene, cyclobutene, cyclopentene,
cyclohexene, cycloheptene and cyclooctene.
[0145] In the present specification, examples of the "heterocycle"
include an aromatic heterocycle and a non-aromatic heterocycle,
each containing, as a ring-constituting atom besides carbon atom, 1
to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and
an oxygen atom.
[0146] In the present specification, examples of the "aromatic
heterocycle" include a 5- to 14-membered (preferably 5- to
10-membered) aromatic heterocycle containing, as a
ring-constituting atom besides carbon atom, 1 to 4 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "aromatic heterocycle" include 5- or
6-membered monocyclic aromatic heterocycles such as thiophene,
furan, pyrrole, imidazole, pyrazole, triazole, isothiazole,
oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,
1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole,
1,3,4-thiadiazole, triazole, tetrazole, triazine and the like; and
8- to 14-membered fused polycyclic (preferably bi or tricyclic)
aromatic heterocycles such as benzothiophene, benzofuran,
benzimidazole, benzoxazole, benzisoxazole, benzothiazole,
benzisothiazole, benzotriazole, imidazopyridine, thienopyridine,
furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine,
thiazolopyridine, imidazopyrazine, imidazopyrimidine,
thienopyrimidine, furopyrimidine, pyrrolopyrimidine,
pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine,
pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene,
phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline,
quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline,
cinnoline, carbazole, .beta.-carboline, phenanthridine, acridine,
phenazine, phenothiazine, phenoxazine and the like.
[0147] In the present specification, examples of the "non-aromatic
heterocycle" include a 3- to 14-membered (preferably 4- to
10-membered) non-aromatic heterocycle containing, as a
ring-constituting atom besides carbon atom, 1 to 4 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "non-aromatic heterocycle" include 3- to
8-membered monocyclic non-aromatic heterocycles such as aziridine,
oxirane, thiirane, azetidine, oxetane, thietane,
tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,
imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,
pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,
tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,
tetrahydropyridine, dihydropyridine, dihydrothiopyran,
tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,
tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,
azepanine, diazepane, azepine, azocane, diazocane, oxepane and the
like; and 9- to 14-membered fused polycyclic (preferably bi or
tricyclic) non-aromatic heterocycles such as dihydrobenzofuran,
dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole,
dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene,
tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine,
indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine,
tetrahydrobenzazepine, tetrahydroquinoxaline,
tetrahydrophenanthridine, hexahydrophenothiazine,
hexahydrophenoxazine, tetrahydrophthalazine,
tetrahydronaphthyridine, tetrahydroquinazoline,
tetrahydrocinnoline, tetrahydrocarbazole,
tetrahydro-.beta.-carboline, tetrahydroacridine,
tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline
and the like.
[0148] In the present specification, examples of the
"nitrogen-containing heterocycle" include a "heterocycle"
containing at least one nitrogen atom as a ring-constituting
atom.
[0149] The definition of each symbol in the formula (I) is
explained in detail in the following.
[0150] G.sup.1 is a carbon atom or a nitrogen atom.
[0151] G.sup.1 is preferably a carbon atom.
[0152] G.sup.2 is a carbon atom or a nitrogen atom.
[0153] G.sup.2 is preferably a carbon atom.
[0154] Ring A is an optionally further substituted 6-membered
nitrogen-containing heterocycle.
[0155] Examples of the "6-membered nitrogen-containing heterocycle"
of the "optionally further substituted 6-membered
nitrogen-containing heterocycle" for Ring A include 6-membered
heterocycles containing at least one nitrogen atom, from among of
the above-mentioned heterocycle, specifically, pyridine,
pyrimidine, pyridazine.
[0156] The "6-membered nitrogen-containing heterocycle" of the
"optionally further substituted 6-membered nitrogen-containing
heterocycle" for Ring A is preferably pyridine or pyrimidine, more
preferably pyridine.
[0157] The "6-membered nitrogen-containing heterocycle" of the
"optionally further substituted 6-membered nitrogen-containing
heterocycle" for Ring A optionally has 1 or 2 substituents at
substitutable position(s), in addition to --N(R.sup.4)--C(R.sup.1)
(R.sup.2)--Ring
[0158] B. Examples of the substituent include substituents selected
from the aforementioned substituent group A. When the number of the
substituents is plural, the respective substituents may be the same
or different.
[0159] Ring A is preferably an optionally further substituted
pyridine.
[0160] Ring A is more preferably pyridine optionally further
substituted by 1 to 3 halogen atoms (e.g., a chlorine atom).
[0161] In another embodiment, Ring A is preferably an optionally
further substituted pyridine or an optionally further substituted
pyrimidine.
[0162] In this embodiment, Ring A is more preferably pyridine or
pyrimidine, each of which is optionally further substituted by 1 to
2 substituents selected from the group consisting of
[0163] (a) a halogen atom (e.g., a chlorine atom),
[0164] (b) a C.sub.1-6 alkyl group (e.g., methyl), and
[0165] (c) a C.sub.3-10 cycloalkyl group (e.g., cyclopropyl).
[0166] In this embodiment, Ring A is still more preferably
(1) pyridine optionally further substituted by 1 to 2 substituents
selected from the group consisting of
[0167] (a) a halogen atom (e.g., a chlorine atom),
[0168] (b) a C.sub.1-6 alkyl group (e.g., methyl), and
[0169] (c) a C.sub.3-10 cycloalkyl group (e.g., cyclopropyl),
or
(2) pyrimidine.
[0170] In this embodiment, Ring A is particularly preferably
pyridine.
[0171] G.sup.3 is an oxygen atom, an optionally substituted
methylene, NR.sup.1, a sulfur atom, S(O) or S(O).sub.2.
[0172] R.sup.1 is a hydrogen atom or a substituent.
[0173] The "methylene" of the "optionally substituted methylene"
for G.sup.3 optionally has 1 or 2 substituents at substitutable
position(s). Examples of the substituent include substituents
selected from the aforementioned substituent group A. When the
number of the substituents is plural, the respective substituents
may be the same or different.
[0174] G.sup.3 is preferably an oxygen atom or NR.sup.1 wherein
R.sup.1 is as defined above.
[0175] G.sup.3 is more preferably an oxygen atom or NR.sup.1
wherein R.sup.1 is a C.sub.1-6 alkyl group (e.g., methyl).
[0176] In another embodiment, G.sup.3 is preferably an oxygen atom,
an optionally substituted methylene, NR.sup.1 wherein R.sup.1 is as
defined above, or a sulfur atom.
[0177] In this embodiment, G.sup.3 is more preferably an oxygen
atom, NR.sup.1 wherein R.sup.1 is a C.sub.1-6 alkyl group (e.g.,
methyl), methylene or a sulfur atom.
[0178] In this embodiment, G.sup.3 is particularly an oxygen
atom.
[0179] X is an optionally substituted ethylene.
[0180] The "ethylene" of the "optionally substituted ethylene" for
X optionally has 1 to 4 substituents at substitutable position(s).
Examples of the substituent include substituents selected from the
aforementioned substituent group A. When the number of the
substituents is plural, the respective substituents may be the same
or different.
[0181] X is preferably ethylene.
[0182] In another embodiment, X is preferably ethylene optionally
substituted by an oxo group.
[0183] In this embodiment, X is particularly preferably
ethylene.
[0184] R.sup.2 and R.sup.3 are each independently a hydrogen atom
or an optionally substituted C.sub.1-6 alkyl group, or R.sup.2 and
R.sup.3 are joined together to form a cycloalkane or a heterocycle,
each of which is optionally substituted.
[0185] The "C.sub.1-6 alkyl group" of the "optionally substituted
C.sub.1-6 alkyl group" optionally has 1 to 5 substituents
(preferably 1 to 3) at substitutable position(s). Examples of the
substituent include substituents selected from the aforementioned
substituent group A. When the number of the substituents is plural,
the respective substituents may be the same or different.
[0186] Examples of the "cycloalkane" of the "cycloalkane or
heterocycle, each of which is optionally substituted" formed by
R.sup.1 and R.sup.2 include a C.sub.3-10 cycloalkane (preferably a
C.sub.3-6 cycloalkane).
[0187] The "cycloalkane or heterocycle" of the "cycloalkane or
heterocycle, each of which is optionally substituted" formed by
R.sup.2 and R.sup.3 has 1 to 5 substituents (preferably 1 to 3) at
substitutable position(s). Examples of the substituent include
substituents selected from the aforementioned substituent group A.
When the number of the substituents is plural, the respective
substituents may be the same or different.
[0188] Preferably, R.sup.2 and R.sup.3 are each a hydrogen atom or
an optionally substituted C.sub.1-6 alkyl group (e.g., methyl), or
R.sup.2 and R.sup.3 are joined together to form an optionally
substituted cycloalkane (preferably a C.sub.3-10 cycloalkane, more
preferably a C.sub.3-6 cycloalkane (e.g., cyclopropane)).
[0189] More preferably, R.sup.2 and R.sup.3 are each a hydrogen
atom or a C.sub.1-6 alkyl group (e.g., methyl), or R.sup.2 and
R.sup.3 are joined together to form a C.sub.3-10 cycloalkane
(preferably a C.sub.3-6 cycloalkane (e.g., cyclopropane)).
[0190] Still more preferably, R.sup.2 is a C.sub.1-6 alkyl group
(e.g., methyl), and R.sup.3 is a hydrogen atom, or R.sup.2 and
R.sup.3 are joined together to form a C.sub.3-10 cycloalkane
(preferably a C.sub.3-6 cycloalkane (e.g., cyclopropane)).
[0191] In another embodiment, still more preferably, R.sup.2 is a
hydrogen atom or a C.sub.1-6 alkyl group (e.g., methyl), and
R.sup.3 is a hydrogen atom, or R.sup.2 and R.sup.3 are joined
together to form a C.sub.3-10 cycloalkane (preferably a C.sub.3-6
cycloalkane (e.g., cyclopropane)).
[0192] In this embodiment, particularly preferably, R.sup.2 is a
C.sub.1-6 alkyl group (e.g., methyl), and R.sup.3 is a hydrogen
atom, or R.sup.2 and R.sup.3 are joined together to form a
C.sub.3-6 cycloalkane (e.g., cyclopropane).
[0193] R.sup.4 is a hydrogen atom or a substituent.
[0194] R.sup.4 is preferably a hydrogen atom.
[0195] Ring B is an optionally further substituted ring.
[0196] Examples of the "ring" of the "optionally further
substituted ring" for Ring B include a hydrocarbon ring and a
heterocycle (preferably a C.sub.6-14 aromatic hydrocarbon ring
(preferably a C.sub.6-10 aromatic hydrocarbon ring, more preferably
benzene), a C.sub.3-10 cycloalkane (preferably a C.sub.3-6
cycloalkane, more preferably cyclohexane) or a 5- to 14-membered
(preferably 5- to 10-membered) aromatic heterocycle (preferably a
5- or 6-membered monocyclic aromatic heterocycle, more preferably
pyridine), more preferably a C.sub.6-10 aromatic hydrocarbon ring
(preferably benzene), a C.sub.3-6 cycloalkane (preferably
cyclohexane) or a 5- or 6-membered monocyclic aromatic heterocycle
(preferably pyridine), particularly preferably benzene).
[0197] The "ring" of the "optionally further substituted ring" for
Ring B optionally has 1 to 5 (preferably 1 to 3) substituents at
substitutable position(s), in addition to --C(R.sup.1) (R.sup.2)
--N(R.sup.4)--Ring A. Examples of the substituent include an
optionally further substituted pyridine substituents selected from
the aforementioned substituent group A. When the number of the
substituents is plural, the respective substituents may be the same
or different.
[0198] Ring B is preferably an optionally further substituted
C.sub.6-14 aromatic hydrocarbon ring (preferably benzene).
[0199] Ring B is more preferably a C.sub.6-14 aromatic hydrocarbon
ring (preferably benzene) optionally further substituted by 1 to 3
(preferably one) substituents selected from the group consisting
of
[0200] (a) a carboxy group,
[0201] (b) a C.sub.1-6 alkoxy-carbonyl group (e.g.,
methoxycarbonyl),
[0202] (c) a cyano group,
[0203] (d) a carbamoyl group,
[0204] (e) a mono- or di-C.sub.1-6 alkyl-carbamoyl group (e.g.,
methylcarbamoyl),
[0205] (f) a mono- or di-C.sub.1-6 alkoxy-carbamoyl group (e.g.,
methoxycarbamoyl, ethoxycarbamoyl),
[0206] (g) a mono- or di-C.sub.7-16 aralkyloxy-carbamoyl group
(e.g., benzyloxycarbamoyl), and
[0207] (h) 5-tetrazolyl,
[preferably optionally further substituted by 1 to 3 (preferably
one) carboxy groups].
[0208] Ring B is still more preferably benzene optionally further
substituted by 1 to 3 (preferably one) substituents selected from
the group consisting of
[0209] (a) a carboxy group,
[0210] (b) a C.sub.1-6 alkoxy-carbonyl group (e.g.,
methoxycarbonyl),
[0211] (c) a cyano group,
[0212] (d) a carbamoyl group,
[0213] (e) a mono- or di-C.sub.1-6 alkyl-carbamoyl group (e.g.,
methylcarbamoyl),
[0214] (f) a mono- or di-C.sub.1-6 alkoxy-carbamoyl group (e.g.,
methoxycarbamoyl, ethoxycarbamoyl),
[0215] (g) a mono- or di-C.sub.7-16 aralkyloxy-carbamoyl group
(e.g., benzyloxycarbamoyl), and
[0216] (h) 5-tetrazolyl,
[preferably optionally further substituted by 1 to 3 (preferably
one) carboxy groups].
[0217] In another embodiment, Ring B is preferably an optionally
further substituted C.sub.6-14 aromatic hydrocarbon ring
(preferably a C.sub.6-10 aromatic hydrocarbon ring, more preferably
benzene), an optionally further substituted C.sub.3-10 cycloalkane
(preferably a C.sub.3-6 cycloalkane, more preferably cyclohexane)
or an optionally further substituted 5- to 10-membered aromatic
heterocycle (preferably a 5- or 6-membered monocyclic aromatic
heterocycle, more preferably pyridine).
[0218] In this embodiment, Ring B is more preferably
(1) a C.sub.6-14 aromatic hydrocarbon ring (preferably a C.sub.6-10
aromatic hydrocarbon ring, more preferably benzene) optionally
further substituted by 1 to 3 (preferably one) substituents
selected from the group consisting of
[0219] (a) a carboxy group,
[0220] (b) a C.sub.1-6 alkoxy-carbonyl group (e.g.,
methoxycarbonyl),
[0221] (c) a cyano group,
[0222] (d) a carbamoyl group,
[0223] (e) a mono- or di-C.sub.1-6 alkyl-carbamoyl group (e.g.,
methylcarbamoyl),
[0224] (f) a mono- or di-C.sub.1-6 alkoxy-carbamoyl group (e.g.,
methoxycarbamoyl, ethoxycarbamoyl),
[0225] (g) a mono- or di-C.sub.7-16 aralkyloxy-carbamoyl group
(e.g., benzyloxycarbamoyl),
[0226] (h) 5-tetrazolyl, and
[0227] (i) a C.sub.1-6 alkoxy group (e.g., methoxy)
[preferably optionally further substituted by 1 to 3 (preferably
one) carboxy groups], (2) a C.sub.3-10 cycloalkane (preferably a
C.sub.3-6 cycloalkane, more preferably cyclohexane), or (3) a 5- to
10-membered aromatic heterocycle (preferably a 5- or 6-membered
monocyclic aromatic heterocycle, more preferably pyridine)
optionally further substituted by 1 to 3 (preferably one) C.sub.1-6
alkyl groups (e.g., methyl). In this embodiment, Ring B is still
more preferably (1) a C.sub.6-10 aromatic hydrocarbon ring
(preferably benzene) optionally further substituted by 1 to 3
(preferably one) substituents selected from the group consisting
of
[0228] (a) a carboxy group,
[0229] (b) a C.sub.1-6 alkoxy-carbonyl group (e.g.,
methoxycarbonyl),
[0230] (c) a cyano group,
[0231] (d) a carbamoyl group,
[0232] (e) a mono- or di-C.sub.1-6 alkyl-carbamoyl group (e.g.,
methylcarbamoyl),
[0233] (f) a mono- or di-C.sub.1-6 alkoxy-carbamoyl group (e.g.,
methoxycarbamoyl, ethoxycarbamoyl),
[0234] (g) a mono- or di-C.sub.7-16 aralkyloxy-carbamoyl group
(e.g., benzyloxycarbamoyl),
[0235] (h) 5-tetrazolyl, and
[0236] (i) a C.sub.1-6 alkoxy group (e.g., methoxy) [preferably
optionally further substituted by 1 to 3 (preferably one) carboxy
groups],
(2) a C.sub.3-6 cycloalkane (preferably cyclohexane), or (3) a 5-
or 6-membered monocyclic aromatic heterocycle (preferably pyridine)
optionally further substituted by 1 to 3 (preferably one) C.sub.1-6
alkyl groups (e.g., methyl).
[0237] In this embodiment, Ring B is particularly preferably
benzene further substituted by one carboxy group.
[0238] Ring C is an optionally further substituted ring.
[0239] Examples of the "ring" of the "optionally further
substituted ring" for Ring C include a hydrocarbon ring and a
heterocycle (preferably a C.sub.6-14 aromatic hydrocarbon ring
(preferably a C.sub.6-10 aromatic hydrocarbon ring, more preferably
benzene, naphthalene), a C.sub.3-10 cycloalkane (preferably a
C.sub.3-6 cycloalkane, more preferably cyclohexane) or a 5- to
14-membered (preferably 5- to 10-membered) aromatic heterocycle
(preferably a 5- or 6-membered monocyclic aromatic heterocycle,
more preferably pyridine, furan, isoxazole), more preferably a
C.sub.6-10 aromatic hydrocarbon ring (preferably benzene,
naphthalene), a C.sub.3-6 cycloalkane (preferably cyclohexane) or a
5- or 6-membered monocyclic aromatic heterocycle (preferably
pyridine, furan, isoxazole)).
[0240] The "ring" of the "optionally further substituted ring" for
Ring C optionally has 1 to 5 (preferably 1 to 3) substituents at
substitutable position(s), in addition to --W--. Examples of the
substituent include substituents selected from the aforementioned
substituent group A. When the number of the substituents is plural,
the respective substituents may be the same or different.
[0241] Ring C is preferably a C.sub.6-14 aromatic hydrocarbon ring
(preferably benzene, naphthalene) or a 5- to 14-membered
(preferably 5- to 10-membered) aromatic heterocycle (preferably
pyridine, furan) (preferably a C.sub.6-14 aromatic hydrocarbon ring
(preferably benzene, naphthalene) or a 5- or 6-membered monocyclic
aromatic heterocycle (preferably pyridine, furan)), each of which
is optionally further substituted.
[0242] Ring C is more preferably a C.sub.6-14 aromatic hydrocarbon
ring (preferably benzene, naphthalene) or a 5- to 14-membered
(preferably 5- to 10-membered) aromatic heterocycle (preferably
pyridine, furan) (preferably a C.sub.6-14 aromatic hydrocarbon ring
(preferably benzene, naphthalene) or a 5- or 6-membered monocyclic
aromatic heterocycle (preferably pyridine, furan)), each of which
is optionally further substituted by 1 to 3 (preferably 1 or 2)
substituents selected from the group consisting of
[0243] (1) a halogen atom (e.g., a fluorine atom, a chlorine
atom),
[0244] (2) an optionally halogenated C.sub.1-6 alkyl group (e.g.,
methyl, trifluoromethyl),
[0245] (3) a C.sub.1-6 alkoxy group (e.g., methoxy), and
[0246] (4) a C.sub.6-14 aryl group (e.g., phenyl).
[0247] Ring C is still more preferably benzene, naphthalene,
pyridine or furan, each of which is optionally further substituted
by 1 to 3 (preferably 1 or 2) substituents selected from the group
consisting of
[0248] (1) a halogen atom (e.g., a fluorine atom, a chlorine
atom),
[0249] (2) an optionally halogenated C.sub.1-6 alkyl group (e.g.,
methyl, trifluoromethyl),
[0250] (3) a C.sub.1-6 alkoxy group (e.g., methoxy), and
[0251] (4) a C.sub.6-14 aryl group (e.g., phenyl).
[0252] In another embodiment, Ring C is preferably a C.sub.6-14
aromatic hydrocarbon ring (preferably a C.sub.6-10 aromatic
hydrocarbon ring, more preferably benzene, naphthalene), a
C.sub.3-10 cycloalkane (preferably a C.sub.3-6 cycloalkane, more
preferably cyclohexane) or a 5- to 14-membered (preferably 5- to
10-membered) aromatic heterocycle (preferably a 5- or 6-membered
monocyclic aromatic heterocycle, more preferably pyridine, furan,
isoxazole) (preferably a C.sub.6-10 aromatic hydrocarbon ring
(preferably benzene, naphthalene), a C.sub.3-6 cycloalkane
(preferably cyclohexane) or a 5- or 6-membered monocyclic aromatic
heterocycle (preferably pyridine, furan, isoxazole)), each of which
is optionally further substituted.
[0253] In this embodiment, Ring C is more preferably a C.sub.6-14
aromatic hydrocarbon ring (preferably a C.sub.6-10 aromatic
hydrocarbon ring, more preferably benzene, naphthalene), a
C.sub.3-10 cycloalkane (preferably a C.sub.3-6 cycloalkane, more
preferably cyclohexane) or a 5- to 14-membered (preferably 5- to
10-membered) aromatic heterocycle (preferably a 5- or 6-membered
monocyclic aromatic heterocycle, more preferably pyridine, furan,
isoxazole) (preferably a C.sub.6-10 aromatic hydrocarbon ring
(preferably benzene, naphthalene), a C.sub.3-6 cycloalkane
(preferably cyclohexane) or a 5- or 6-membered monocyclic aromatic
heterocycle (preferably pyridine, furan, isoxazole)), each of which
is optionally further substituted by 1 to 3 (preferably 1 or 2)
substituents selected from the group consisting of
[0254] (1) a halogen atom (e.g., a fluorine atom, a chlorine
atom),
[0255] (2) an optionally halogenated C.sub.1-6 alkyl group (e.g.,
methyl, trifluoromethyl),
[0256] (3) a C.sub.1-6 alkoxy group (e.g., methoxy), and
[0257] (4) a C.sub.6-14 aryl group (e.g., phenyl).
[0258] In this embodiment, Ring C is further more preferably
benzene, naphthalene, cyclohexane, pyridine, furan or isoxazole,
each of which is optionally further substituted by 1 to 3
(preferably 1 or 2) substituents selected from the group consisting
of
[0259] (1) a halogen atom (e.g., a fluorine atom, a chlorine
atom),
[0260] (2) an optionally halogenated C.sub.1-6 alkyl group (e.g.,
methyl, trifluoromethyl),
[0261] (3) a C.sub.1-6 alkoxy group (e.g., methoxy), and
[0262] (4) a C.sub.6-14 aryl group (e.g., phenyl).
[0263] In this embodiment, Ring C is still more preferably benzene
further substituted by 1 or 2 substituents selected from the group
consisting of
[0264] (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),
and
[0265] (2) a C.sub.1-6 alkoxy group (e.g., methoxy).
[0266] In this embodiment, Ring C is particularly preferably
benzene further substituted by 1 or 2 halogen atoms (e.g., a
fluorine atom, a chlorine atom).
[0267] W is a bond, or a spacer in which the number of atoms in the
main chain is 1 to 4.
[0268] Examples of the "spacer in which the number of atoms in the
main chain is 1 to 4" for W include spacers wherein the main chain
consists of 1 to 4 atoms selected from a carbon atom, a nitrogen
atom, a sulfur atom (optionally oxidized) and an oxygen atom, each
of which optionally has substituent(s) selected from the
aforementioned substituent group A at substitutable
position(s).
[0269] Specific examples of the "spacer in which the number of
atoms in the main chain is 1 to 4" for W include
(1) a bond; (2) a C.sub.1-4 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --CH.sub.2--CH(CH.sub.3)--,
--CH(CH.sub.3)--CH.sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4-- etc.) optionally substituted by the
aforementioned substituent group A (preferably a halogen atom
(e.g., a fluorine atom, a chlorine atom), an oxo group and a
hydroxy group); (3) a C.sub.2-4 alkenylene group (e.g.,
--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--
etc.) optionally substituted by the aforementioned substituent
group A; (4) --Z-- wherein Z is O, NR.sup.6 (R.sup.6 is a hydrogen
atom or a substituent), S, S(O), or S(O).sub.2; (5)
--(CH.sub.2).sub.m1--Z-- (CH.sub.2).sub.m2-- wherein Z is as
defined above, m1 and m2 are each independently an integer of 0 to
3, and m1+m2 is an integer of 1 to 3; (6)
--Z.sup.1--(CH.sub.2).sub.m--Z.sup.2-- wherein Z.sup.1 and Z.sup.2
are each independently O, C(O), NR.sup.6 (R.sup.6 is a hydrogen
atom or a substituent), S, S(O) or S(O).sub.2, and m is an integer
of 1 to 2; (7) --CO--NR.sup.6-- or --NR.sup.6--CO-- wherein R.sup.6
is as defined above; (8) --S(O).sub.2--NR.sup.6-- or
--NR.sup.6--S(O).sub.2-- wherein R.sup.6 is as defined above; (9) a
C.sub.3-6 cycloalkylene (e.g., cyclopropylene, cyclobutylene,
cyclopentylene, cyclohexylene etc.); (10) a divalent non-aromatic
heterocyclic group (e.g., 1,2-aziridinediyl, 1,3-azetidinediyl,
1,3-pyrrolidinediyl, 1,3-piperidinediyl, 1,4-piperidinediyl,
1,4-morpholinediyl etc.); (11) --Z.sup.1--Y--Z.sup.2-- wherein
Z.sup.1 and Z.sup.2 are as defined above, and Y is a divalent
non-aromatic heterocyclic group (e.g., 1,2-aziridinediyl,
1,3-azetidinediyl, 1,3-pyrrolidinediyl, 1,3-piperidinediyl etc.);
and the like.
[0270] W is preferably a spacer in which the number of atoms in the
main chain is 1 to 4.
[0271] W is more preferably
(1) a C.sub.1-4 alkylene group (e.g., --CH.sub.2--), or (2)
--(CH.sub.2).sub.m1--O-- wherein m1 is an integer of 0 to 3 (e.g.,
--CH.sub.2CH.sub.2O--).
[0272] W is still more preferably --CH.sub.2-- or
--CH.sub.2CH.sub.2O-- (wherein the left bond is bonded to the
nitrogen atom, and the right bond is bonded to Ring C).
[0273] In another embodiment, W is more preferably
(1) a C.sub.1-4 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--) optionally substituted by an oxo group, or
(2) --(CH.sub.2).sub.m1--O-- wherein m1 is an integer of 0 to 3
(e.g., --CH.sub.2CH.sub.2O--).
[0274] In this embodiment, W is still more preferably --CH.sub.2--,
--(CH.sub.2).sub.2--, --CH.sub.2CH.sub.2O-- (wherein the left bond
is bonded to the nitrogen atom, and the right bond is bonded to
Ring C) or --C(.dbd.O)--.
[0275] In this embodiment, W is particularly preferably
--CH.sub.2--.
[0276] Preferable examples of compound (I) include the following
compounds.
[0277] [Compound A-1]
[0278] Compound (I) wherein
[0279] G.sup.1 is a carbon atom or a nitrogen atom,
[0280] G.sup.2 is a carbon atom or a nitrogen atom,
[0281] Ring A is an optionally further substituted pyridine,
[0282] G.sup.3 is an oxygen atom or NR.sup.1 wherein R.sup.1 is as
defined above,
[0283] X is an optionally substituted ethylene,
[0284] R.sup.2 and R.sup.3 are each a hydrogen atom or an
optionally substituted C.sub.1-6 alkyl group (e.g., methyl), or
R.sup.2 and R.sup.3 are joined together to form an optionally
substituted cycloalkane (preferably a C.sub.3-10 cycloalkane, more
preferably a C.sub.3-6 cycloalkane (e.g., cyclopropane)),
[0285] R.sup.4 is a hydrogen atom,
[0286] Ring B is an optionally further C.sub.6-14 aromatic
hydrocarbon ring (preferably benzene),
[0287] Ring C is a C.sub.6-14 aromatic hydrocarbon ring (preferably
benzene, naphthalene) or a 5- to 14-membered (preferably 5- to
10-membered) aromatic heterocycle (preferably pyridine, furan)
(preferably a C.sub.6-14 aromatic hydrocarbon ring (preferably
benzene, naphthalene) or a 5- or 6-membered monocyclic aromatic
heterocycle (preferably pyridine, furan)), each of which is
optionally further substituted, and
[0288] W is a spacer in which the number of atoms in the main chain
is 1 to 4.
[0289] [Compound B-1]
[0290] Compound (I) wherein
[0291] G.sup.1 is a carbon atom,
[0292] G.sup.2 is a carbon atom,
[0293] Ring A is pyridine optionally further substituted by 1 to 2
halogen atoms (e.g., a chlorine atom),
[0294] G.sup.3 is an oxygen atom or NR.sup.1 wherein R.sup.1 is a
C.sub.1-6 alkyl group (e.g., methyl),
[0295] X is ethylene,
[0296] R.sup.2 and R.sup.3 are each a hydrogen atom or a C.sub.1-6
alkyl group (e.g., methyl), or R.sup.2 and R.sup.3 are joined
together to form a C.sub.Iilo cycloalkane (preferably a C.sub.3-6
cycloalkane (e.g., cyclopropane)),
[0297] R.sup.4 is a hydrogen atom,
[0298] Ring B is a C.sub.6-14 aromatic hydrocarbon ring (preferably
benzene) optionally further substituted by 1 to 3 (preferably one)
substituents selected from the group consisting of [0299] (a) a
carboxy group, [0300] (b) a C.sub.1-6 alkoxy-carbonyl group (e.g.,
methoxycarbonyl), [0301] (c) a cyano group, [0302] (d) a carbamoyl
group, [0303] (e) a mono- or di-C.sub.1-6 alkyl-carbamoyl group
(e.g., methylcarbamoyl), [0304] (f) a mono- or di-C.sub.1-6
alkoxy-carbamoyl group (e.g., methoxycarbamoyl, ethoxycarbamoyl),
[0305] (g) a mono- or di-C.sub.7-16 aralkyloxy-carbamoyl group
(e.g., benzyloxycarbamoyl), and [0306] (h) 5-tetrazolyl,
[preferably optionally further substituted by 1 to 3 (preferably
one) carboxy groups],
[0307] Ring C is a C.sub.6-14 aromatic hydrocarbon ring (preferably
benzene, naphthalene) or a 5- to 14-membered (preferably 5- to
10-membered) aromatic heterocycle (preferably pyridine, furan)
(preferably a C.sub.6-14 aromatic hydrocarbon ring (preferably
benzene, naphthalene) or a 5- or 6-membered monocyclic aromatic
heterocycle (preferably pyridine, furan)), each of which is
optionally further substituted by 1 to 3 (preferably 1 or 2)
substituents selected from the group consisting of [0308] (1) a
halogen atom (e.g., a fluorine atom, a chlorine atom), [0309] (2)
an optionally halogenated C.sub.1-6 alkyl group (e.g., methyl,
trifluoromethyl), [0310] (3) a C.sub.1-6 alkoxy group (e.g.,
methoxy), [0311] (4) a C.sub.6-14 aryl group (e.g., phenyl),
and
[0312] W is [0313] (1) a C.sub.1-4 alkylene group (e.g.,
--CH.sub.2--), or [0314] (2) --(CH.sub.2).sub.m1--O-- wherein m1 is
an integer of 0 to 3 (e.g., --CH.sub.2CH.sub.2O--).
[0315] [Compound C-1]
[0316] Compound (I) wherein
[0317] G.sup.1 is a carbon atom,
[0318] G.sup.2 is a carbon atom, Ring A is pyridine optionally
further substituted by 1 to 2 halogen atoms (e.g., a chlorine
atom),
[0319] G.sup.3 is an oxygen atom or NR.sup.1 wherein R.sup.1 is a
C.sub.1-6 alkyl group (e.g., methyl),
[0320] X is ethylene,
[0321] R.sup.2 is a C.sub.1-6 alkyl group (e.g., methyl), and
R.sup.3 is a hydrogen atom, or R.sup.2 and R.sup.3 are joined
together to form a C.sub.3-10 cycloalkane (preferably a C.sub.3-6
cycloalkane (e.g., cyclopropane)),
[0322] R.sup.4 is a hydrogen atom,
[0323] Ring B is benzene optionally further substituted by 1 to 3
(preferably one) substituents selected from the group consisting of
[0324] (a) a carboxy group, [0325] (b) a C.sub.1-6 alkoxy-carbonyl
group (e.g., methoxycarbonyl), [0326] (c) a cyano group, [0327] (d)
a carbamoyl group, [0328] (e) a mono- or di-C.sub.1-6
alkyl-carbamoyl group (e.g., methylcarbamoyl), [0329] (f) a mono-
or di-C.sub.1-6 alkoxy-carbamoyl group (e.g., methoxycarbamoyl,
ethoxycarbamoyl), [0330] (g) a mono- or di-C.sub.7-16
aralkyloxy-carbamoyl group (e.g., benzyloxycarbamoyl), and [0331]
(h) 5-tetrazolyl, [preferably optionally further substituted by 1
to 3 (preferably one) carboxy groups],
[0332] Ring C is benzene, naphthalene, pyridine or furan, each of
which is optionally further substituted by 1 to 3 (preferably 1 or
2) substituents selected from the group consisting of [0333] (1) a
halogen atom (e.g., a fluorine atom, a chlorine atom), [0334] (2)
an optionally halogenated C.sub.1-6 alkyl group (e.g., methyl,
trifluoromethyl), [0335] (3) a C.sub.1-6 alkoxy group (e.g.,
methoxy), [0336] (4) a C.sub.6-14 aryl group (e.g., phenyl),
and
[0337] W is --CH.sub.2-- or --CH.sub.2CH.sub.2O-- (wherein the left
bond is bonded to the nitrogen atom, and the right bond is bonded
to Ring C).
[0338] [Compound A-2]
[0339] Compound (I) wherein
[0340] G.sup.1 is a carbon atom or a nitrogen atom,
[0341] G.sup.2 is a carbon atom or a nitrogen atom, Ring A is an
optionally further substituted pyridine or an optionally further
substituted pyrimidine,
[0342] G.sup.3 is an oxygen atom, an optionally substituted
methylene, NR.sup.1 wherein R.sup.1 is as defined above, or a
sulfur atom,
[0343] X is an optionally substituted ethylene,
[0344] R.sup.2 and R.sup.3 are each a hydrogen atom or an
optionally substituted C.sub.1-6 alkyl group (e.g., methyl), or
R.sup.2 and R.sup.3 are joined together to form an optionally
substituted cycloalkane (preferably a C.sub.3-10 cycloalkane, more
preferably a C.sub.3-6 cycloalkane (e.g., cyclopropane)),
[0345] R.sup.4 is a hydrogen atom,
[0346] Ring B is an optionally further substituted C.sub.6-14
aromatic hydrocarbon ring (preferably a C.sub.6-10 aromatic
hydrocarbon ring, more preferably benzene), an optionally further
substituted C.sub.3-10 cycloalkane (preferably a C.sub.3-6
cycloalkane, more preferably cyclohexane) or an optionally further
substituted 5- to 10-membered aromatic heterocycle (preferably a 5-
or 6-membered monocyclic aromatic heterocycle, more preferably
pyridine),
[0347] Ring C is a C.sub.6-14 aromatic hydrocarbon ring (preferably
a C.sub.6-10 aromatic hydrocarbon ring, more preferably benzene,
naphthalene), a C.sub.3-10 cycloalkane (preferably a C.sub.3-6
cycloalkane, more preferably cyclohexane) or a 5- to 14-membered
(preferably 5- to 10-membered) aromatic heterocycle (preferably a
5- or 6-membered monocyclic aromatic heterocycle, more preferably
pyridine, furan, isoxazole) (preferably a C.sub.6-10 aromatic
hydrocarbon ring (preferably benzene, naphthalene), a C.sub.3-6
cycloalkane (preferably cyclohexane) or a 5- or 6-membered
monocyclic aromatic heterocycle (preferably pyridine, furan,
isoxazole)), each of which is optionally further substituted,
and
[0348] W is a spacer in which the number of atoms in the main chain
is 1 to 4.
[0349] [Compound B-2]
[0350] Compound (I) wherein
[0351] G.sup.1 is a carbon atom,
[0352] G.sup.2 is a carbon atom or a nitrogen atom, Ring A is
pyridine or pyrimidine, each of which is optionally further
substituted by 1 to 2 substituents selected from the group
consisting of [0353] (a) a halogen atom (e.g., a chlorine atom),
[0354] (b) a C.sub.1-6 alkyl group (e.g., methyl), and [0355] (c) a
C.sub.3-10 cycloalkyl group (e.g., cyclopropyl),
[0356] G.sup.3 is an oxygen atom, NR.sup.1 wherein R.sup.1 is a
C.sub.1-6 alkyl group (e.g., methyl), methylene or a sulfur
atom,
[0357] X is ethylene optionally substituted by an oxo group,
[0358] R.sup.2 and R.sup.3 are each a hydrogen atom or a C.sub.1-6
alkyl group (e.g., methyl), or R.sup.2 and R.sup.3 are joined
together to form a C.sub.3-10 cycloalkane (preferably a C.sub.3-6
cycloalkane (e.g., cyclopropane)),
[0359] R.sup.4 is a hydrogen atom, Ring B is
(1) a C.sub.6-14 aromatic hydrocarbon ring (preferably a C.sub.6-10
aromatic hydrocarbon ring, more preferably benzene) optionally
further substituted by 1 to 3 (preferably one) substituents
selected from the group consisting of [0360] (a) a carboxy group,
[0361] (b) a C.sub.1-6 alkoxy-carbonyl group (e.g.,
methoxycarbonyl), [0362] (c) a cyano group, [0363] (d) a carbamoyl
group, [0364] (e) a mono- or di-C.sub.1-6 alkyl-carbamoyl group
(e.g., methylcarbamoyl), [0365] (f) a mono- or di-C.sub.1-6
alkoxy-carbamoyl group (e.g., methoxycarbamoyl, ethoxycarbamoyl),
[0366] (g) a mono- or di-C.sub.7-16 aralkyloxy-carbamoyl group
(e.g., benzyloxycarbamoyl), [0367] (h) 5-tetrazolyl, and [0368] (i)
a C.sub.1-6 alkoxy group (e.g., methoxy) [preferably optionally
further substituted by 1 to 3 (preferably one) carboxy groups], (2)
a C.sub.3-10 cycloalkane (preferably a C.sub.3-6 cycloalkane, more
preferably cyclohexane), or (3) a 5- to 10-membered aromatic
heterocycle (preferably a 5- or 6-membered monocyclic aromatic
heterocycle, more preferably pyridine) optionally further
substituted by 1 to 3 (preferably one) C.sub.1-6 alkyl groups
(e.g., methyl),
[0369] Ring C is a C.sub.6-14 aromatic hydrocarbon ring (preferably
a C.sub.6-10 aromatic hydrocarbon ring, more preferably benzene,
naphthalene), a C.sub.3-10 cycloalkane (preferably a C.sub.3-6
cycloalkane, more preferably cyclohexane) or a 5- to 14-membered
(preferably 5- to 10-membered) aromatic heterocycle (preferably a
5- or 6-membered monocyclic aromatic heterocycle, more preferably
pyridine, furan, isoxazole) (preferably a C.sub.6-10 aromatic
hydrocarbon ring (preferably benzene, naphthalene), a C.sub.3-6
cycloalkane (preferably cyclohexane) or a 5- or 6-membered
monocyclic aromatic heterocycle (preferably pyridine, furan,
isoxazole)), each of which is optionally further substituted by 1
to 3 (preferably 1 or 2) substituents selected from the group
consisting of [0370] (1) a halogen atom (e.g., a fluorine atom, a
chlorine atom), [0371] (2) an optionally halogenated C.sub.1-6
alkyl group (e.g., methyl, trifluoromethyl), [0372] (3) a C.sub.1-6
alkoxy group (e.g., methoxy), and [0373] (4) a C.sub.6-14 aryl
group (e.g., phenyl), and
[0374] W is
(1) a C.sub.1-4 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--) optionally substituted by an oxo group, or
(2) --(CH.sub.2).sub.m1--O-- wherein m1 is an integer of 0 to 3
(e.g., --CH.sub.2CH.sub.2O--).
[0375] [Compound C-2]
[0376] Compound (I) wherein
[0377] G.sup.1 is a carbon atom,
[0378] G.sup.2 is a carbon atom or a nitrogen atom,
[0379] Ring A is
(1) pyridine optionally further substituted by 1 to 2 substituents
selected from the group consisting of [0380] (a) a halogen atom
(e.g., a chlorine atom), [0381] (b) a C.sub.1-6 alkyl group (e.g.,
methyl), and [0382] (c) a C.sub.3-10 cycloalkyl group (e.g.,
cyclopropyl), or (2) pyrimidine,
[0383] G.sup.3 is an oxygen atom, NR.sup.1 wherein R.sup.1 is a
C.sub.1-6 alkyl group (e.g., methyl), methylene or a sulfur atom, X
is ethylene optionally substituted by an oxo group,
[0384] R.sup.2 and R.sup.3 are each a hydrogen atom or a C.sub.1-6
alkyl group (e.g., methyl), or R.sup.2 and R.sup.3 are joined
together to form a C.sub.3-10 cycloalkane (preferably a C.sub.3-6
cycloalkane (e.g., cyclopropane)),
[0385] R.sup.4 is a hydrogen atom,
[0386] Ring B is
(1) a C.sub.6-14 aromatic hydrocarbon ring (preferably a C.sub.6-10
aromatic hydrocarbon ring, more preferably benzene) optionally
further substituted by 1 to 3 (preferably one) substituents
selected from the group consisting of [0387] (a) a carboxy group,
[0388] (b) a C.sub.1-6 alkoxy-carbonyl group (e.g.,
methoxycarbonyl), [0389] (c) a cyano group, [0390] (d) a carbamoyl
group, [0391] (e) a mono- or di-C.sub.1-6 alkyl-carbamoyl group
(e.g., methylcarbamoyl), [0392] (f) a mono- or di-C.sub.1-6
alkoxy-carbamoyl group (e.g., methoxycarbamoyl, ethoxycarbamoyl),
[0393] (g) a mono- or di-C.sub.2-16 aralkyloxy-carbamoyl group
(e.g., benzyloxycarbamoyl), [0394] (h) 5-tetrazolyl, and [0395] (i)
a C.sub.1-6 alkoxy group (e.g., methoxy) [preferably optionally
further substituted by 1 to 3 (preferably one) carboxy groups], (2)
a C.sub.3-10 cycloalkane (preferably a C.sub.3-6 cycloalkane, more
preferably cyclohexane), or (3) a 5- to 10-membered aromatic
heterocycle (preferably a 5- or 6-membered monocyclic aromatic
heterocycle, more preferably pyridine) optionally further
substituted by 1 to 3 (preferably one) C.sub.1-6 alkyl groups
(e.g., methyl), Ring C is a C.sub.6-14 aromatic hydrocarbon ring
(preferably a
[0396] C.sub.6-10 aromatic hydrocarbon ring, more preferably
benzene, naphthalene), a C.sub.3-10 cycloalkane (preferably a
C.sub.3-6 cycloalkane, more preferably cyclohexane) or a 5- to
14-membered (preferably 5- to 10-membered) aromatic heterocycle
(preferably a 5- or 6-membered monocyclic aromatic heterocycle,
more preferably pyridine, furan, isoxazole) (preferably a
C.sub.6-10 aromatic hydrocarbon ring (preferably benzene,
naphthalene), a C.sub.3-6 cycloalkane (preferably cyclohexane) or a
5- or 6-membered monocyclic aromatic heterocycle (preferably
pyridine, furan, isoxazole)), each of which is optionally further
substituted by 1 to 3 (preferably 1 or 2) substituents selected
from the group consisting of [0397] (1) a halogen atom (e.g., a
fluorine atom, a chlorine atom), [0398] (2) an optionally
halogenated C.sub.1-6 alkyl group (e.g., methyl, trifluoromethyl),
[0399] (3) a C.sub.1-6 alkoxy group (e.g., methoxy), and [0400] (4)
a C.sub.6-14 aryl group (e.g., phenyl), and
[0401] W is
(1) a C.sub.1-4 alkylene group (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--) optionally substituted by an oxo group, or
(2) --(CH.sub.2).sub.m1--O-- wherein m1 is an integer of 0 to 3
(e.g., --CH.sub.2CH.sub.2O--).
[0402] [Compound D-2]
[0403] Compound (I) wherein
[0404] G.sup.1 is a carbon atom,
[0405] G.sup.2 is a carbon atom or a nitrogen atom,
[0406] Ring A is
(1) pyridine optionally further substituted by 1 to 2 substituents
selected from the group consisting of [0407] (a) a halogen atom
(e.g., a chlorine atom), [0408] (b) a C.sub.1-6 alkyl group (e.g.,
methyl), and [0409] (c) a C.sub.3-10 cycloalkyl group (e.g.,
cyclopropyl), or (2) pyrimidine,
[0410] G.sup.3 is an oxygen atom, NR.sup.1 wherein R.sup.1 is a
C.sub.1-6 alkyl group (e.g., methyl), methylene or a sulfur
atom,
[0411] X is ethylene optionally substituted by an oxo group,
[0412] R.sup.2 is a hydrogen atom or a C.sub.1-6 alkyl group (e.g.,
methyl), and R.sup.3 is a hydrogen atom, or R.sup.2 and R.sup.3 are
joined together to form a C.sub.3-10 cycloalkane (preferably a
C.sub.3-6 cycloalkane (e.g., cyclopropane)),
[0413] R.sup.4 is a hydrogen atom,
[0414] Ring B is
(1) a C.sub.6-10 aromatic hydrocarbon ring (preferably benzene)
optionally further substituted by 1 to 3 (preferably one)
substituents selected from the group consisting of [0415] (a) a
carboxy group, [0416] (b) a C.sub.1-6 alkoxy-carbonyl group (e.g.,
methoxycarbonyl), [0417] (c) a cyano group, [0418] (d) a carbamoyl
group, [0419] (e) a mono- or di-C.sub.1-6 alkyl-carbamoyl group
(e.g., methylcarbamoyl), [0420] (f) a mono- or di-C.sub.1-6
alkoxy-carbamoyl group (e.g., methoxycarbamoyl, ethoxycarbamoyl),
[0421] (g) a mono- or di-C.sub.7-16 aralkyloxy-carbamoyl group
(e.g., benzyloxycarbamoyl), [0422] (h) 5-tetrazolyl, and [0423] (i)
a C.sub.1-6 alkoxy group (e.g., methoxy) [preferably optionally
further substituted by 1 to 3 (preferably one) carboxy groups], (2)
a C.sub.3-6 cycloalkane (preferably cyclohexane), or (3) a 5- or
6-membered monocyclic aromatic heterocycle (preferably pyridine)
optionally further substituted by 1 to 3 (preferably one) C.sub.1-6
alkyl groups (e.g., methyl),
[0424] Ring C is benzene, naphthalene, cyclohexane, pyridine, furan
or isoxazole, each of which is optionally further substituted by 1
to 3 (preferably 1 or 2) substituents selected from the group
consisting of [0425] (1) a halogen atom (e.g., a fluorine atom, a
chlorine atom), [0426] (2) an optionally halogenated C.sub.1-6
alkyl group (e.g., methyl, trifluoromethyl), [0427] (3) a C.sub.1-6
alkoxy group (e.g., methoxy), and [0428] (4) a C.sub.6-14 aryl
group (e.g., phenyl), and
[0429] W is --CH.sub.2--, --(CH.sub.2).sub.2--,
--CH.sub.2CH.sub.2O-- (wherein the left bond is bonded to the
nitrogen atom, and the right bond is bonded to Ring C) or
--C(.dbd.O)--.
[0430] [Compound E-2]
[0431] Compound (I) wherein
[0432] G.sup.1 is a carbon atom,
[0433] G.sup.2 is a carbon atom,
[0434] Ring A is pyridine,
[0435] G.sup.3 is an oxygen atom,
[0436] X is ethylene,
[0437] R.sup.2 is a C.sub.1-6 alkyl group (e.g., methyl), and
R.sup.3 is a hydrogen atom, or R.sup.2 and R.sup.3 are joined
together to form a C.sub.3-6 cycloalkane (e.g., cyclopropane),
[0438] R.sup.4 is a hydrogen atom,
[0439] Ring B is benzene further substituted by one carboxy
group,
[0440] Ring C is benzene further substituted by 1 or 2 substituents
selected from the group consisting of [0441] (1) a halogen atom
(e.g., a fluorine atom, a chlorine atom), and [0442] (2) a
C.sub.1-6 alkoxy group (e.g., methoxy), and
[0443] W is --CH.sub.2--.
[0444] [Compound F-2]
[0445] Compound (I) wherein
[0446] G.sup.1 is a carbon atom,
[0447] G.sup.2 is a carbon atom,
[0448] Ring A is pyridine,
[0449] G.sup.3 is an oxygen atom,
[0450] X is ethylene,
[0451] R.sup.2 is a C.sub.1-6 alkyl group (e.g., methyl), and
R.sup.3 is a hydrogen atom, or R.sup.2 and R.sup.3 are joined
together to form a C.sub.3-6 cycloalkane (e.g., cyclopropane),
[0452] R.sup.4 is a hydrogen atom,
[0453] Ring B is benzene further substituted by one carboxy
group,
[0454] Ring C is benzene further substituted by 1 to 2 halogen
atoms (e.g., a fluorine atom, a chlorine atom), and
[0455] W is --CH.sub.2--.
[0456] When compound (I) is in a form of a salt, examples thereof
include metal salts, an ammonium salt, salts with organic base,
salts with inorganic acid, salts with organic acid, salts with
basic or acidic amino acid, and the like. Preferable examples of
the metal salt include alkali metal salts such as sodium salt,
potassium salt and the like; alkaline earth metal salts such as
calcium salt, magnesium salt, barium salt and the like; an aluminum
salt, and the like. Preferable examples of the salt with organic
base include salts with trimethylamine, triethylamine, pyridine,
picoline, 2,6-lutidine, ethanolamine, diethanolamine,
triethanolamine, cyclohexylamine, dicyclohexylamine,
N,N'-dibenzylethylenediamine and the like. Preferable examples of
the salt with inorganic acid include salts with hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and
the like. Preferable examples of the salt with organic acid include
salts with formic acid, acetic acid, trifluoroacetic acid, phthalic
acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric
acid, succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid and the like.
Preferable examples of the salt with basic amino acid include salts
with arginine, lysine, ornithine and the like. Preferable examples
of the salt with acidic amino acid include salts with aspartic
acid, glutamic acid and the like.
[0457] Among them, a pharmaceutically acceptable salt is
preferable. For example, when a compound has an acidic functional
group, examples thereof include inorganic salts such as alkali
metal salts (e.g., sodium salt, potassium salt etc.), alkaline
earth metal salts (e.g., calcium salt, magnesium salt etc.) and the
like, ammonium salt etc., and when a compound has a basic
functional group, examples thereof include salts with inorganic
acid such as hydrochloric acid, hydrobromic acid, nitric acid,
sulfuric acid, phosphoric acid and the like, and salts with organic
acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid,
tartaric acid, maleic acid, citric acid, succinic acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
and the like.
[0458] Compound (I) may be prepared by any process known to be
applicable to the preparation of chemically-related compounds. Such
processes are provided as one embodiment of the invention, and are
illustrated by the following representative process. Necessary
starting materials may be obtained by standard procedure of organic
chemistry. The preparation of such starting materials is described
in conjunction with the following representative process and within
the following examples. Alternatively, necessary starting materials
are obtained by a method known per se or a method analogous
thereto.
[0459] The starting material and/or the production intermediate for
the compound (I) may form a salt. While the salt is not
particularly limited as long as the reaction can be performed,
examples thereof include those similar to the salts of compound (I)
and the like.
[0460] When the starting material has an amino group, a carboxyl
group, a hydroxy group or a heterocyclic group, these groups may be
protected by a protecting group generally used in peptide chemistry
and the like. By removing the protecting group as necessary after
the reaction, the objective compound can be obtained. The
protection and deprotection can be performed according to a method
known per se, for example, the method described in "Protective
Groups in Organic Synthesis, 3rd Ed", John Wiley and Sons, Inc.
(1999) (Theodora W. Greene, Peter G. M. Wuts). Preferable examples
of the protecting group include a tert-butylcarbamate group, a
benzylcarbamate group, a benzyl group, a methyl group, an ethyl
group, a tert-butyl and the like.
[0461] The compound obtained in each step can be used directly as
the reaction mixture or as a crude product for the next reaction.
It can also be isolated from a reaction mixture by a conventional
method, and can be easily purified by a separation means such as
recrystallization, distillation, chromatography and the like. When
the compound in the formula is commercially available, a
commercially available product can also be used directly.
[0462] Unless otherwise specified, each symbol in the general
formulas in the schemes is as defined above.
[0463] Compound (I) is prepared as outlined in Schemes below:
##STR00008##
[0464] As shown in Scheme 1, compound (I) may be prepared by
reacting compound (II) with compound (III) wherein W is as defined
above, and Y is a leaving group such as a halogen atom, a C.sub.1-6
alkylsulfonyl group or a C.sub.6-14 arylsulfonyl group, or Y/WY may
be a formyl group (reductive alkylation/amination), or Y may be a
hydroxy group (cross coupling reaction), or WY may be a halogen
atom or a triflate (Ullman or Buchwald coupling) or a boronic acid
or a boronate ester (Chan-Evans-Lam coupling). The functional group
in compound (II) or (III) may be protected if necessary, and after
the N-alkylation reaction or N-arylation reaction, it can be
removed by a conventional means. Compound (I) having an ester
moiety may be further hydrolyzed to obtain the corresponding
carboxylic acid or its salt, which may be further derivatized.
Compound (I) may be further derivatized by introducing
substituent(s) according known methods reported in literature.
Compound (III) may be a commercially available product, or can also
be prepared according to a method known per se or a method
analogous thereto.
##STR00009##
[0465] As shown in Scheme 2, compound (I) may be prepared by
coupling compound (II) with compound (III) wherein WY is --C(O)OH
or --S(O).sub.2OH, or a reactive derivative thereof such as an acid
halide (e.g., an acid chloride, an acid bromide, sulfonyl chloride)
or a mixed anhydride (e.g., a mixed anhydride with a
chloroformate). The functional group in compound (II) or (III) may
be protected if necessary, and after the amide/sulfonamide coupling
reaction, it can be removed by a conventional means. Compound (I)
having an ester moiety may be further hydrolyzed to obtain the
corresponding carboxylic acid or its salt, which may be further
derivatized.
##STR00010##
[0466] As shown in Scheme 3, compound (I) may be prepared by
coupling compound (II) with compound (III) wherein WY is --NC(O),
or with compound (III) wherein WY is NH.sub.2 and reagents such as
carbonylimidazolide (CDI), or with compound (III) wherein WY is a
C.sub.1-6 alkoxy-carbonylamino group. The functional group in
compound (II) or (III) may be protected if necessary, and after the
synthesis of urea derivative, it can be removed by a conventional
means. Compound (I) having an ester moiety may be further
hydrolyzed to obtain the corresponding carboxylic acid or its salt,
which may be further derivatized.
##STR00011##
[0467] As shown in Scheme 4, compound (I) may be prepared by
reacting compound (IV) wherein L is a leaving group such as a
halogen atom, a C.sub.1-6 alkoxy group, a C.sub.6-14 aryloxy group,
a sulfanyl group, a C.sub.1-6 alkylthio group, a C.sub.6-14
arylthio group, a C.sub.1-6 alkylsulfinyl group, a C.sub.6-14
arylsulfinyl group, a C.sub.1-6 alkylsulfonyl group, a C.sub.6-14
arylsulfonyl group and a boronic acid group, with compound (V)
(N-arylation reaction). Functional groups in compound (IV) or (V)
may be protected if necessary, and after the N-arylation reaction,
it can be removed by conventional means. Compound (I) having an
ester moiety may be further hydrolyzed to obtain the corresponding
carboxylic acid, which may be further derivatized.
##STR00012##
[0468] As shown in Scheme 5, compound (Ib) may be prepared by
carbonylation of compound (Ia) wherein R.sup.5 is a halogen atom,
preferably a bromine atom. The functional group in compound (Ia)
may be protected if necessary, and after the carbonylation, it can
be removed by a conventional means. Compound (Ia) may be prepared
according to the method Schemes 1 to 4 wherein ring B is
substituted by R.sup.5. Alternatively, compound (Ib) may also be
prepared according to the method Schemes 1 to 4 wherein ring B is
substituted by a group of the formula:
--(CR.sup.7R.sup.8).sub.nC(O) OR.sup.6.
##STR00013##
[0469] As shown in Scheme 6, compound (Ic) may be prepared by ester
hydrolysis of compound (Ib) by a conventional means.
##STR00014##
[0470] As shown in Scheme 7, compound (Id) may be prepared by amide
coupling of compound (Ic) with the corresponding amine or amine
derivative.
##STR00015##
[0471] As shown in Scheme 8, compound (Ie) may be prepared from
compound (Ia) wherein Ring B is further substituted by a cyano
group, by conversion of the cyano group to a 5-tetrazolyl group by
a conventional means (Tetrazole formation).
##STR00016##
[0472] As shown in Scheme 9, compound (II) may be prepared by
reacting compound (VI) with compound (VII), wherein L.sub.1 and
L.sub.2 are each independently a leaving group, preferably a
bromine atom. The functional group in compound (VI) may be
protected if necessary, and after the cyclization it can be removed
by a conventional means.
##STR00017##
[0473] As shown in Scheme 10, compound (VI) may be prepared by
reacting compound (VIII) wherein L is as defined above, with
compound (V) (N-arylation reaction), and subjecting the resulting
compound (IX) to reduction.
##STR00018##
[0474] As shown in Scheme 11, compound (II) may be prepared by
reduction of compound (X). The functional group in compound (X) may
be protected if necessary, and after the reduction it can be
removed by a conventional means.
##STR00019##
[0475] As shown in Scheme 12, compound (IV) may be prepared by
reacting compound (XI) with compound (III) wherein W is as defined
above, and Y is a leaving group such as a halogen atom, a C.sub.1-6
alkylsulfonyl group or a C.sub.6-14 arylsulfonyl group, or Y/WY may
be a formyl group (reductive alkylation/amination), or Y may be a
hydroxy group (cross coupling reaction), or WY may be a halogen
atom or a triflate (Ullman or Buchwald coupling) or a boronic acid
or a boronate ester (Chan-Evans-Lam coupling), or WY is --C(O)OH or
--S(O).sub.2OH, or a reactive derivative thereof such as an acid
halide (e.g., an acid chloride, an acid bromide, and sulfonyl
chloride) or a mixed anhydride (e.g., a mixed anhydride with a
chloroformate), or WY is --NC(O), NH.sub.2 or a C.sub.1-6
alkoxy-carbonylamino group. The functional group in compound (XI)
or (III) may be protected if necessary, and after the synthesis of
compound (IV), it can be removed by a conventional means.
##STR00020##
[0476] As shown in scheme 13, compound (XI) may be prepared by
reduction of compound (VIII) wherein L is as defined above to
obtain compound (XII), and subjecting the resulting compound (XII)
to cyclization with compound (VII).
[0477] N-Alkylation:
[0478] Alkyl compounds having a suitable leaving group such as a
halogen atom, a C.sub.1-6 alkylsulfonyl group and a C.sub.6-14
arylsulfonyl group may be reacted with an amine. The reaction may
be carried out in the absence or presence of a base, in an
appropriate solvent or without solvent.
[0479] Preferred base is selected from organic non-nucleophilic
bases such as triethylamine, diisopropylethylamine (Hunig's base),
pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyrimidine,
N-methylpyrrolidine and diazabicyclo[5.4.0]undec-7ene (DBU); alkali
or alkaline earth metal carbonates such as sodium carbonate and
potassium carbonate; alkali metal hydrides such as sodium hydride;
and phosphazene bases such as
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine (BEMP). Preferred examples of the solvent inert to the reaction
include polar solvents such as acetonitrile, alcohols (e.g.,
methanol, ethanol, propanol, n-butanol etc.), chlorinated solvents
(e.g., chloroform, dichloromethane, 1,2-dichloroethane etc.),
ethers (e.g., tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane
(DME) etc.) and amides (e.g., N,N-dimethylformamide (DMF),
[0480] N,N-dimethylacetamide (DMA), N-methylpyrrolidine (NMP)
etc.), and non-polar solvents (e.g., toluene etc.), along with a
phase transfer catalyst. Additionally, the N-alkylation may be
carried out in presence of an ionic liquid such as
1-butyl-3-methylimidazolium tetrafluorophosphate [Bmim(PF4)],
1-butyl-3-methylimidazolium hexafluorophosphate [Bmim(PF6)] and
tetrabutylammonium chloride [TBAC]. The ionic liquid may be used as
a reaction solvent, or it may be used as an additive when the
N-alkylation is carried out in the above-mentioned solvent. In
addition, microwave irradiation may be employed to enhance the rate
of the N-alkylation.
[0481] Alternatively, N-alkylation may be carried out by cross
coupling of an appropriate amine and alcohol under Mitsunobu
reaction condition using a phosphine (e.g., triarylphosphine,
tricycloalkylphosphine etc.) and a dialkyl azodicarboxylate (e.g.,
diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate
(DIAD) etc.). The cross coupling is carried out in an appropriate
solvent such as THF and dioxane at 0 to 40.degree. C. to reflux
temperature.
[0482] Alternatively, N-alkylation may be carried out by using
reductive amination (reductive alkylation) using an appropriate
amine, aldehyde and reducing agent (e.g., sodium borohydride,
sodium cyanoborohydride (NaBH.sub.3CN), sodium
triacetoxyborohydride (NaBH(OCOCH.sub.3).sub.3) etc.). The
preferred solvents for this reaction are toluene, 1,4-dioxane,
chlorinated solvents such as dichloromethane, 1,2-dichloroethane
etc.
[0483] N-Arylation:
[0484] Aromatic compounds having a suitable leaving group such as a
halogen atom, a C.sub.1-6 alkoxy group, a C.sub.6-14 aryloxy group,
a sulfanyl group, a C.sub.1-6 alkylthio group, a C.sub.6-14
arylthio group, a C.sub.1-6 alkylsulfinyl group, a C.sub.6-14
arylsulfinyl group, a C.sub.1-6 alkylsulfonyl group, a C.sub.6-14
arylsulfonyl group and a boronic acid group, may be reacted with a
primary or secondary amine. The reaction may be carried in presence
of a metal catalyst such as copper, palladium, iron and rhodium,
and a ligand such as diamines, amino acids, xanthphos. The reaction
may be carried out in the absence or presence of a base, in an
appropriate solvent or without solvent.
[0485] Preferred base is selected from organic non-nucleophilic
bases such as triethylamine, diisopropylethylamine (Hunig's base),
pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyrimidine,
N-methylpyrrolidine and diazabicyclo[5.4.0]undec-7ene (DBU); alkali
or alkaline earth metal carbonates such as sodium carbonate and
potassium carbonate; alkali metal hydrides such as sodium hydride;
and phosphazene bases such as
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine (BEMP). Preferred polar solvent inert to the reaction includes
alcohols (e.g., methanol, ethanol, propanol, n-butanol etc.),
ethers (e.g., tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane
(DME) etc.), and amides (e.g., N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA), N-methylpyrrolidine (NMP) etc.).
Alternatively, the reaction may be carried out in a melt without
addition of a solvent. The reaction is carried out at elevated
temperatures, preferably from approximately 60.degree. C. to reflux
temperature. When WY or L is a boronic acid group, the reaction may
be carried out in the presence of a suitable catalyst.
[0486] Amide Coupling:
[0487] Condition-I:
[0488] Amide coupling may be carried out using any suitable amide
coupling reagents such as oxalyl chloride, thionyl chloride,
BOP-Cl, DCC, HOBt, HOAt, HATU, EDCI, propylphosphonic anhydride
(T3P), alkyl chloroformate and the like. Preferred base is selected
from organic non-nucleophillic bases such as triethylamine,
diisopropylethyl amine, pyridine, N-methylpyrrolidine,
N,N-dimethylaminopyridine, DBU, other hindered amines and
pyridines. The amide coupling may be carried out in the presence of
a solvent such as dichloromethane, dichloroethane, DMF,
N,N-dimethylacetamide, THF, acetonitrile and mixtures thereof. The
reaction may be carried out at a temperature ranging from
-20.degree. C. to 150.degree. C., preferably from about 0.degree.
C. to 100.degree. C. The reaction may be carried out optionally in
presence of a catalytic amount of DMF.
[0489] Condition-II:
[0490] When R.sup.6 is not H, amide coupling may be carried out by
heating ester and amine either in the absence of a solvent or in
presence of a high boiling solvent such as toluene, xylene and
DMSO. The amide coupling may be carried out in presence of a
trialkyl aluminium (Chem. Commun., 2008, 1100-1102).
[0491] Sulfonamide Coupling:
[0492] Sulfonamide may be prepared by reacting an appropriate amine
with an appropriate sulfonyl halide in the presence of a base such
as organic non-nucleophillic bases (e.g., triethylamine,
diisopropylethylamine, N-methylpyrrolidine,
N,N-dimethylaminopyridine, DBU etc.), other hindered amines and
pyridines. The sulfonamide coupling may be carried out in the
presence of a solvent such as dichloromethane, dichloroethane, THF,
1,4-dioxane, acetonitrile, N,N-dimethylformamide (DMF) and mixtures
thereof.
[0493] Synthesis of Urea Derivatives:
[0494] Urea derivatives (unsymmetrical) may be prepared by reacting
amine with an appropriate coupling regent such as alkyl
chloroformate, CDI, triphosgene, S,S-dimethyl dithiocarbonate
(DMDTC), carbonylimidazolide, phenyl
4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate etc. Then the
intermediate may be coupled with different amine (e.g., substituted
aniline, substituted alkylamine, substituted cycloalkylamine
etc.).
[0495] Alternatively, urea formation may be carried out using any
suitable coupling regent (e.g., substituted alkoxycarbonylamino
group, substituted isocyanate etc.). The reaction may be carried
out in the absence or presence of a base. Preferred base is
selected from organic non-nucleophillic bases (e.g., triethylamine,
diisopropylethylamine, pyridine, N-methylpyrrolidine,
N,N-dimethylaminopyridine, DBU etc.). The urea formation may be
carried out in the presence of a solvent such as chlorobenzene,
dichloromethane, dichloroethane, DMF, N,N-dimethylacetamide, THF,
acetonitrile, water and mixtures thereof. The urea formation may be
carried out at a temperature ranging from-.degree. C. to
150.degree. C., preferably from about 0.degree. C. to 100.degree.
C. The urea formation may be carried out optionally in presence of
a catalytic amount of N,N-dimethylformamide (DMF).
[0496] Carbonylation Reaction:
[0497] Carbonylation reaction may be carried out by reacting an
aryl halide with carbon monoxide in presence of a catalyst and/or a
base in an inert solvent. Examples of the suitable catalyst include
palladium reagents such as palladium acetate and palladium
dibenzylacetone; and nickel catalysts. Preferred base is selected
from N,N-diisopropylethylamine, N-methylmorpholine, triethylamine
etc. If required, this reaction may be carried out in the presence
or absence of an additive such as
1,1'-bis(diphenylphosphino)ferrocene, triphenylphosphine and
1,3-bis-(diphenylphosphine)propane. The reaction may be carried out
in a suitable solvent such as acetone, nitromethane, DMF, DMSO,
NMP, acetonitrile, DCM, EDC, THF, methanol, ethanol and
1,4-dioxane. While the reaction temperature varies depending on the
kind of the solvent and reagent used for the reaction, it is
generally -20.degree. C. to 150.degree. C., preferably 50.degree.
C. to 80.degree. C.
[0498] Ester Hydrolysis:
[0499] Ester hydrolysis may be carried out under general
saponification conditions employing an inorganic base such as
alkali and alkaline earth metal hydroxides, carbonates and
bicarbonates (e.g., lithium hydroxide, sodium hydroxide, potassium
hydroxide, sodium hydride, sodium carbonate, potassium carbonate,
cesium carbonate etc.) in the presence of a solvent such as water,
methanol, ethanol, diethyl ether, THF, DME, DMF, DMSO and mixtures
thereof. These reactions may be carried out at 0.degree. C. to
refluxing temperature.
[0500] Alternatively, ester hydrolysis may be carried out under
acidic condition, for example, in presence of a hydrogen halide
(e.g., hydrochloric acid, hydrobromic acid etc.), a sulfonic acid
(e.g., sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid,
pyridium p-toluenesulfonate etc.) or a carboxylic acid (e.g.,
acetic acid, trifluoroacetic acid etc.). The suitable solvent
includes alcohols (e.g., methanol, ethanol, propanol, butanol,
2-methoxyethanol, ethylene glycol etc.); ethers (e.g., diethyl
ether, THF, 1,4-dioxane, DME etc.); halogenated solvents (e.g.,
DCM, EDC, chloroform etc.); hexamethylphophoramide and DMSO. The
reaction may be carried out at temperature in the range from
-20.degree. C. to 100.degree. C., preferably from 20.degree. C. to
35.degree. C.
[0501] Tetrazole Formation:
[0502] Aryl tetrazole (5H-substituted tetrazole) may be prepared by
converting a cyano group into a tetrazole group in absence or
presence of an inert solvent such as acetone, DMF, DMSO, NMP and
water. Suitable tetrazole forming reagent includes sodium azide,
lithium azide, trialkyltin azide and trimethylsilylazide. This
reaction may be carried out in presence or absence of a catalyst
such as dialkyltin oxide (alkyl is methyl or butyl), alkylamino
hydrochloride or hydrobromide, lithium chloride and copper
sulphate. The reaction may be carried out in the presence or
absence of an acid or a base. Examples of the suitable base include
trimethylamine, triethylamine and N,N-diisopropylethylamine, and
examples of the suitable acid include ammonium chloride, hydrogen
chloride, aluminium chloride and zinc bromide. The reaction may be
carried out at temperature 50.degree. C. to 200.degree. C.
[0503] Cyclization for formation of a fused ring containing Ring
A:
[0504] Cyclization reaction is used for formation of a fused ring
containing Ring A. The fused ring may be prepared by reacting
appropriately substituted pyridine ring with 1,2-dibromoethane,
1-bromo-2-chloroethane, 2-chloroacetyl chloride, sulfonium
(2-bromoethyl)diphenyl salt with trifluoromethanesulfonic acid,
2-bromoacetyl chloride, 2-bromoacetyl bromide and
1-bromo-2,2-diethoxyethane, 2-bromoethanol, 2-bromoethyl
methanesulfonate and 2-bromoethyl 4-methylbenzenesulfonate.
[0505] Alternatively, the fused ring may be prepared by reacting
appropriately substituted pyridine ring with ethyl bromoacetate,
followed by ester hydrolysis and cyclization. If required, the
product obtained after cyclization may be further subjected to a
reaction such as reduction with preferred reducing agent such as
lithium aluminium hydride, borane and THF. The cyclization reaction
may be carried out in the absence or presence of a base and in an
appropriate solvent.
[0506] A preferred base is selected from organic non-nucleophilic
bases such as triethylamine, N,N-diisopropylethylamine (Hunig's
base), pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyrimidine, N-methylpyrrolidine and
diazabicyclo[5.4.0]undec-7ene (DBU); alkali or alkaline earth metal
carbonates such as sodium carbonate, potassium carbonate, sodium
bicarbonate, cesium carbonate, potassium acetate and potassium
fluoride; alkali metal hydrides such as sodium hydride, and
phosphazene bases such as
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine (BEMP). The preferred polar solvent inert to the reaction
includes alcohols (e.g., methanol, ethanol, propanol, tert-butanol
and n-butanol) or ethers (e.g., tetrahydrofuran (THF), 1,4-dioxane,
dimethoxyethane (DME)), dimethylformamide (DMF), dimethylacetamide
(DMA), N-methylpyrrolidine (NMP), dimethyl sulfoxide (DMSO), water,
acetonitrile, acetone and 1,2-dichloroethane. The reaction may be
carried out at elevated temperatures, preferably from approximately
30.degree. C. to 150.degree. C. or at reflux temperature of
solvent.
[0507] Reduction:
[0508] Reduction may be carried out using any suitable catalyst
such as Pd/C, Pd(OH).sub.2, platinum(IV) oxide(PtO.sub.2), Raney
nickel in presence of hydrogen atmosphere. Alternatively, reduction
may be carried out using any suitable reducing reagent such as
lithium aluminium hydride, sodium dithionite, iron in acetic acid,
stannous chloride, samarium dichloride, tin(II) chloride, titanium
(III) chloride, zinc/acetic acid etc. The reaction may be carried
out in the presence of a solvent such as methanol, ethanol, ethyl
acetate, acetic acid, HCl, THF, acetone, dichloromethane,
dichloroethane, acetonitrile and mixtures thereof. The reaction may
be carried out at a temperature ranging from -20.degree. C. to
150.degree. C., preferably from about 0.degree. C. to 100.degree.
C. The Reduction may be carried out optionally in presence of a
catalytic amount of acid and/or base.
[0509] Compound (I) contains a stereoisomer depending to the kind
of a substituent, and each stereoisomer and a mixture thereof are
encompassed in the present invention.
[0510] Compound (I) may be a hydrate or a non-hydrate.
[0511] When desired, compound (I) can be synthesized by performing
deprotection reaction, acylation reaction, alkylation reaction,
hydrogenation reaction, oxidation reaction, reduction reaction,
reaction of carbon chain extension, substituent exchange reaction
singly or two or more thereof in combination.
[0512] When the objective product is obtained as a free form by the
above-mentioned reaction, it can be converted to a salt according
to a conventional method, or when the objective product is obtained
as a salt, it can be converted to a free form or other salt
according to a conventional method. The thus-obtained compound (I)
can also be isolated and purified from a reaction mixture according
to a known method such as phase transfer, concentration, solvent
extraction, distillation, crystallization, recrystallization,
chromatography and the like.
[0513] When compound (I) contains a configurational isomer, a
diastereomer, a conformer and the like, each can be isolated
according to the above-mentioned separation and purification
methods, if desired. In addition, when compound (I) is racemic,
d-form and 1-form can be isolated according to a conventional
optical resolution.
[0514] In each of the above-mentioned reactions, when the compound
has a functional group such as an amino group, a hydroxy group or a
carboxyl group, the reaction can be carried out after a protecting
group generally used in peptide chemistry and the like is
introduced into these groups. By removing the protecting group as
necessary after the reaction, the objective compound can be
obtained.
[0515] Examples of the protecting group include formyl, C.sub.1-6
alkyl-carbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl,
C.sub.1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl
etc.), phenyloxycarbonyl, C.sub.7-10 aralkyloxy-carbonyl (e.g.,
benzyloxycarbonyl etc.), trityl, phthaloyl and the like, each of
which is optionally substituted. Examples of the substituent
include a halogen atom (e.g., fluorine, chlorine, bromine, iodine
etc.), C.sub.1-6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl
etc.), nitro and the like. The number of substituents is, for
example, 1 to 3.
[0516] The removal method of the protecting group can be carried
out according to a method known per se, and for example, a method
using acid, base, ultraviolet rays, hydrazine, phenylhydrazine,
sodium N-methyldithiocarbamate, tetrabutylammonium fluoride,
palladium acetate and the like, a reduction method, and the like
can be employed.
[0517] The thus-obtained compound (I), other reaction intermediate
therefor and starting materials thereof can be isolated and
purified from a reaction mixture according to a method known per
se, for example, extraction, concentration, neutralization,
filtration, distillation, recrystallization, column chromatography,
thin layer chromatography, preparative high performance liquid
chromatography (preparative HPLC), moderate-pressure preparative
liquid chromatography (moderate-pressure preparative LC) and the
like.
[0518] A salt of compound (I) can be produced according to a method
known per se. For example, when compound (I) is a basic compound,
it can be produced by adding an inorganic acid or organic acid, or
when compound (I) is an acidic compound, by adding an organic base
or inorganic base.
[0519] When compound (I) contains an optical isomer, each optical
isomer and a mixture thereof are encompassed in the scope of the
present invention, and these isomers can be subjected to optical
resolution or can be produced respectively, according to a method
known per se, if desired.
[0520] When compound (I) contains a configurational isomer, a
diastereomer, a conformer and the like, each can be isolated
according to the above-mentioned separation and purification
methods, if desired. In addition, when compound (I) is racemic,
S-form and R-form can be isolated according to a conventional
optical resolution.
[0521] When compound (I) contains a stereoisomer, each isomer and a
mixture thereof are encompassed in the present invention.
[0522] Compound (I) may be a prodrug, and the prodrug of compound
(I) refers to a compound which is converted to compound (I) as a
result of a reaction with an enzyme, gastric acid, etc. under
physiological conditions in vivo, thus a compound that undergoes
enzymatic oxidation, reduction, hydrolysis etc. to convert to
compound (I) and a compound that undergoes hydrolysis and the like
by gastric acid, etc. to convert to compound (I).
[0523] Examples of the prodrug for compound (I) include
(1) a compound obtained by subjecting an amino group in compound
(I) to acylation, alkylation or phosphorylation (e.g., a compound
obtained by subjecting an amino group in compound (I) to
eicosanoylation, alanylation, pentylaminocarbonylation,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,
tetrahydrofurylation, pyrrolidylmethylation,
pivaloyloxymethylation, tert-butylation, ethoxycarbonylation,
tert-butoxycarbonylation, acetylation, cyclopropylcarbonylation and
the like); (2) a compound obtained by subjecting a hydroxy group in
compound (I) to acylation, alkylation, phosphorylation or boration
(e.g., a compound obtained by subjecting a hydroxy group in
compound (I) to acetylation, palmitoylation, propanoylation,
pivaloylation, succinylation, fumarylation, alanylation or
dimethylaminomethylcarbonylation and the like); (3) a compound
obtained by subjecting a carboxyl group in compound (I) to
esterification or amidation (e.g., a compound obtained by
subjecting a carboxyl group in compound (I) to ethyl
esterification, phenyl esterification, carboxymethyl
esterification, dimethylaminomethyl esterification,
pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl
esterification, phthalidyl esterification,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,
cyclohexyloxycarbonylethyl esterification or methylamidation and
the like) and the like. Any of these compounds can be produced from
compound (I) according to a method known per se.
[0524] A prodrug of compound (I) may also be one which is converted
to compound (I) under physiological conditions as described in
"IYAKUHIN no KAIHATSU (Development of Pharmaceuticals)", Vol. 7,
Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN
(1990).
[0525] In the present specification, compound (I) and a prodrug
thereof are sometimes collectively abbreviated as "the compound of
the present invention".
[0526] When compound (I) has isomers such as optical isomer,
stereoisomer, positional isomer, rotamer and the like, such isomers
and a mixture thereof are also encompassed in compound (I). For
example, when compound (I) has optical isomers, an optical isomer
resolved from this compound is also encompassed in compound (I).
These isomers can be obtained as a single product according to
synthesis methods or separation methods known per se (e.g.,
concentration, solvent extraction, column chromatography,
recrystallization, etc.).
[0527] Compound (I) may be a crystal, and a single crystal form and
a mixture of crystal forms are both encompassed in compound (I).
The crystal can be produced by crystallizing according to a
crystallization method known per se.
[0528] Compound (I) may be a hydrate, a non-hydrate, a solvate or a
non-solvate.
[0529] Compound (I) may be labeled with an isotope (e.g., .sup.3H,
.sup.11C, .sup.14C, .sup.18F, .sup.35S, .sup.125I etc.) and the
like.
[0530] Compound (I) also encompasses a deuterium conversion form
wherein .sup.1H is converted to .sup.2H(D).
[0531] Compound (I) may be a pharmaceutically acceptable cocrystal
or a salt thereof. The cocrystal or a salt thereof means a
crystalline substance constituted with two or more special solids
at room temperature, each having different physical properties
(e.g., structure, melting point, melting heat, hygroscopicity,
solubility and stability etc.). The cocrystal or a salt thereof can
be produced according to a cocrystallization a method known per
se.
[0532] Compound (I) may also be used as a PET tracer.
[0533] The compound of the present invention has low toxicity, and
may be used as it is or in the form of a pharmaceutical composition
by mixing with a pharmacologically acceptable carrier etc. to
mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse,
swine, monkey) as an agent for the prophylaxis or treatment of
various diseases mentioned below.
[0534] As pharmacologically acceptable carriers, various organic or
inorganic carrier substances conventionally used as preparation
materials can be used. These are incorporated as excipient,
lubricant, binder and disintegrant for solid preparations, or
solvent, solubilizing agent, suspending agent, isotonicity agent,
buffer and soothing agent for liquid preparations, and the like,
and preparation additives such as preservative, antioxidant,
colorant, sweetening agent and the like can be added as
necessary.
[0535] Preferable examples of the excipient include lactose,
sucrose, D-mannitol, D-sorbitol, starch, gelatinated starch,
dextrin, crystalline cellulose, low-substituted
hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic,
pullulan, light anhydrous silicic acid, synthesis aluminum silicate
and magnesium alumino metasilicate.
[0536] Preferable examples of the lubricant include magnesium
stearate, calcium stearate, talc and colloidal silica.
[0537] Preferable examples of the binder include gelatinated
starch, sucrose, gelatin, gum arabic, methylcellulose,
carboxymethylcellulose, sodium carboxymethylcellulose, crystalline
cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan,
hydroxypropylcellulose, hydroxypropylmethylcellulose and
polyvinylpyrrolidone.
[0538] Preferable examples of the disintegrant include lactose,
sucrose, starch, carboxymethylcellulose, calcium
carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl
starch, light anhydrous silicic acid and low-substituted
hydroxypropylcellulose.
[0539] Preferable examples of the solvent include water for
injection, physiological brine, Ringer's solution, alcohol,
propylene glycol, polyethylene glycol, sesame oil, corn oil, olive
oil and cottonseed oil.
[0540] Preferable examples of the solubilizing agents include
polyethylene glycol, propylene glycol, D-mannitol, trehalose,
benzyl benzoate, ethanol, trisaminomethane, cholesterol,
triethanolamine, sodium carbonate, sodium citrate, sodium
salicylate and sodium acetate.
[0541] Preferable examples of the suspending agent include
surfactants such as stearyltriethanolamine, sodium lauryl sulfate,
lauryl aminopropionate, lecithin, benzalkonium chloride,
benzethonium chloride, glycerol monostearate and the like;
hydrophilic polymers such as polyvinyl alcohol,
polyvinylpyrrolidone, sodium carboxymethylcellulose,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose and the like; polysorbates, and
polyoxyethylene hydrogenated castor oil.
[0542] Preferable examples of the isotonicity agent include sodium
chloride, glycerol, D-mannitol, D-sorbitol and glucose.
[0543] Preferable examples of the buffer include buffers such as
phosphate, acetate, carbonate, citrate and the like.
[0544] Preferable examples of the soothing agent include benzyl
alcohol.
[0545] Preferable examples of the preservative include
p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol,
dehydroacetic acid and sorbic acid.
[0546] Preferable examples of the antioxidant include sulfite and
ascorbate.
[0547] Preferable examples of the colorant include aqueous
water-soluble food tar colors (e.g., food colors such as Food
[0548] Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food
Color Blue Nos. 1 and 2 and the like), water insoluble lake dyes
(e.g., aluminum salt of the above-mentioned water-soluble food tar
color) and natural dyes (e.g., .beta.-carotene, chlorophyll, ferric
oxide red).
[0549] Preferable examples of the sweetening agent include
saccharin sodium, dipotassium glycyrrhizinate, aspartame and
stevia.
[0550] Examples of the dosage form of the pharmaceutical
composition include oral preparations such as tablet (including
sugar-coated tablet, film-coated tablet, sublingual tablet, orally
disintegrating tablet), capsules (including soft capsule,
microcapsule), granule, powder, troche, syrup, emulsion,
suspension, films (e.g., orally disintegrable films) and the like;
and parenteral agents such as injection (e.g., subcutaneous
injection, intravenous injection, intramuscular injection,
intraperitoneal injection, drip infusion), external preparations
(e.g., dermal preparation, ointment), suppository (e.g., rectal
suppository, vaginal suppository), pellet, nasal preparation,
pulmonary preparation (inhalant), eye drop and the like.
[0551] These may be respectively safely administered orally or
parenterally (e.g., topically, rectally, intravenously
administered).
[0552] These preparations may be a release control preparation
(e.g., sustained-release microcapsule) such as an immediate-release
preparation, a sustained-release preparation and the like.
[0553] The pharmaceutical composition can be produced according to
a method conventionally used in the field of pharmaceutical
formulation, for example, the method described in the Japanese
Pharmacopoeia, and the like.
[0554] While the content of the compound of the present invention
in the pharmaceutical composition may vary depending on the dosage
form, dose of the compound of the present invention and the like,
it is for example, about 0.1 to 100 wt %.
[0555] During production of an oral preparation, coating may be
applied as necessary for the purpose of masking of taste, enteric
property or durability.
[0556] Examples of the coating base to be used for coating include
sugar coating base, water-soluble film coating base, enteric film
coating base and sustained-release film coating base.
[0557] As the sugar coating base, sucrose is used. Moreover, one or
more kinds selected from talc, precipitated calcium carbonate,
gelatin, gum arabic, pullulan, carnauba wax and the like may be
used in combination.
[0558] Examples of the water-soluble film coating base include
cellulose polymers such as hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
methylhydroxyethyl cellulose etc.; synthetic polymers such as
polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate
copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone etc.;
and polysaccharides such as pullulan etc.
[0559] Examples of the enteric film coating base include cellulose
polymers such as hydroxypropylmethyl cellulose phthalate,
hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl
cellulose, cellulose acetate phthalate etc.; acrylic polymers such
as methacrylic acid copolymer L [Eudragit L (trade name)],
methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)],
methacrylic acid copolymer S [Eudragit S (trade name)] etc.; and
naturally occurring substances such as shellac etc.
[0560] Examples of the sustained-release film coating base include
cellulose polymers such as ethyl cellulose etc.; and acrylic
polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS
(trade name)], ethyl acrylate-methyl methacrylate copolymer
suspension [Eudragit NE (trade name)] etc.
[0561] The above-mentioned coating bases may be used after mixing
with two or more kinds thereof at appropriate ratios. For coating,
for example, a light shielding agent such as titanium oxide, red
ferric oxide and the like can be used.
[0562] The compound of the present invention may show low toxicity
(e.g., acute toxicity, chronic toxicity, genetic toxicity,
reproductive toxicity, cardiotoxicity, carcinogenicity) and a few
side effects. Therefore, it may be used as an agent for the
prophylaxis or treatment or a diagnostic of various diseases in a
mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse,
rat).
[0563] Since the compound of the present invention have superior
EP4 receptor antagonistic action, they may be also useful as safe
medicaments based on such action.
[0564] For example, the medicament of the present invention
containing the compound of the present invention may be used for a
mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep,
monkey, human etc.) as an agent for the prophylaxis or treatment of
EP4 receptor associated diseases, specifically, the diseases
described in (1)-(7) below.
(1) inflammatory diseases (e.g., acute pancreatitis, chronic
pancreatitis, asthma, adult respiratory distress syndrome, chronic
obstructive pulmonary disease (COPD), inflammatory bone disease,
inflammatory pulmonary disease, inflammatory bowel disease, celiac
disease, hepatitis, systemic inflammatory response syndrome (SIRS),
postoperative or posttraumatic inflammation, pneumonia, nephritis,
meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury,
meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia,
bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis
etc.), (2) autoimmune diseases (e.g., psoriasis, rheumatoid
arthritis, inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis etc.), Sjogren's syndrome, Behcet's disease,
multiple sclerosis, systemic lupus erythematosus, ankylopoietic
spondylarthritis, polymyositis, dermatomyositis (DM), polyarteritis
nodosa (PN), mixed connective tissue disease (MCTD), scleroderma,
profundus lupus erythematosus, chronic thyroiditis, Graves'
disease, autoimmune gastritis, type I and type II diabetes,
autoimmune hemolytic anemia, autoimmune neutropenia,
thrombocytopenia, atopic dermatitis, chronic active hepatitis,
myasthenia gravis, graft versus host disease, Addison's disease,
abnormal immunoresponse, arthritis, dermatitis, radiodermatitis
etc.) (especially, psoriasis, rheumatoid arthritis, inflammatory
bowel disease, Sjogren's syndrome, Behcet's disease, multiple
sclerosis and systemic lupus erythematosus), (3) osteoarticular
degenerative disease (e.g., rheumatoid arthritis, osteoporosis,
osteoarthritis etc.), (4) neoplastic diseases [e.g., malignant
tumor, angiogenesis glaucoma, infantile hemangioma, multiple
myeloma, acute myeloblastic leukemia, chronic sarcoma, multiple
myeloma, chronic myelogenous leukemia, metastasis melanoma,
Kaposi's sacroma, vascular proliferation, cachexia, metastasis of
the breast cancer, cancer (e.g., colorectal cancer (e.g., familial
colorectal cancer, hereditary nonpolyposis colorectal cancer,
gastrointestinal stromal tumor etc.), lung cancer (e.g., non-small
cell lung cancer, small cell lung cancer, malignant mesothelioma
etc.), mesothelioma, pancreatic cancer (e.g., pancreatic duct
cancer etc.), gastric cancer (e.g., mucinous adenocarcinoma,
adenosquamous carcinoma etc.), papillary adenocarcinoma, breast
cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ,
inflammatory breast cancer etc.), ovarian cancer (e.g., ovarian
epithelial carcinoma, extragonadal germ cell tumor, ovarian germ
cell tumor, ovarian low malignant potential tumor etc.), prostate
cancer (e.g., hormone-dependent prostate cancer, non-hormone
dependent prostate cancer etc.), liver cancer (e.g., primary liver
cancer, extrahepatic bile duct cancer etc.), thyroid cancer (e.g.,
medullary thyroid carcinoma etc.), kidney cancer (e.g., renal cell
carcinoma, transitional cell carcinoma in kidney and urinary duct
etc.), uterine cancer, brain tumor (e.g., pineal astrocytoma,
pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma
etc.), melanoma, sarcoma, urinary bladder cancer, hematologic
cancer and the like including multiple myeloma, hypophyseal
adenoma, glioma, acoustic neurinoma, retinoblastoma, pharyngeal
cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus
cancer, duodenal cancer, colorectal cancer, rectal cancer,
hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder
cancer, penile cancer, urinary duct cancer, testis tumor, vulvar
cancer, cervix cancer, endometrial cancer, uterus sarcoma,
cholionic disease, vaginal cancer, skin cancer, fungoid mycosis,
basal cell tumor, soft tissue sarcoma, malignant lymphoma,
Hodgkin's disease, myelodysplastic syndrome, acute lymphocytic
leukemia, chronic lymphocytic leukemia, adult T cell leukemia,
chronic bone marrow proliferative disease, pancreatic endocrine
tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma,
cancer of unknown primary), (5) cardiovascular disease (e.g., heart
disease (e.g., cardiac hypertrophy, acute heart failure and chronic
heart failure including congestive, cardiomyopathy, angina
pectoris, myocarditis, arrhythmia, tachycardia, myocardial
infarction), myocardial ischemia, venous insufficiency, heart
failure after myocardial infarction, hypertension, cor pulmonale,
arteriosclerosis including atherosclerosis (e.g., aortic aneurysm
(e.g., abdominal aortic aneurysm, thoracic aortic aneurysm,
thoracoabdominal aortic aneurysm), coronary atherosclerosis,
cerebral atherosclerosis, peripheral arterial disease,
arteriosclerosis obliterans, chronic arterial occlusion),
intervention (e.g., percutaneous transluminal coronary angioplasty,
stent placement, coronary angioscopy, intravascular ultrasound,
thrombolysis therapy), vascular hypertrophy or vascular occluson
and organ dysfunction after heart transplant, vascular reocclusion
and restenosis after bypass surgery), (6) hormone-dependent
diseases (sex hormone-dependent cancers (e.g., prostate cancer,
uterine cancer, breast cancer, pituitary tumor), prostatic
hyperplasia, endometriosis, uterine fibroid, precocious puberty,
dysmenorrhea, amenorrhea, premenstrual syndrome, polycystic ovary
syndrome), (7) acute and chronic pain (e.g., neuropathic pain
(e.g., peripheral neuropathy, diabetic neuropathy, post herpetic
neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV
neuropathy, phantom limb pain, carpal tunnel syndrome, central
post-stroke pain, and pain associated with chronic alcoholism,
hypothyroidism, uremia, multiple sclerosis, spinal cord injury,
Parkinson's disease, epilepsy and vitamin deficiency), inflammatory
pain (e.g., osteoarthritis, ankylosing spondylitis), visceral pain
(e.g., pain associated with gastrointestinal disorders
(gastro-esophageal reflux, dyspepsia, irritable bowel syndrome
(IBS), functional abdominal pain syndrome (FAPS), inflammatory
bowel disease (IBD), Crohn's disease, ileitis, ulcerative
colitis)), pain from central nervous system trauma,
strains/sprains, burns, myocardial infarction and acute
pancreatitis, postoperative pain, renal colic, posttraumatic pain,
back pain, cancer pain (e.g., tumor related pain (e.g., bone pain,
headache, facial pain or visceral pain), pain associated with
cancer therapy (e.g., pain associated with postchemotherapy
syndrome, chronic postsurgical pain syndrome, post radiation
syndrome), chemotherapy, immunotherapy, hormonal therapy or
radiotherapy), pain resulting from musculo-skeletal disorders
(e.g., myalgia, fibromyalgia, spondylitis, sero-negative
(non-rheumatoid) arthropathies, non-articular rheumatism,
dystrophinopathy, glycogenosis, polymyositis and pyomyositis),
heart and vascular pain (e.g., pain caused by angina, myocardical
infarction, mitral stenosis, pericarditis, Raynaud's phenomenon,
scleroderma and skeletal muscle ischemia), head pain (e.g.,
migraine (including migraine with aura and migraine without aura),
cluster headache, tension-type headache, mixed headache and
headache associated with vascular disorders), orofacial pain (e.g.,
dental pain, otic pain, burning mouth syndrome and
temporomandibular myofascial pain)).
[0565] The medicament of the present invention may be preferably
used as an agent for the prophylaxis or treatment of rheumatoid
arthritis, aortic aneurysm (e.g. abdominal aortic aneurysm,
thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.),
endometriosis, ankylosing spondylitis, inflammatory breast cancer
and the like.
[0566] Here, the above-mentioned "prophylaxis" of a disease means,
for example, administration of a medicament containing the compound
of the present invention to patients who are expected to have a
high risk of the onset due to some factor relating to the disease
but have not developed the disease or patients who have developed
the disease but do not have a subjective symptom, or administration
of a medicament containing the compound of the present invention to
patients who are feared to show recurrence of the disease after
treatment of the disease.
[0567] The dose of the compound of the present invention may vary
depending on the administration subject, route of administration,
target disease, symptoms, etc. For example, when it is administered
orally to an adult patient (body weight 60 kg), its dose may be
about 0.01 to 100 mg/kg body weight per dose, preferably 0.05 to 30
mg/kg body weight per dose, more preferably 0.1 to 10 mg/kg body
weight per dose and this amount is desirably administered in 1 to 3
portions daily.
[0568] The compound of the present invention can also be used
together with other medicaments.
[0569] Hereinafter, a medicament to be used in combination with the
compound of the present invention is referred to as "concomitant
drug", and a combination of the compound of the present invention
and concomitant drug is referred to as "the combination agent of
the present invention".
[0570] For example, when the compound of the present invention is
used as a prophylactic or therapeutic agent for EP4 receptor
associated disease, it can be used in combination with the
following drugs.
(1) non-steroidal anti-inflammatory drug (NSAIDs)
(i) Classical NSAIDs
[0571] alcofenac, aceclofenac, sulindac, tolmetin, etodolac,
fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam,
tenoxicam, lornoxicam, nabumeton, acetaminophen, phenacetin,
ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic
acid, flufenamic acid, diclofenac sodium, loxoprofen sodium,
phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen,
oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine,
piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen,
gabexate mesylate, camostat mesylate, ulinastatin, colchicine,
probenecid, sulfinpyrazone, benzbromarone, allopurinol, sodium
aurothiomalate, hyaluronate sodium, sodium salicylate, morphine
hydrochloride, salicylic acid, atropine, scopolamine, morphine,
pethidine, levorphanol, oxymorphone or a salt thereof and the
like.
(ii) cyclooxygenase inhibitor (COX-1 selective inhibitor, COX-2
selective inhibitor etc.)
[0572] salicylic acid derivatives (e.g., celecoxib, aspirin),
etoricoxib, valdecoxib, diclofenac, indomethacin, loxoprofen and
the like.
(iii) nitric oxide-releasing NSAIDs. (iv) JAK inhibitor
tofacitinib, ruxolitinib and the like. (2) disease-modifying
anti-rheumatic drugs (DMARDs) (i) Gold preparation
[0573] auranofin and the like.
(ii) penicillamine
[0574] D-penicillamine and the like.
(iii) aminosalicylic acid preparation
[0575] sulfasalazine, mesalazine, olsalazine, balsalazide and the
like.
(iv) antimalarial drug
[0576] chloroquine and the like.
(v) pyrimidine synthesis inhibitor
[0577] leflunomide and the like.
(vi) prograf (3) anti-cytokine drug (I) protein drug (i) TNF
inhibitor
[0578] etanercept, infliximab, adalimumab, certolizumab pegol,
golimumab, PASSTNF-.alpha., soluble TNF-.alpha. receptor,
TNF-.alpha. binding protein, anti-TNF-.alpha. antibody and the
like.
(ii) interleukin-1 inhibitor
[0579] anakinra (interleukin-1 receptor antagonist), soluble
interleukin-1 receptor and the like.
(iii) interleukin-6 inhibitor
[0580] tocilizumab (anti-interleukin-6 receptor antibody),
anti-interleukin-6 antibody and the like.
(iv) interleukin-10 drug
[0581] interleukin-10 and the like.
(v) interleukin-12/23 inhibitor
[0582] ustekinumab, briakinumab (anti-interleukin-12/23 antibody)
and the like.
(II) non-protein drug (i) MAPK inhibitor
[0583] BMS-582949 and the like.
(ii) gene modulator
[0584] inhibitor of molecule involved in signal transduction, such
as NF-.kappa., NF-.kappa.B, IKK-1, IKK-2, AP-1 and the like, and
the like.
(iii) cytokine production inhibitor
[0585] iguratimod, tetomilast and the like.
(iv) TNF-.alpha. converting enzyme inhibitor (v)
interleukin-1.beta. converting enzyme inhibitor
[0586] VX-765 and the like.
(vi) interleukin-6 antagonist
[0587] HMPL-004 and the like.
(vii) interleukin-8 inhibitor
[0588] IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin and
the like.
(viii) chemokine antagonist
[0589] CCR9 antagonist (CCX-282, CCX-025), MCP-1 antagonist and the
like.
(ix) interleukin-2 receptor antagonist
[0590] denileukin, diftitox and the like.
(x) therapeutic vaccines
[0591] TNF-.alpha. vaccine and the like.
(xi) gene therapy drug
[0592] gene therapy drugs aiming at promoting the expression of
gene having an anti-inflammatory action such as interleukin-4,
interleukin-10, soluble interleukin-1 receptor, soluble TNF-.alpha.
receptor and the like.
(xii) antisense compound
[0593] ISIS 104838 and the like.
(4) integrin inhibitor natalizumab, vedolizumab, AJM300, TRK-170,
E-6007 and the like. (5) immunomodulator (immunosuppressant)
[0594] methotrexate, cyclophosphamide, MX-68, atiprimod
dihydrochloride, BMS-188667, CKD-461, rimexolone, cyclosporine,
tacrolimus, gusperimus, azathiopurine, antilymphocyte serum,
freeze-dried sulfonated normal immunoglobulin, erythropoietin,
colony stimulating factor, interleukin, interferon and the
like.
(6) steroid
[0595] dexamethasone, hexestrol, methimazole, betamethasone,
triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone
acetonide, predonisolone, methylpredonisolone, cortisone acetate,
hydrocortisone, fluorometholone, beclomethasone dipropionate,
estriol and the like.
(7) angiotensin converting enzyme inhibitor
[0596] enalapril, captopril, ramipril, lisinopril, cilazapril,
perindopril and the like.
(8) angiotensin II receptor antagonist
[0597] candesartan, candesartan cilexetil, azilsartan, azilsartan
medoxomil, valsartan, irbesartan, olmesartan, eprosartan and the
like.
(9) diuretic drug
[0598] hydrochlorothiazide, spironolactone, furosemide, indapamide,
bendrofluazide, cyclopenthiazide and the like.
(10) cardiotonic drug
[0599] digoxin, dobutamine and the like.
(11) .beta. receptor antagonist
[0600] carvedilol, metoprolol, atenolol and the like.
(12) Ca sensitizer
[0601] MCC-135 and the like.
(13) Ca channel antagonist
[0602] nifedipine, diltiazem, verapamil and the like.
(14) anti-platelet drug, anticoagulator
[0603] heparin, aspirin, warfarin and the like.
(15) HMG-CoA reductase inhibitor
[0604] atorvastatin, simvastatin and the like.
(16) contraceptive (i) sex hormone or derivatives thereof
[0605] gestagen or a derivative thereof (progesterone,
17.alpha.-hydroxy progesterone, medroxyprogesterone,
medroxyprogesterone acetate, norethisterone, norethisterone
enanthate, norethindrone, norethindrone acetate, norethynodrel,
levonorgestrel, norgestrel, ethynodiol diacetate, desogestrel,
norgestimate, gestodene, progestin, etonogestrel, drospirenone,
dienogest, trimegestone, nestorone, chlormadinone acetate,
mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM-310525)
or a combination agent of a gestagen or a derivative thereof and an
estrogen or a derivative thereof (estradiol, estradiol benzoate,
estradiol cypionate, estradiol dipropionate, estradiol enanthate,
estradiol hexahydrobenzoate, estradiol phenylpropionate, estradiol
undecanoate, estradiol valerate, estrone, ethinylestradiol,
mestranol) and the like.
(ii) antiestrogen
[0606] ormeloxifene, mifepristone, Org-33628 and the like.
(iii) spermatocide
[0607] ushercell and the like.
(17) others (i) T cell inhibitors (ii) inosine monophosphate
dehydrogenase (IMPDH) inhibitor
[0608] mycophenolate mofetil and the like.
(iii) adhesion molecule inhibitor
[0609] ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, ICAM-1 and
the like.
(iv) thalidomide (v) cathepsin inhibitor (vi) matrix
metalloprotease (MMPs) inhibitor
[0610] V-85546 and the like.
(vii) glucose-6-phosphate dehydrogenase inhibitor (viii)
Dihydroorotate dehydrogenase (DHODH) inhibitor (ix)
phosphodiesterase IV(PDE IV) inhibitor
[0611] roflumilast, CG-1088 and the like.
(x) phospholipase A.sub.2 inhibitor (xi) iNOS inhibitor
[0612] VAS-203 and the like.
(xii) microtubule stimulating drug
[0613] paclitaxel and the like.
(xiii) microtuble inhibitor
[0614] reumacon and the like.
(xiv) MHC class II antagonist (xv) prostacyclin agonist
[0615] iloprost and the like.
(xvi) CD4 antagonist
[0616] zanolimumab and the like.
(xvii) CD23 antagonist (xviii) LTB4 receptor antagonist
[0617] DW-1305 and the like.
(xix) 5-lipoxygenase inhibitor
[0618] zileuton and the like.
(xx) cholinesterase inhibitor
[0619] galanthamine and the like.
(xxi) tyrosine kinase inhibitor
[0620] Tyk2 inhibitor (the compounds described in WO 2010/142752)
and the like.
(xxii) cathepsin B inhibitor (xxiii) adenosine deaminase
inhibitor
[0621] pentostatin and the like.
(xxiv) osteogenesis stimulator (xxv) dipeptidylpeptidase inhibitor
(xxvi) collagen agonist (xxvii) capsaicin cream (xxviii) hyaluronic
acid derivative
[0622] synvisc (hylan G-F 20), orthovisc and the like.
(xxix) glucosamine sulfate (xxx) amiprilose (xxxi) CD-20
inhibitor
[0623] rituximab, ibritumomab, tositumomab, ofatumumab and the
like.
(xxxii) BAFF inhibitor
[0624] belimumab, tabalumab, atacicept, A-623 and the like.
(xxxiii) CD52 inhibitor
[0625] alemtuzumab and the like.
(xxxiv) IL-17 inhibitor
[0626] secukinumab (AIN-457), LY-2439821, AMG827 and the like
[0627] Other concomitant drugs besides the above-mentioned include,
for example, antibacterial agent, antifungal agent, antiprotozoal
agent, antibiotic, antitussive and expectorant drug, sedative,
anesthetic, antiulcer drug, antiarrhythmic agent, hypotensive
diuretic drug, anticoagulant, tranquilizer, antipsychotic,
antitumor drug, hypolipidemic drug, muscle relaxant, antiepileptic
drug, antidepressant, antiallergic drug, cardiac stimulants,
therapeutic drug for arrhythmia, vasodilator, vasoconstrictor,
therapeutic drug for diabetes, antinarcotic, vitamin, vitamin
derivative, antiasthmatic, therapeutic agent for
pollakisuria/anischuria, antipruritic drug, therapeutic agent for
atopic dermatitis, therapeutic agent for allergic rhinitis,
hypertensor, endotoxin-antagonist or -antibody, signal transduction
inhibitor, inhibitor of inflammatory mediator activity, antibody to
inhibit inflammatory mediator activity, inhibitor of
anti-inflammatory mediator activity, antibody to inhibit
anti-inflammatory mediator activity and the like. Specific examples
thereof include the following.
(1) antibacterial agent (i) sulfa drug
[0628] sulfamethizole, sulfisoxazole, sulfamonomethoxine,
sulfamethizole, salazosulfapyridine, silver sulfadiazine and the
like.
(ii) quinolone antibacterial agent
[0629] nalidixic acid, pipemidic acid trihydrate, enoxacin,
norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin
hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin
and the like.
(iii) antiphthisic
[0630] isoniazid, ethambutol (ethambutol hydrochloride),
p-aminosalicylic acid (calcium p-aminosalicylate), pyrazinamide,
ethionamide, protionamide, rifampicin, streptomycin sulfate,
kanamycin sulfate, cycloserine and the like.
(iv) antiacidfast bacterium drug
[0631] diaphenylsulfone, rifampicin and the like.
(v) antiviral drug
[0632] idoxuridine, acyclovir, vidarabine, gancyclovir and the
like.
(vi) anti-HIV agent
[0633] zidovudine, didanosine, zalcitabine, indinavir sulfate
ethanolate, ritonavir and the like.
(vii) antispirochetele (viii) antibiotic
[0634] tetracycline hydrochloride, ampicillin, piperacillin,
gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin,
amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline,
rolitetracycline, doxycycline, ampicillin, piperacillin,
ticarcillin, cephalothin, cephapirin, cephaloridine, cefaclor,
cephalexin, cefroxadine, cefadroxil, cefamandole, cefotoam,
cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil,
cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin,
cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime,
cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin,
cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime,
cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin,
aztreonam or a salt a salt thereof, griseofulvin, lankacidin-group
[Journal of Antibiotics (J. Antibiotics), 38, 877-885(1985)], azole
compound
[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-
-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-tria-
zolone, fluconazole, itraconazole and the like] and the like.
(2) antifungal agent (i) polyethylene antibiotic (e.g.,
amphotericin B, nystatin, trichomycin) (ii) griseofulvin,
pyrrolnitrin and the like (iii) cytosine metabolism antagonist
(e.g., flucytosine) (iv) imidazole derivative (e.g., econazole,
clotrimazole, miconazole nitrate, bifonazole, croconazole) (v)
triazole derivative (e.g., fluconazole, itraconazole) (vi)
thiocarbamic acid derivative (e.g., trinaphthol) and the like. (3)
antiprotozoal agent
[0635] metronidazole, tinidazole, diethylcarbamazine citrate,
quinine hydrochloride, quinine sulfate and the like.
(4) antitussive and expectorant drug
[0636] ephedrine hydrochloride, noscapine hydrochloride, codeine
phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride,
ephedrine hydrochloride, methylephedrine hydrochloride, noscapine
hydrochloride, alloclamide, chlophedianol, picoperidamine,
cloperastine, protokylol, isoproterenol, salbutamol, terbutaline,
oxymetebanol, morphine hydrochloride, dextromethorfan hydrobromide,
oxycodone hydrochloride, dimemorphan phosphate, tipepidine
hibenzate, pentoxyverine citrate, clofedanol hydrochloride,
benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol
hydrochloride, acetylcysteine, ethyl cysteine hydrochloride,
carbocysteine and the like.
(5) sedative
[0637] chlorpromazine hydrochloride, atropine sulfate,
phenobarbital, barbital, amobarbital, pentobarbital, thiopental
sodium, thiamylal sodium, nitrazepam, estazolam, flurazepam,
haloxazolam, triazolam, flunitrazepam, bromovalerylurea, chloral
hydrate, triclofos sodium and the like.
(6) anesthetic (6-1) local anesthetic
[0638] cocaine hydrochloride, procaine hydrochloride, lidocaine,
dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine
hydrochloride, bupivacaine hydrochloride, oxybuprocaine
hydrochloride, ethyl aminobenzoate, oxethazaine and the like.
(6-2) general anesthetic (i) inhalation anesthetic (e.g., ether,
halothane, nitrous oxide, isoflurane, enflurane), (ii) intravenous
anesthetic (e.g., ketamine hydrochloride, droperidol, thiopental
sodium, thiamylal sodium, pentobarbital) and the like. (7)
antiulcer drug
[0639] histidine hydrochloride, lansoprazole, metoclopramide,
pirenzepine, cimetidine, ranitidine, famotidine, urogastrone,
oxethazaine, proglumide, omeprazole, sucralfate, sulpiride,
cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and the
like.
(8) antiarrhythmic agent (i) sodium channel blocker (e.g.,
quinidine, procainamide, disopyramide, ajmaline, lidocaine,
mexiletine, phenytoin), (ii) .beta.-blocker (e.g., propranolol,
alprenolol, bufetolol hydrochloride, oxprenolol, atenolol,
acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol
hydrochloride), (iii) potassium channel blocker (e.g., amiodarone),
(iv) calcium channel blocker (e.g., verapamil, diltiazem) and the
like. (9) hypotensive diuretic drug
[0640] hexanethonium bromide, clonidine hydrochloride,
hydrochlorothiazide, trichlormethiazide, furosemide, ethacrynic
acid, bumetanide, mefruside, azosemide, spironolactone, potassium
canrenoate, triamterene, amiloride, acetazolamide, D-mannitol,
isosorbide, aminophylline and the like.
(10) anticoagulant
[0641] heparin sodium, sodium citrate, activated protein C, tissue
factor pathway inhibitor, antithrombin III, dalteparin sodium,
warfarin potassium, argatroban, gabexate, sodium citrate, ozagrel
sodium, ethyl icosapentate, beraprost sodium, alprostadil,
ticlopidine hydrochloride, pentoxifylline, dipyridamole,
tisokinase, urokinase, streptokinase and the like.
(11) tranquilizer
[0642] diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam,
oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam,
fludiazepam, hydroxyzine and the like.
(12) antipsychotic
[0643] chlorpromazine hydrochloride, prochlorperazine,
trifluoperazine, thioridazine hydrochloride, perphenazine maleate,
fluphenazine enanthate, prochlorperazine maleate, levomepromazine
maleate, promethazine hydrochloride, haloperidol, bromperidol,
spiperone, reserpine, clocapramine hydrochloride, sulpiride,
zotepine and the like.
(13) antitumor drug
[0644] 6-O--(N-chloroacetylcarbamoyl)fumagillol, bleomycin,
methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin,
neocarzinostatin, cytosine arabinoside, fluorouracil,
tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole,
bestatin, azimexon, glycyrrhizin, doxorubicin hydrochloride,
aclarubicin hydrochloride, bleomycin hydrochloride, peplomycin
sulfate, vincristine sulfate, vinblastine sulfate, irinotecan
hydrochloride, cyclophosphamide, melphalan, busulfan, thiotepa,
procarbazine hydrochloride, cisplatin, azathioprine,
mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone,
testosterone propionate, testosterone enanthate, mepitiostane,
fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelin
acetate and the like.
(14) hypolipidemic drug
[0645] clofibrate, ethyl
2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionate [Chemical
and Pharmaceutical Bulletin (Chem. Pharm. Bull), 38, 2792-2796
(1990)], pravastatin, simvastatin, probucol, bezafibrate,
clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and
the like.
(15) muscle relaxant
[0646] pridinol, tubocurarine, pancuronium, tolperisone
hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone,
mephenesin, chlorzoxazone, eperisone, tizanidine and the like.
(16) antiepileptic drug
[0647] phenytoin, ethosuximide, acetazolamide, chlordiazepoxide,
trimethadione, carbamazepine, phenobarbital, primidone, sulthiame,
sodium valproate, clonazepam, diazepam, nitrazepam and the
like.
(17) antidepressant
[0648] imipramine, clomipramine, noxiptiline, phenelzine,
amitriptyline hydrochloride, nortriptyline hydrochloride,
amoxapine, mianserin hydrochloride, maprotiline hydrochloride,
sulpiride, fluvoxamine maleate, trazodone hydrochloride and the
like.
(18) antiallergic drug
[0649] diphenhydramine, chlorpheniramine, tripelennamine,
metodilamine, clemizole, diphenylpyraline, methoxyphenamine, sodium
cromoglicate, tranilast, repirinast, amlexanox, ibudilast,
ketotifen, terfenadine, mequitazine, azelastine hydrochloride,
epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast
and the like.
(19) cardiac stimulants
[0650] trans-.pi.-oxocamphor, terephyllol, aminophylline,
etilefrine, dopamine, dobutamine, denopamine, aminophylline,
vesnarinone, amrinone, pimobendan, ubidecarenone, digitoxin,
digoxin, methyldigoxin, lanatoside C, G-strophanthin and the
like.
(20) vasodilator
[0651] oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan,
clonidine, methyldopa, guanabenz and the like.
(21) vasoconstrictor
[0652] dopamine, dobutamine denopamine and the like.
(22) hypotensive diuretic
[0653] hexanethonium bromide, pentolinium, mecamylamine, ecarazine,
clonidine, diltiazem, nifedipine and the like.
(23) therapeutic drug for diabetes
[0654] tolbutamide, chlorpropamide, acetohexamide, glibenclamide,
tolazamide, acarbose, epalrestat, troglitazone, glucagon,
glymidine, glipizide, phenformin, buformin, metformin and the
like.
(24) antinarcotic
[0655] levallorphan, nalorphine, naloxone or a salt thereof and the
like.
(25) liposoluble vitamins (i) vitamin A: vitamin A.sub.1, vitamin
A.sub.2 and retinol palmitate (ii) vitamin D: vitamin D.sub.1,
D.sub.2, D.sub.3, D.sub.4 and D.sub.5 (iii) vitamin E:
.alpha.-tocopherol, .beta.-tocopherol, .gamma.-tocopherol,
.delta.-tocopherol, dl-.alpha.-tocopherol nicotinate (iv) vitamin
K: vitamin K.sub.1, K.sub.2, K.sub.3 and K.sub.4 (v) folic acid
(vitamin M) and the like. (26) vitamin derivative
[0656] various derivatives of vitamins, for example, vitamin
D.sub.3 derivatives such as 5,6-trans-cholecalciferol,
2,5-hydroxycholecalciferol, 1-.alpha.-hydroxycholecalciferol and
the like, vitamin D.sub.2 derivatives such as
5,6-trans-ergocalciferol and the like, and the like.
(27) antiasthmatic
[0657] isoprenaline hydrochloride, salbutamol sulfate, procaterol
hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride,
tulobuterol hydrochloride, orciprenaline sulfate, fenoterol
hydrobromide, ephedrine hydrochloride, ipratropium bromide,
oxitropium bromide, flutropium bromide, theophylline,
aminophylline, sodium cromoglicate, tranilast, repirinast,
amlexanox, ibudilast, ketotifen, terfenadine, mequitazine,
azelastine, epinastine, ozagrel hydrochloride, pranlkast hydrate,
seratrodast, dexamethasone, prednisolone, hydrocortisone,
hydrocortisone sodium succinate, beclometasone dipropionate and the
like.
(28) therapeutic agent for pollakisuria/anischuria
[0658] flavoxate hydrochloride and the like.
(29) therapeutic agent for atopic dermatitis
[0659] sodium cromoglicate and the like.
(30) therapeutic agent for allergic rhinitis
[0660] sodium cromoglicate, chlorpheniramine maleate, alimemazine
tartrate, clemastine fumarate, homochlorcyclizine hydrochloride,
fexofenadine, mequitazine and the like.
(31) hypertensor
[0661] dopamine, dobutamine, denopamine, digitoxin, digoxin,
methyldigoxin, lanatoside C, G-strophanthin and the like.
(32) others
[0662] hydroxycam, diacerein, megestrol acetate, nicergoline,
prostaglandins and the like.
[0663] In another embodiment, when the compound of the present
invention is used as an agent for the prophylaxis or treatment of
chronic or acute pain, from among EP4 receptor associated disease,
it can be used in combination with the following drugs.
(1) opioid analgesic, for example, morphine, heroin, hydromorphone,
oxymorphone, levorphanol, levallorphan, methadone, meperidine,
fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone,
propoxyphene, nalmefene, nalorphine, naloxone, naltrexone,
buprenorphine, butorphanol, nalbuphine or pentazocine; (2)
non-steroidal antiinflammatory drug (NSAID), for example, aspirin,
diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin,
phenylbutazone, piroxicam, sulindac, tolmetin or zomepirac;
cyclooxygenase-2 (COX-2) inhibitors, for example, celecoxib,
rofecoxib, meloxicam,
4-(4-cyclohexyl-2-methyl-1,3-oxazol-5-yl)-2-fluorobenzenesulfonamide,
L-745, L-337,
N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide,
N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide or
N-(methylsulfonyl)-2-(cyclohexyloxy)-4-nitroaniline; or a
pharmaceutically acceptable salt thereof; (3) barbiturate sedative,
for example, amobarbital, aprobarbital, butabarbital, butabital,
mephobarbital, metharbital, methohexital, pentobarbital,
phenobartital, secobarbital, talbutal, theamylal or thiopental or a
pharmaceutically acceptable salt thereof; (4) benzodiazepine having
a sedative action, for example, chlordiazepoxide, clorazepate,
diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam
or a pharmaceutically acceptable salt thereof; (5) H1 antagonist
having a sedative action, for example, diphenhydramine, pyhlamine,
promethazine, chlorpheniramine or chlorcyclizine or a
pharmaceutically acceptable salt thereof; (6) sedative, for
example, loxoprofen sodium, acetaminophen, acetylsalicylic acid,
glutethimide, meprobamate, methaqualone or dichloralphenazone or a
pharmaceutically acceptable salt thereof; (7) skeletal muscle
relaxant, for example, baclofen, cahsoprodol, chlorzoxazone,
cyclobenzaphne, methocarbamol or orphrenadine or a pharmaceutically
acceptable salt thereof; (8) NMDA receptor antagonist, for example,
dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its
metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine,
memantine, pyrroloquinoline quinone or
cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid or a
pharmaceutically acceptable salt thereof; (9) .alpha.-adrenergic,
for example, doxazosin, tamsulosin, clonidine or
4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-
-2-yl)-5-(2-pyridyl)quinazoline; (10) tricyclic antidepressant, for
example, desipramine, imipramine, clomipramine, doxepin,
amythptiline or nortriptiline; (11) anticonvulsant, for example,
carbamazepine, lamotrigine or valproate; (12) tachykinin (NK)
antagonist (particularly an NK-3, NK-2 or NK-1 antagonist), for
example,
5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorop-
henyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one,
lanepitant, dapitant or
3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine
(2S, 3S); (13) muscarinic antagonist, for example, oxybutin,
tolterodine, propiverine, tropsium chloride or darifenacin; (14)
COX-2 inhibitor, for example, celecoxib, rofecoxib or valdecoxib;
(15) non-selective COX inhibitor (preferably, having a protective
effect on the gastrointestinal tract), for example,
nitroflurbiprofen; (16) coal-tar analgesic, particularly
paracetamol; (17) neuroleptic, for example, droperidol; (18)
vanilloid receptor agonist (e.g., resinferatoxin) or antagonist
(e.g., capsazepine); (19) .beta.-adrenergic, for example,
propranolol; (20) local anaesthetic, for example, mexiletine,
tocainide or lidocaine; (21) corticosteriod, for example,
dexamethasone or prednisone; (22) serotonin receptor agonist or
antagonist; (23) cholinergic (nicotinic) analgesic; (24) tramadol
hydrochloride; (25) PDEV inhibitor, such as sildenafil, vardenafil
or taladafil; (26) .alpha.-2-.delta. ligand, for example,
gabapentin or pregabalin; (27) canabinoid; and (28) antidepressant
(e.g., amitriptyline, trazodone, duloxetine, milnacipran,
fluoxetine, paroxetine, sertraline, citalopram and imipramine),
anticonvulsant (e.g., phenytoin or carbamazepine), narcotic drug
(e.g., methadone, tramadol), Chinese herbal medicine (e.g.,
gosha-jinki-gan, shakuyaku-kanzoh-toh) and vitamin.
[0664] For combined use, the administration time of the compound of
the present invention and the concomitant drug is not restricted,
and the compound of the present invention or the concomitant drug
may be administered to an administration subject simultaneously, or
may be administered at different times. The dosage of the
concomitant drug may be determined according to the dose clinically
used, and can be appropriately selected depending on an
administration subject, administration route, disease, combination
and the like.
[0665] The administration form of the combined use is not
particularly limited, and the compound of the present invention and
a concomitant drug only need to be combined on administration.
Examples of such administration mode include the following:
(1) administration of a single preparation obtained by
simultaneously processing the compound of the present invention and
the concomitant drug, (2) simultaneous administration of two kinds
of preparations of the compound of the present invention and the
concomitant drug, which have been separately produced, by the same
administration route, (3) administration of two kinds of
preparations of the compound of the present invention and the
concomitant drug, which have been separately produced, by the same
administration route in a staggered manner, (4) simultaneous
administration of two kinds of preparations of the compound of the
present invention and the concomitant drug, which have been
separately produced, by different administration routes, (5)
administration of two kinds of preparations of the compound of the
present invention and the concomitant drug, which have been
separately produced, by different administration routes in a
staggered manner (e.g., administration in the order of the compound
of the present invention and the concomitant drug, or in the
reverse order) and the like.
[0666] The mixing ratio of the compound of the present invention
and a concomitant drug in the combination agent of the present
invention can be appropriately selected based on the subject of
administration, administration route, disease and the like.
[0667] For example, while the content of the compound of the
present invention in the combination agent of the present invention
varies depending on the preparation form, it is generally about
0.01-100 wt %, preferably about 0.1-50 wt %, more preferably about
0.5-20 wt %, of the whole preparation.
[0668] The content of the concomitant drug in the combination agent
of the present invention varies depending on the preparation form,
and generally about 0.01 to 100% by weight, preferably about 0.1 to
50% by weight, further preferably about 0.5 to 20% by weight, of
the entire preparation.
[0669] While the content of the additive such as a carrier and the
like in the combination agent of the present invention varies
depending on the form of a preparation, it is generally about 1 to
99.99% by weight, preferably about 10 to 90% by weight, based on
the preparation.
[0670] When the compound of the present invention and the
concomitant drug are separately prepared, the same content may be
adopted.
[0671] The dose of the combination agent varies depending on the
kind of the compound of the present invention, administration
route, symptom, age of patients and the like. For example, for oral
administration to patients (body weight about 60 kg) with
inflammatory bowel disease (IBD), about 0.1 mg/kg body weight-about
30 mg/kg body weight, preferably about 1 mg/kg body weight-20 mg/kg
body weight, of compound (I) can be administered once to several
portions per day.
[0672] The dose of the pharmaceutical composition of the present
invention as a sustained-release preparation varies depending on
the kind and content of compound (I), dosage form, period of
sustained drug release, subject animal of administration (e.g.,
mammals such as mouse, rat, hamster, guinea pig, rabbit, cat, dog,
bovine, horse, swine, sheep, monkey, human etc.), and
administration object. For example, for application by parenteral
administration, about 0.1 to about 100 mg of compound (I) needs to
be released from the administered preparation per 1 week.
[0673] Any amount of the concomitant drug can be adopted as long as
the side effects do not cause a problem. The daily dosage in terms
of the concomitant drug varies depending on the severity, age, sex,
body weight, sensitivity difference of the subject, administration
period, interval, and nature, pharmacology, kind of the
pharmaceutical preparation, kind of effective ingredient, and the
like, and not particularly restricted, and the amount of a drug is,
in the case of oral administration for example, generally about
0.001 to 2000 mg, preferably about 0.01 to 500 mg, further
preferably about 0.1 to 100 mg, per 1 kg of a mammal and this is
generally administered once to 4-times, divided in a day.
[0674] When the combination agent of the present invention is
administered, the compound of the present invention and the
concomitant drug can be administered simultaneously, or may be
administered in a staggered manner. When administered at a time
interval, the interval varies depending on the effective
ingredient, dosage form and administration method, and, for
example, when the concomitant drug is administered first, a method
in which the compound of the present invention is administered
within time range of from 1 minute to 3 days, preferably from 10
minutes to 1 day, more preferably from 15 minutes to 1 hour, after
administration of the concomitant drug is an example. When the
compound of the present invention is administered first, a method
in which the concomitant drug is administered within time range of
from 1 minute to 1 day, preferably from 10 minutes to 6 hours, more
preferably from 15 minutes to 1 hour after administration of the
compound of the present invention is an example.
EXAMPLES
[0675] The present invention is explained in detail in the
following by referring to Preparations, Examples, Experimental
Examples and Formulation Examples, which are not to be construed as
limitative, and the invention may be changed within the scope of
the present invention.
[0676] In the following Examples, the "room temperature" generally
means about 10.degree. C. to about 35.degree. C. The ratios
indicated for mixed solvents are volume mixing ratios, unless
otherwise specified. % means wt %, unless otherwise specified.
[0677] In silica gel column chromatography, basic silica gel means
use of aminopropylsilane-bound silica gel. In HPLC (high
performance liquid chromatography), C18 means use of
octadecyl-bound silica gel. The ratios of elution solvents are
volume mixing ratios, unless otherwise specified.
[0678] .sup.1H NMR (proton nuclear magnetic resonance spectrum) was
measured by Fourier-transform type NMR. For the analysis,
ACD/SpecManager (trade name) and the like were used. Peaks with
very mild protons such as a hydroxy group, an amino group and the
like are not described.
[0679] MS (mass spectrum) was measured by LC/MS (liquid
chromatography mass spectrometer). As ionization method, ESI
(Electro Spray Ionization) method or APCI (Atomospheric Pressure
Chemical Ionization) method was used. The data indicates those
found. Generally, a molecular ion peak is observed. In the case of
a salt, a molecular ion peak or fragment ion peak of free form is
generally observed.
Preparation 1: 2-Chloro-3-nitropyridin-4-ol
##STR00021##
[0680] Step 1: 3-Nitropyridine-2,4-diol
[0681] 2,4-Dihydroxypyridine (100 g, 901 mmol) was added portion
wise to cooled (0-10.degree. C.) concentrated sulfuric acid (300
mL) while stirring. The reaction mixture was stirred further for 40
minutes at room temperature. Fuming nitric acid (40 mL) was added
slowly thereto over a period of 1 hour, and the reaction
temperature was maintained below 5.degree. C. The reaction mixture
was poured slowly into cold water (3000 mL) keeping the temperature
below 5.degree. C. The resulting suspension was stirred at ambient
temperature for 2 hours. The solid was collected by filtration and
washed with water (1000 mL). The obtained solid was dried under
vacuum to give the title compound (125 g, 88%).
[0682] MS(ESI) m/z: 157.1 (M+1). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 6.02 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.2 Hz,
1H), 11.85 (br s, 1H), 12.40 (br s, 1H).
Step 2: 2,4-Dichloro-3-nitropyridine
[0683] A mixture of 3-nitropyridine-2,4-diol (100 g, 640 mmol) and
phosphorous oxychloride (500 mL) was heated at 120.degree. C. for
18 hours. The reaction completion was confirmed by TLC, then the
phosphorous oxychloride was removed under vacuum, and the resulting
residue was dissolved in water (1000 mL). The aqueous phase was
extracted with ethyl acetate (3.times.700 mL), and the combined
organic layers were washed successively with water (250 mL) and
brine (500 mL), dried over sodium sulfate and concentrated under
vacuum to give a crude product. The crude product was purified by
silica gel (100-200) column chromatography with 5-10% ethyl acetate
in hexane as a mobile phase to give the title compound as an
off-white solid (100 g, 81%).
[0684] MS(ESI) m/z: 192.9 (M+1); .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.48 (d, J=5.2 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H).
Step 3: 2-Chloro-3-nitropyridin-4-ol
[0685] To a solution of 2,4-dichloro-3-nitropyridine (100 g, 518
mmol) in N,N-dimethylformamide (500 mL) was added sodium acetate
(106 g, 1295 mmol) at room temperature. The mixture was stirred at
120.degree. C. for 5 hours. The reaction completion was confirmed
by TLC, then the mixture was cooled to room temperature and diluted
with water (500 mL) followed by aqueous 2N HCl solution to adjust
the pH<4. The aqueous layer was extracted with ethyl acetate
(5.times.750 mL). The combined organic layers were washed with
brine, dried over sodium sulfate and under vacuum to give a crude
product. The crude product was triturated with water, and the
resulting solid was collected by filtration, and dried under vacuum
to give the title compound (63 g, 65%).
[0686] MS(ESI) m/z: 175.1 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.10 (d, J=6.0 Hz, 1H), 8.25 (d, J=5.6 Hz,
1H), 13.10 (br s, 1H).
Preparation 2: 2-Chloro-N-methyl-3-nitropyridin-4-amine
##STR00022##
[0687] Step 1: 4-Chloro-3-nitropyridin-2-ol
[0688] To a mixture of DMF (7 mL) and acetonitrile (75 mL) was
added a solution of oxalyl chloride (8.2 mL, 96.15 mmol) in
acetonitrile (15 mL) in drop wise manner. After complete addition,
the solution was stirred for 10 minute, and
3-nitropyridine-2,4-diol (10 g, 64.10 mmol) was added thereto, and
the mixture was continued to stir at room temperature for 30
minutes. The reaction completion was confirmed by TLC, then the
acetonitrile was removed under vacuum. The resulting residue was
diluted with ice cold water (100 mL), and the precipitated solid
was collected by filtration, and washed with cold water (20 mL)
followed by n-hexane (20 mL). The obtained solid was dried under
vacuum to give the title compound (90 g, 81%).
[0689] MS (ESI) m/z: 174.9 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 6.59 (d, J=6.8 Hz, 1H), 7.76 (d, J=6.8 Hz,
1H), 13.10 (br s, 1H).
Step 2: 4-(Methylamino)-3-nitropyridin-2-ol
[0690] To a solution of 4-chloro-3-nitropyridin-2-ol (4 g, 23 mmol)
in acetonitrile (40 mL) were added DIPEA (16.5 mL, 92 mmol) and a
solution of methylamine (2 M in THF, 34.5 mL, 69 mmol). The
reaction mixture was heated at 100.degree. C. for 2 hours under
argon atmosphere. The reaction completion was confirmed by TLC,
then the acetonitrile was removed under vacuum. The resulting
residue was triturated with diethyl ether (100 mL), and the
precipitated solid was collected by filtration, and dried under
vacuum to give the title compound (3.7 g, 95%). MS (ESI) m/z: 169.9
(M+1); .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 2.95 (d, J=4.8
Hz, 3H), 5.94 (d, J=7.2 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.76 (br
s, 1H), 8.95 (d, J=3.6 Hz, 1H).
Step 3: 2-Chloro-N-methyl-3-nitropyridin-4-amine
[0691] A round bottom flask was charged with
4-(methylamino)-3-nitropyridin-2-ol (3.7 g, 22 mmol) and
phosphorous oxychloride (40 mL), and the mixture was heated at
120.degree. C. for 2 hours. The reaction completion was confirmed
by TLC, and then the phosphorous oxychloride was removed under
vacuum. The resulting residue was diluted with water (100 mL), and
the aqueous layer was extracted with ethyl acetate (3.times.40 mL).
The combined organic layers were washed successively with water (50
mL) and brine (40 mL), dried over sodium sulfate and concentrated
under vacuum to give the title compound (3.5 g, 85%).
[0692] MS (ESI) m/z: 187.9 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 2.81 (d, J=4.8 Hz, 3H), 6.87 (d, J=6.4 Hz,
1H), 7.43 (d, J=3.2 Hz, 1H), 8.03 (d, J=6.0 Hz, 1H).
Preparation 3: Methyl
4-[(1S)-1-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-5-ylamino)ethyl]benzoa-
te
##STR00023##
[0693] Step 1: Methyl
4-[(1S)-1-[(4-hydroxy-3-nitro-2-pyridyl)amino]ethyl]benzoate
[0694] A round bottom flask was charged with a mixture of
2-chloro-3-nitropyridin-4-ol (20 g, 115 mmol) and methyl
4-[(1S)-1-aminoethyl]benzoate (31 g, 173 mmol). The flask was
immersed in preheated oil bath at 160.degree. C., and the mixture
was stirred for 20-30 mins. The reaction completion was confirmed
by TLC, then the mixture was cooled to room temperature, and
triturated with ethanol (200 mL). The solid was collected by
filtration, washed with cold ethanol (50 mL) and dried under vacuum
to give the title compound as a yellow solid (30 g, 83%).
[0695] MS(ESI) m/z: 318.1 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.54 (d, J=6.8 Hz, 3H), 3.83 (s, 3H), 5.25
(br s, 1H), 6.05 (br s, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.4
Hz, 2H), 8.50 (br s, 1H), 11.30 (br s, 1H).
Step 2: Methyl
4-[(1S)-1-[(3-amino-4-hydroxy-2-pyridyl)amino]ethyl]benzoate
[0696] A flame dried flask was purged with argon and charged methyl
4-[(1S)-1-[(4-hydroxy-3-nitro-2-pyridyl)amino]ethyl]benzoate (30 g,
95 mmol) and ethyl acetate (600 mL). The flask was degassed for 15
minutes (argon sparge), and Pd/C (6 g, 5.6 mmol, 10% w/w) was added
thereto. Hydrogen balloon was placed over it and argon was replaced
by hydrogen using vacuum. The reaction mixture was stirred at room
temperature for 18 hours under hydrogen atmosphere. After
completion of the reaction by TLC, the reaction mixture was passed
through celite pad and washed with ethyl acetate (1000 mL). The
filtrate and washing were concentrated under vacuum to give the
title compound as a light brown solid (25 g, 91%). MS(ESI) m/z:
288.2 (M+1); .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.44 (d,
J=6.8 Hz, 3H), 3.82 (s, 3H), 5.15-5.30 (m, 1H), 5.76 (d, J=7.2 Hz,
1H), 6.07 (d, J=5.2 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 7.48 (d, J=8.4
Hz, 2H), 7.86 (d, J=8.0 Hz, 2H).
Step 3: Methyl
4-[(1S)-1-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-5-ylamino)ethyl]benzoa-
te
[0697] To a solution of methyl
4-[(1S)-1-[(3-amino-4-hydroxy-2-pyridyl)amino]ethyl]benzoate (25 g,
87 mmol) in N,N-dimethylformamide (125 mL) were added potassium
carbonate (48 g, 348 mmol) and 1,2-dibromoethane (65 g, 348 mmol)
at room temperature. The reaction mixture was stirred at
120.degree. C. for 2 hours. The reaction completion was confirmed
by TLC, then the mixture was cooled to room temperature. The
reaction mixture was diluted with water (500 mL), and the aqueous
layer was extracted with ethyl acetate (3.times.750 mL). The
combined organic layers were washed with brine, dried over sodium
sulfate and concentrated under vacuum. The obtained residue was
dissolved in diethyl ether, and 2M HCl in diethyl ether was added
thereto. The resulting solid was collected by filtration and
re-dissolved in aqueous bicarbonate solution, and the solution was
extracted with ethyl acetate (3.times.150 mL). The combined organic
layers were washed with brine, dried over sodium sulfate and
concentrated under vacuum to give the title compound (28 g,
84%).
[0698] MS(ESI) m/z: 314.2 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.56 (d, J=6.8 Hz, 3H), 2.62 (br s, 1H),
3.40 (t, J=3.6 Hz, 2H), 3.89 (s, 3H), 4.16-4.19 (m, 2H), 4.52-4.53
(m, 1H), 5.30-5.31 (m, 1H), 6.21 (d, J=6.0 Hz, 1H), 7.45 (d, J=8.4
Hz, 2H), 7.55 (d, J=5.6 Hz, 1H), 7.97-8.09 (m, 2H).
Preparation 4: Methyl
4-[1-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-5
ylamino)cyclopropyl]benzoate
##STR00024##
[0699] Step 1: 4-Benzyloxy-2-chloro-3-nitropyridine
[0700] A round bottom flask was charged with
2-chloro-3-nitropyridin-4-ol (25 g, 144 mmol), benzyl bromide (20.4
mL, 172 mmol), potassium carbonate (39.5 g, 286 mmol) and DMF (125
mL). The reaction mixture was heated at 100.degree. C. for 18
hours, and the reaction completion was confirmed by TLC. The
reaction mixture was cooled to room temperature, diluted with water
(1.5 L) and extracted with ethyl acetate (3.times.250 mL). The
combined organic layers were washed with brine (500 mL), and dried
over sodium sulfate and evaporated under vacuum. The obtained
residue was purified by silica gel (100-200) column chromatography
with 20-25% ethyl acetate in hexane as a mobile phase to give the
title compound as an off-white solid (13 g, 34%).
[0701] MS (ESI) m/z: 265.0 (M+1), .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 5.26 (s, 2H), 6.61 (d, J=8.0 Hz, 1H),
7.19-7.21 (m, 2H), 7.42-7.47 (m, 4H).
Step 2: Methyl
4-[1-[(4-benzyloxy-3-nitro-2-pyridyl)amino]cyclopropyl]benzoate
[0702] A round bottom flask was charged with a mixture of
4-benzyloxy-2-chloro-3-nitropyridine (13.0 g, 49 mmol) and methyl
4-(1-aminocyclopropyl)benzoate (18.8 g, 98 mmol). The flask was
immersed in preheated oil bath at 160.degree. C., and the mixture
was stirred for 1 hour. The reaction completion was confirmed by
TLC, then the mixture was cooled to room temperature, and the
residue was triturated with ethanol and filtered to give the title
compound as an off-white solid (15 g, 73%).
[0703] MS(ESI) m/z: 419.9 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6); .delta. 0.64 (dd, J=4.8, 6.8 Hz, 2H), 1.02 (dd,
J=6.0, 8.4 Hz, 2H), 3.82 (s, 3H), 5.33 (s, 2H), 6.07 (d, J=7.2 Hz,
1H), 7.04 (d, J=7.6 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.32-7.36 (m,
1H), 7.42-7.44 (m, 3H), 7.70 (d, J=7.6 Hz, 1H), 7.79 (d, J=8.4 Hz,
2H).
Step 3: Methyl 4-[1-[(3-amino-4-hydroxy-2-pyridyl) amino]
cyclopropyl]benzoate
[0704] A flame dried flask was purged with argon and charged with
methyl
4-[1-[(4-benzyloxy-3-nitro-2-pyridyl)amino]cyclopropyl]benzoate (15
g, 35.8 mmol) and methanol:DCM (1:9) (150 mL). The flask was
degassed for 15 minutes (argon sparge), and Pd/C (6 g, 5.7 mmol,
10% w/w) was added thereto. Hydrogen balloon was placed over it,
and argon was replaced by hydrogen using vacuum. The reaction
mixture was stirred at room temperature for 18 hours under hydrogen
atmosphere. After completion of the reaction by TLC, the reaction
mixture was passed through celite pad and washed with methanol:DCM
(1:10) (1500 mL). The filtrate and washing were concentrated under
vacuum to give the title compound as a light brown solid (9.3 g,
87%).
[0705] MS(ESI) m/z: 300.0 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.35-1.42 (m, 4H), 3.81 (s, 3H), 6.24 (d,
J=6.0 Hz, 1H), 7.11 (d, J=6.4 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 7.83
(d, J=8.4 Hz, 2H).
Step 4: Methyl 4-[1-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-5
ylamino)cyclopropyl]benzoate
[0706] To a solution of methyl
4-[1-[(3-amino-4-hydroxy-2-pyridyl)amino]cyclopropyl]benzoate (9.3
g, 31 mmol) in N,N-dimethylformamide (90 mL) were added potassium
carbonate (17 g, 124 mmol) and 1,2-dibromoethane (23 g, 124 mmol).
The reaction mixture was stirred at 120.degree. C. for 2 hours. The
reaction completion was confirmed by TLC, then the mixture was
cooled to room temperature. The reaction mixture was diluted with
water (500 mL), and the aqueous layer was extracted with ethyl
acetate (3.times.350 mL). The combined organic layers were washed
with brine, dried over sodium sulfate and concentrated under
vacuum. The obtained residue was triturated with diethyl ether, and
the solid was collected by filtration and dried under vacuum to
give the title compound as an off-white solid (7.44 g, 73%).
MS(ESI) m/z: 326.0 (M+1); .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.26-1.27 (m, 2H), 1.33-1.34 (m, 2H), 3.32-3.33 (m, 2H),
3.81 (s, 3H), 4.12 (t, J=4.0 Hz, 2H), 4.69 (br s, 1H), 6.07 (d,
J=6.0 Hz, 1H), 6.40 (br s, 1H), 7.17 (d, J=6.0 Hz, 1H), 7.22 (d,
J=8.0 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H).
Preparation 5: Methyl
4-[(1S)-1-[(1-methyl-3,4-dihydro-2H-pyrido[3,4-b]pyrazin-5-yl)amino]ethyl-
]benzoate
##STR00025##
[0707] Step 1: Methyl
4-[(1S)-1-[[4-(methylamino)-3-nitro-2-pyridyl] amino] ethyl]
benzoate
[0708] A round bottom flask was charged with a mixture of
2-chloro-N-methyl-3-nitropyridin-4-amine (2.0 g, 16.7 mmol) and
methyl 4-[(1S)-1-aminoethyl]benzoate (3.8 g, 21.4 mmol). The flask
was immersed in preheated oil bath at 160.degree. C., and the
mixture was stirred for 1 hour. The reaction completion was
confirmed by TLC, then the mixture was cooled to room temperature,
and the residue was diluted with a mixture of methanol and DCM
(1:10, 100 mL) to give a crude product. The crude product was
purified by silica gel (100-200) column chromatography with 2-5%
methanol in DCM as a mobile phase to give the title compound (3.3
g, 94%).
[0709] MS (ESI) m/z: 330.9 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6); .delta. 1.53 (d, J=6.8 Hz, 3H), 2.91 (d, J=5.2 Hz,
3H), 3.83 (s, 3H), 5.46 (m, J=6.8 Hz, 1H), 6.08 (d, J=6.0 Hz, 1H),
7.50 (d, J=8.0 Hz, 2H), 7.72 (d, J=6.4 Hz, 1H), 7.90 (d, J=8.4 Hz,
2H), 9.11 (d, J=4.8 Hz, 1H), 9.23 (d, J=7.2 Hz, 1H).
Step 2: Methyl 4-[(1S)-1-[[3-amino-4-(methylamino)-2-pyridyl]
amino] ethyl] benzoate
[0710] A flame dried flask was purged with argon and charged with
methyl 4-[(1S)-1-[[4-(methylamino)-3-nitro-2-pyridyl]
amino]ethyl]benzoate (3.3 g, 10 mmol) and ethyl acetate (65 mL).
The flask was degassed for 15 minutes (argon sparge), and Pd/C
(0.66 g, 0.63 mmol, 10% w/w) was added thereto. Hydrogen balloon
was placed over it, and argon was replaced by hydrogen using
vacuum. The reaction mixture was stirred at room temperature for 18
hours under hydrogen atmosphere. After completion of the reaction
by TLC, the reaction mixture was passed through celite pad and
washed with ethyl acetate (150 mL). The filtrate and washing were
concentrated under vacuum to give the title compound as an
off-white solid (2.4 g, 80%). MS (ESI) m/z: 301.0 (M+1); .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 1.43 (d, J=7.2 Hz, 3H), 2.69
(d, J=5.2 Hz, 3H), 3.82 (s, 3H), 3.85 (br s, 2H), 5.15 (d, J=4.8
Hz, 1H), 5.23 (m, J=6.8 Hz, 1H); 5.57 (d, J=7.6 Hz, 1H), 5.89 (d,
J=5.6 Hz, 1H), 7.21 (d, J=5.6 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.85
(d, J=8.4 Hz, 2H).
Step 3: Methyl
4-[(1S)-1-[(1-methyl-3,4-dihydro-2H-pyrido[3,4-b]pyrazin-5-yl)amino]ethyl-
]benzoate
[0711] To a solution of methyl
4-[(1S)-1-[[3-amino-4-(methylamino)-2-pyridyl]amino]ethyl]benzoate
(2.4 g, 8 mmol) in N,N-dimethylformamide (25 mL) were added
potassium carbonate (4.4 g, 32 mmol) and 1,2-dibromoethane (2.74
mL, 32 mmol). The reaction mixture was stirred at 120.degree. C.
for 2 hours. The reaction completion was confirmed by TLC, then the
mixture was cooled to room temperature and diluted with water (200
mL), and the aqueous layer was extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were washed with
brine, dried over sodium sulfate and concentrated under vacuum to
give the title compound as a solid product (2.1 g, crude), which
was used in the next step without further purification.
[0712] MS(ESI) m/z: 327.0 (M+1).
[0713] The compounds of Preparations 6-8 were synthesized in a
similar manner to that of Preparation 3.
TABLE-US-00001 TABLE 1 Pre. MS(ESI)m/z: No. Structure IUPAC Name (M
+ 1) 6 ##STR00026## N-[(4- methoxyphenyl)methyl]-3,4-
dihydro-2H-pyrido[4,3- b][1,4]oxazin-5-amine 271.9 7 ##STR00027##
N-[(3-methyl-2- pyridyl)methyl]-3,4- dihydro-2H-pyrido[4,3-
b][1,4]oxazin-5-amine 256.8 8 ##STR00028##
N-(cyclohexylmethyl)-3,4- dihydro-2H-pyrido[4,3-
b][1,4]oxazin-5-amine 247.8
Preparation 9: Methyl
4-[(1S)-1-[(3-oxo-4H-pyrido[4,3-b][1,4]thiazin-5-yl)amino]ethyl]benzoate
##STR00029##
[0714] Step 1: Methyl
4-[(1S)-1-[(4-chloro-3-nitro-2-pyridyl)amino]ethyl]benzoate
[0715] A mixture of methyl
4-[(1S)-1-[(4-hydroxy-3-nitro-2-pyridyl)amino]ethyl]benzoate (4.5
g, 14.19 mmol) and POCl.sub.3 (45 mL) was heated at 110.degree. C.
for 1 hour. The product formation was confirmed by TLC. The mixture
was evaporated to dryness then quenched by aq. sodium bicarbonate
solution, and the obtained solid was collected by thltration,
washed with n-hexane and dried to give the title compound (4.0 g,
84%).
[0716] MS(EI) m/z: 336.0 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.48 (d, J=6.8 Hz, 3H), 3.82 (s, 3H),
5.33-5.37 (m, 1H), 6.86 (d, J=5.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H),
7.79 (d, J=7.2 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 8.08 (d, J=5.2 Hz,
1H).
Step 2: Methyl
4-[(1S)-1-[[4-(2-ethoxy-2-oxoethyl)sulfanyl-3-nitro-2-pyridyl]amino]ethyl-
]benzoate
[0717] To a solution of methyl
4-[(1S)-1-[(4-chloro-3-nitro-2-pyridyl)amino]ethyl]benzoate (2.0 g,
5.97 mmol) in acetone (30 mL) were added triethylamine (0.83 mL,
5.97 mmol) and ethyl mercaptoacetate (0.65 mL, 5.97 mmol), and the
mixture was heated at 60.degree. C. under nitrogen for 2 hours. The
product formation was confirmed by TLC. The reaction mixture was
cooled to room temperature, then filtered through celite pad, and
washed with acetone, and the filtrate was evaporated under vacuo to
give the title compound (2.4 g, 96%).
[0718] MS(EI) m/z: 420.2 (M+1); .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 1.24-1.28 (m, 3H), 1.62 (d, J=6.8 Hz, 3H), 3.65 (s, 2H),
3.90 (s, 3H), 4.17-4.24 (m, 2H), 5.49-5.53 (m, 1H), 6.55 (d, J=5.2
Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.97-8.00 (m, 3H), 8.94 (d, J=6.8
Hz, 1H).
Step 3: Methyl
4-[(1S)-1-[(3-oxo-4H-pyrido[4,3-b][1,4]thiazin-5-yl)amino]ethyl]benzoate
[0719] To a solution of methyl 4-[(1S)-1-[[4-(2-ethoxy-2-oxoethyl)
sulfanyl-3-nitro-2-pyridyl]amino]ethyl]benzoate (2.4 g, 5.72 mmol)
in acetic acid (30 mL) was added iron powder (5.72 g, 103.10 mmol).
The reaction mixture was stirred and heated at 90.degree. C. for 1
hour, and the product formation was confirmed by TLC. The reaction
mixture was cooled to room temperature, and evaporated to dryness.
Aq. NaHCO.sub.3 solution (20 mL) was added thereto, and the mixture
was extracted with ethyl acetate (3.times.25 mL). The combined
organic layers were washed with brine (25 mL) and dried over sodium
sulfate. The organic layer was evaporated under vacuo to give the
title compound (1.85 g, 94%).
[0720] MS(EI) m/z: 344.0 (M+1).sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.47 (d, J=6.8 Hz, 3H), 3.49 (s, 2H), 3.82 (s, 3H),
5.21-5.24 (m, 1H), 5.53 (d, J=4.8 Hz, 1H), 6.68 (d, J=6.8 Hz, 1H),
7.49-7.51 (m, 3H), 7.89 (d, J=8.0 Hz, 2H), 10.06 (br s, 1H).
Preparation 10: Methyl
4-[(1S)-1-(1,2,3,4-tetrahydro-1,7-naphthyridin-8-ylamino)ethyl]benzoate
##STR00030##
[0721] Step 1: 1,7-Naphthyridin-8-amine
[0722] To a mixture of pyridine-2,3-diamine (10.0 g, 91.74 mmol),
sodium 3-nitrobenzenesulfonate (41.3 g, 183.5 mmol) and glycerol
(33.5 mL, 458.7 mmol) were added water (60 mL) and sulfuric acid
(40 mL). The reaction mixture was heated at 135.degree. C. for 6
days. The product formation was confirmed by TLC. The mixture was
cooled to room temperature, and poured into ice-cold water. The pH
of the mixture was adjusted to 8-9 with saturated NaOH solution
(aq.). The aqueous layer was extracted with ethyl acetate
(3.times.100 mL). The combined organic layers were washed with
brine (100 mL) and dried over sodium sulfate. The organic layer was
evaporated under vacuo, then the crude material was purified by
column chromatography using 5-10% methanol in DCM as a mobile phase
to give the title compound (3.0 g, 22%).
[0723] MS (EI) m/z: 145.8 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 6.90-6.92 (m, 3H), 7.67 (dd, J=3.6 & 8.0
Hz, 1H), 7.86 (d, J=6.0 Hz, 1H), 8.16 (dd, J=2.0 & 8.4 Hz, 1H),
8.78 (dd, J=1.2, 4.0 Hz, 1H).
Step 2: 1,7-Naphthyridin-8-ol
[0724] To a mixture of 1,7-naphthyridin-8-amine (3.0 g, 20.7 mmol)
in water (5.6 mL) and sulfuric acid (24 mL, 455.2 mmol) was added
sodium nitrite (1.42 g, 20.7 mmol) at 0.degree. C. The reaction
mixture was stirred at room temperature for 18 hours. The product
formation was confirmed by TLC. To the reaction mixture was added
aq. NaHCO.sub.3 solution, and the mixture was extracted with
chloroform:methanol (9:1) (3.times.50 mL). The combined organic
layers were washed with brine (50 mL) and dried over sodium
sulfate. The organic layer was evaporated under vacuo to give the
title compound (2.0 g, 67%).
[0725] MS(EI) m/z: 147.1 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 6.54 (d, J=7.2 Hz, 1H), 7.26 (d, J=6.8 Hz,
1H), 7.67 (dd, J=4.0, 8.0 Hz, 1H), 8.10 (dd, J=2.0, 8.4 Hz, 1H),
8.74-8.75 (m, 1H), 11.55 (br s, 1H).
Step 3: 8-Chloro-1,7-naphthyridine
[0726] A solution of 1,7-naphthyridin-8-ol (2.0 g, 13.7 mmol) in
POCl.sub.3 (20 mL) was heated at 100.degree. C. for 16 hours, and
the product formation was confirmed by TLC. The reaction mixture
was cooled to room temperature, and evaporated to dryness. Aq.
NaHCO.sub.3 solution (20 mL) was added thereto, and the mixture was
extracted with ethyl acetate (3.times.25 mL). The combined organic
layers were washed with brine (25 mL) and dried over sodium
sulfate. The organic layer was evaporated under vacuo, and the
residue was purified by column chromatography using 2-5% methanol
in DCM as a mobile phase to give the title compound (1.4 g,
62%).
[0727] MS(EI) m/z: 165.3 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.64 (d, J=6.0 Hz, 1H), 7.70 (dd, J=4.0
& 8.4 Hz, 1H), 8.22 (dd, J=1.6 & 8.4 Hz, 1H), 8.40 (d,
J=6.0 Hz, 1H), 9.15 (dd, J=1.6 & 4.0 Hz, 1H)
Step 4: Methyl
4-[(1S)-1-(1,7-naphthyridin-8-ylamino)ethyl]benzoate
[0728] A mixture of 8-chloro-1,7-naphthyridine (1.4 g, 8.5 mmol)
and methyl 4-[(1S)-1-aminoethyl]benzoate (1.52 g, 8.5 mmol) was
stirred in preheated oil bath at 150.degree. C. for 6 hours. The
product formation was confirmed by TLC. The reaction mixture was
cooled to room temperature, diluted with mixture of methanol and
DCM (1:10, 20 mL), adsorbed on silica gel, and purified by
combiflash column chromatography with 20-25% ethyl acetate in
hexane as a mobile phase to give the title compound (1.5 g,
57%).
[0729] MS(ESI) m/z: 308.3 (M+1); .sup.1H NMR (400 MHz, CDCl.sub.3);
.delta. 1.69 (d, J=7.2 Hz, 3H), 3.88 (s, 3H), 4.95-5.15 (m, 1H),
6.79 (d, J=6.0 Hz, 1H), 7.18-7.22 (m, 1H), 7.50-7.54 (m, 3H),
7.92-8.00 (m, 4H), 8.73 (dd, J=2.0 & 4.4 Hz, 1H).
Step 5: Methyl
4-[(1S)-1-(1,2,3,4-tetrahydro-1,7-naphthyridin-8-ylamino)ethyl]benzoate
[0730] To a suspension of methyl
4-[(1S)-1-(1,7-naphthyridin-8-ylamino)ethyl]benzoate (1.5 g, 4.88
mmol) in methanol (30 mL) was added Pd(OH).sub.2 (0.3 g, 20% w/w)
under argon atmosphere. Hydrogen balloon was placed over it and
argon was replaced by hydrogen using vacuum. The reaction mixture
was stirred at room temperature for 2 days under hydrogen
atmosphere, and the product formation was confirmed by TLC. The
reaction mixture was filtered through celite pad, washed with
methanol:DCM (1:10, 150 mL), and the filtrated was concentrated
under vacuum. The residue was purified by combiflash column
chromatography using 10-15% ethyl acetate in hexane as mobile phase
to give the title compound (1.2 g, 79%).
[0731] MS(ESI) m/z: 312.0 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.44 (d, J=6.8 Hz, 3H), 1.76-1.78 (m, 2H),
2.56 (t, J=6.4 Hz, 2H), 3.26 (t, J=6.0 Hz, 2H), 3.82 (s, 3H), 4.97
(br s, 1H), 5.21-5.24 (m, 1H), 7.78 (d, J=6.8 Hz, 1H), 6.15 (d,
J=4.8 Hz, 1H), 7.12 (d, J=4.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H),
7.86-7.88 (m, 2H)
Preparation 11: Methyl
4-[(1S)-1-[(6-oxo-5H-pyrimido[4,5-b][1,4]oxazin-4-yl)amino]ethyl]benzoate
##STR00031##
[0732] Step 1: Methyl
4-[(1S)-1-[(6-chloro-5-nitropyrimidin-4-yl)amino]ethyl]benzoate
[0733] A solution of 4,6-dichloro-5-nitropyrimidine (3.0 g, 15.46
mmol) and methyl 4-[(1S)-1-aminoethyl]benzoate (2.77 g, 15.46 mmol)
in tetrahydrofuran (60.0 mL) was cooled to 0.degree. C. To the
above mixture was added triethylamine (6.5 mL, 46.4 mmol). The
reaction mixture was stirred at room temperature for 2.0 hours.
Progress of the reaction was monitored by TLC. After completion of
the reaction, the reaction mixture was diluted with water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). The combined
organic layers were washed with water (100 mL) and brine (100 mL),
and dried over sodium sulfate. The organic layer was evaporated
under vacuum, and the residue was purified by combiflash with 8-12%
ethyl acetate in hexane as a mobile phase to give the title
compound as solid (3.5 g, 67%).
[0734] MS(ESI) m/z: (M+1) 337.2 [M(.sup.35Cl)+1]; 339.2
[M(.sup.37Cl)+1]; .sup.1H NMR CDCl.sub.3: .delta. 1.64 (d, J=6.8
Hz, 3H), 3.91 (s, 3H), 5.48-5.52 (m, 1H), 7.40 (d, J=8.4 Hz, 2H),
7.80 (d, J=7.6 Hz 1H), 8.03 (m, 2H), 8.34 (s, 1H).
Step 2: Methyl
4-[(1S)-1-[[6-(2-methoxy-2-oxoethoxy)-5-nitropyrimidin-4-yl]amino]ethyl]b-
enzoate
[0735] To a solution of methyl
4-[(1S)-1-[(6-chloro-5-nitropyrimidin-4-yl)amino]ethyl]benzoate
(2.9 g, 8.6 mmol) and methyl glycolate (0.8 mL, 10.3 mmol) in
tetrahydrofuran (50 mL) was added slowly potassium tert-butoxide
(1M in THF) (10.33 mL, 10.33 mmol). The reaction mixture was
stirred at room temperature for 3 hours. Progress of the reaction
was monitored by TLC. After completion of the reaction, the
reaction mixture was diluted with water (25 mL) and extracted with
ethyl acetate (3.times.50 mL). The combined organic layers were
washed with water (25 mL) and brine (25 mL), and dried over sodium
sulfate. The organic layer was evaporated under vacuum, and the
residue was purified by combiflash with 15-20% ethyl acetate in
hexane as a mobile phase to give the title compound as solid (2.7
g, 80%). MS(ESI) m/z: (M+1) 391.2; .sup.1H NMR CDCl.sub.3: .delta.
1.63 (d, J=7.6 Hz, 3H), 3.77 (s, 3H), 3.91 (s, 3H), 5.03 (s, 2H),
5.52-5.56 (m, 1H), 7.41 (d, J=8.4 Hz, 2H), 8.02 (m, 2H), 8.14 (s,
1H), 8.71 (d, J=6.8 Hz 1H)
Step 3: Methyl
4-[(1S)-1-[(6-oxo-5H-pyrimido[4,5-b][1,4]oxazin-4-yl)amino]ethyl]benzoate
[0736] A mixture of methyl
4-[(1S)-1-[[6-(2-methoxy-2-oxoethoxy)-5-nitropyrimidin-4-yl]amino]ethyl]b-
enzoate (2.5 g, 6.4 mmol) and iron powder (1.4 g, 25.6 mmol) in
acetic acid (12.5 mL) was heated at 100.degree. C. for 3 hours.
Progress of the reaction was monitored by TLC. After completion of
the reaction, acetic acid was evaporated, and the residue was
dissolved in water, and the solution was basified with saturated
sodium bicarbonate solution to pH 9. The aqueous layer was
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were washed with water (25 mL) and brine (25 mL), and dried
over sodium sulfate. The organic layer was evaporated under vacuum,
and the residue was purified by combiflash with 50% ethyl acetate
in hexane as a mobile phase to give the title compound as solid
(1.7 g, 74%). MS(ESI) m/z: (M+1) 329.0;
[0737] .sup.1H NMR CDCl.sub.3: .delta. 1.59 (d, J=6.8 Hz, 3H), 3.91
(s, 3H), 4.73-4.83 (m, 2H), 5.41-5.45 (m, 1H), 5.95 (d, J=6.8 Hz,
1H), 7.43 (d, J=8.4 Hz, 2H), 7.99 (m, 2H), 8.07 (s, 1H), 10.82 (s,
1H).
Preparation 12:
4-Chloro-5-[(3-chlorophenyl)methyl]-6,7-dihydropyrimido[4,5-b][1,4]oxazin-
e
##STR00032##
[0738] Step 1: 4,6-dichloropyrimidin-5-amine
[0739] To a suspension of 4,6-dichloro-5-nitropyrimidine (15 g,
77.3 mmol) in a mixture of ethanol (75 mL) and H.sub.2O (4.5 mL)
were added iron powder (12.95 g, 231.98 mmol) and CaCl.sub.2 (8.58
g, 77.32 mmol). The resulting suspension was stirred at 60.degree.
C. for 30 min. Progress of the reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was filtered to
remove the iron residues, which were washed with ethyl acetate
(2.times.20 mL). The combined organic extracts were washed with
H.sub.2O (3.times.10 mL) and brine (2.times.10 mL), and dried over
Na.sub.2SO.sub.4. The organic layer was evaporated under vacuum,
and the residue was directly loaded onto a silica column and eluted
using 20% ethyl acetate in hexane to give the title compound (3.6
g, 28%).
[0740] MS(ESI) m/z: 164.3 [M(.sup.35Cl)+1], 166.3 [M(.sup.37Cl)+1];
.sup.1H NMR CDCl.sub.3: .delta. 4.50 (br s, 2H), 8.21 (s, 1H).
Step 2:
N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4,6-dichloropyrimidin-5--
amine
[0741] A solution of 4,6-dichloropyrimidin-5-amine (1.0 g, 6.1
mmol) and 2-bromoethoxy-tert-butyl(dimethyl)silane (1.56 mL, 7.32
mmol) in N,N-dimethylformamide (10.0 mL) was cooled to 0.degree. C.
To the above mixture was added sodium hydride (60% on oil) (0.29 g,
7.3 mmol). The reaction mixture was stirred at room temperature for
5 hours. Progress of the reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was diluted with
water (50 mL). The aqueous layer was extracted with ethyl acetate
(3.times.25 mL). The combined organic layers were washed with water
(25 mL) and brine (25 mL), and dried over sodium sulfate. The
organic layer was evaporated under vacuum, and the residue was
purified by combiflash with 5-10% ethyl acetate in hexane as a
mobile phase to give the title compound as oil (0.87 g, 43%).
[0742] MS(ESI) m/z: (M+1) 322.0 [M(.sup.35Cl)+1], 323.9
[M(.sup.37Cl)+1]; .sup.1H NMR CDCl.sub.3: .delta. 0.07 (s, 6H),
0.90 (s, 9H), 3.57-3.61 (m, 2H), 3.78 (t, J=4.8 Hz, 2H), 4.74 (br
s, 1H), 8.24 (s, 1H).
Step 3: 2-[(4,6-dichloropyrimidin-5-yl)amino]ethanol
[0743] A solution of
N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4,6-dichloropyrimidin-5-amine
(1.7 g, 5.27 mmol) in tetrahydrofuran (20.0 mL) was cooled to
0.degree. C. To the solution was added slowly tetrabutylammonium
fluoride (1M in THF) (5.3 mL, 5.3 mmol). The reaction mixture was
stirred at room temperature for 2 hours. Progress of the reaction
was monitored by TLC. After completion of the reaction, the
reaction mixture was diluted with water (50 mL). The aqueous layer
was extracted with ethyl acetate (3.times.25 mL). The combined
organic layers were washed with saturated NaHCO.sub.3 (25 mL) and
brine (25 mL), and dried over sodium sulfate. The organic layer was
evaporated under vacuum, and the residue was purified by combiflash
with 20-25% ethyl acetate in hexane as a mobile phase to give the
title compound as oil (1.0 g, 91%).
[0744] MS(ESI) m/z: 207.5; .sup.1H NMR (400 M Hz, CDCl.sub.3):
.delta. 1.76 (br s, 1H), 3.62-3.66 (m, 2H), 3.82-3.85 (m, 2H), 4.59
(br s, 1H), 8.28 (s, 1H).
Step 4: 4-Chloro-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazine
[0745] To a solution of
2-[(4,6-dichloropyrimidin-5-yl)amino]ethanol (1.0 g, 4.80 mmol) in
tetrahydrofuran (10.0 mL) was added slowly potassium tert-butoxide
(1M in THF) (7.20 mL, 7.20 mmol). The reaction mixture was stirred
at room temperature for 4 hours. Progress of the reaction was
monitored by TLC. After completion of the reaction, the reaction
mixture was diluted with water (25 mL). The aqueous layer was
extracted with ethyl acetate (3.times.25 mL). The combined organic
layers were washed with water (25 mL) and brine (25 mL), and dried
over sodium sulfate. The organic layer was evaporated under vacuum,
and the residue was purified by combiflash with 25-30% ethyl
acetate in hexane as a mobile phase to give the title compound as
solid (0.4 g, 49%).
[0746] MS(ESI) m/z: (M+1) 172.3.0 [M(.sup.35Cl)+1], 174.3
[M(.sup.37Cl)+1]; .sup.1H NMR CDCl.sub.3: .delta. 3.53-3.56 (m,
2H), 4.27 (br s, 1H), 4.51 (t, J=4.6 Hz, 2H), 8.06 (s, 1H)
Step 5:
4-Chloro-5-[(3-chlorophenyl)methyl]-6,7-dihydropyrimido[4,5-b][1,4-
]oxazine
[0747] A solution of 4-chloro-6,7-dihydro-5H-pyrimido[4,5-b]
[1,4]oxazine (0.15 g, 0.87 mmol) in N,N-dimethylformamide (5.0 mL)
was cooled to 0.degree. C. To the above mixture was added sodium
hydride (60% on oil) (0.052 g, 1.31 mmol). 3-Chlorobenzyl bromide
(0.16 mL, 1.31 mmol) was added thereto after 15 min. The reaction
mixture was stirred at room temperature for 2.0 hours. Progress of
the reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was diluted with water (50 mL). The
aqueous layer was extracted with ethyl acetate (3.times.25 mL). The
combined organic layers were washed with water (25 mL) and brine
(25 mL), and dried over sodium sulfate. The organic layer was
evaporated under vacuum, and the residue was purified by combiflash
with 5-10% ethyl acetate in hexane as a mobile phase to give the
title compound as solid (0.2 g, 77%) MS(ESI) m/z: (M+1) 295.8
[M(.sup.35Cl)+1], 297.8 [M(.sup.37Cl)+1]; .sup.1H NMR CDCl.sub.3:
.delta. 3.06 (t, J=4.6 Hz, 2H), 4.25 (s, 2H), 4.41 (t, J=4.8 Hz,
2H), 7.26-7.33 (m, 2H), 7.38-7.41 (m, 1H), 7.54 (s. 1H), 8.34 (s,
1H).
Example A1: Methyl
4-[(1S)-1-[(4-benzyl-2,3-dihydropyrido[4,3-b][1,4]oxazin-5-yl)amino]ethyl-
]benzoate
##STR00033##
[0749] To a solution methyl
4-[(1S)-1-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-5-ylamino)ethyl]benzoa-
te (Preparation 3, 0.15 g, 0.43 mmol) in N,N-dimethylformamide (10
mL) were added potassium carbonate (0.21 g, 1.50 mmol) and benzyl
bromide (0.09 g, 0.52 mmol) at room temperature. The mixture was
stirred at 120.degree. C. for 2 hours. The reaction completion was
confirmed by TLC, then the mixture was cooled to room temperature,
water (20 mL) was added thereto, and the aqueous layer was
extracted with ethyl acetate (3.times.20 mL). The combined organic
layers were washed with brine and dried over sodium sulfate. The
organic layer was evaporated under vacuum, and the residue was
purified by silica gel (100-200) column chromatography with 10-20%
ethyl acetate in hexane as a mobile phase to give the title
compound as colorless oil (0.115 g, 66%).
[0750] MS(ESI) m/z: 404.2 (M+1); .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 1.49 (d, J=6.4 Hz, 3H), 3.04 (t, J=4.0 Hz, 2H), 3.88 (s,
3H), 4.02 (d, J=3.2 Hz, 2H), 4.21 (t, J=4.8 Hz, 2H), 5.11 (d, J=6.4
Hz, 1H), 5.20-5.26 (m, 1H), 6.22 (d, J=6.0 Hz, 1H), 7.36-7.32 (m,
3H), 7.43-7.38 (m, 4H), 7.66 (d, J=5.6 Hz, 1H), 7.92 (d, J=8.0 Hz,
2H).
Example A2: Methyl
4-[(1S)-1-[[4-[(3-chlorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazi-
n-5-yl]amino]ethyl]benzoate
##STR00034##
[0752] To a solution of methyl
4-[(1S)-1-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-5-ylamino)ethyl]benzoa-
te (Preparation 3, 20 g, 52 mmol) in N,N-dimethylformamide (200 mL)
were added potassium carbonate (60 g, 156 mmol) and 3-chlorobenzyl
bromide (12.8 g, 62 mmol) at room temperature. The mixture was
stirred at 120.degree. C. for 2 hours. The reaction completion was
confirmed by TLC, then the mixture was cooled to room temperature,
water (500 mL) was added thereto, and the aqueous layer was
extracted with ethyl acetate (3.times.750 mL). The combined organic
layers were washed with brine and dried over sodium sulfate. The
organic layer was evaporated under vacuum, and the residue was
purified by silica gel (100-200) column chromatography with 10-20%
ethyl acetate in hexane as a mobile phase to give the title
compound as colorless oil (15 g, 65%). MS(ESI) m/z: 438.0 (M+1);
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.49 (d, J=6.8 Hz, 3H),
3.04 (t, J=4.8 Hz, 2H), 3.89 (s, 3H), 3.98 (s, 2H), 4.21 (m, 2H),
4.98 (d, J=6.8 Hz, 1H), 5.30-5.24 (m, 1H), 6.27 (d, J=5.6 Hz, 1H),
7.35-7.25 (m, 5H), 7.43 (s, 1H), 7.67 (d, J=6.0 Hz, 1H), 7.93 (d,
J=8.4 Hz, 2H).
Example A3: Methyl
4-[(1S)-1-[[4-[2-(4-fluorophenoxy)ethyl]-2,3-dihydropyrido[4,3-b][1,4]oxa-
zin-5-yl]amino]ethyl]benzoate
##STR00035##
[0754] The title compound was obtained as an oil (0.16 g, 62%) in a
similar manner to that of Example A2 using the compound obtained in
Preparation 3 (0.20 g, 0.57 mmol) and
1-(2-bromoethoxy)-4-fluoro-benzene (0.15 g, 0.68 mmol).
[0755] MS(ESI) m/z: 452.3 (M+1).
Example A4: Methyl
4-[1-[[4-[(3,4-difluorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazin-
-5-yl]amino]cyclopropyl]benzoate
##STR00036##
[0757] The title compound was obtained as an off-white solid (6 g,
87%) in a similar manner to that of Example A2 using the compound
obtained in Preparation 4 (5.0 g, 15.4 mmol) and 3,4-difluorobenzyl
bromide (3.8 g, 18.4 mmol).
[0758] MS(ESI) m/z: 451.9 (M+1); .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 1.43-1.46 (m, 2H), 1.31-1.34 (m, 2H), 1.43-1.46 (m, 2H),
3.05 (t, J=4.4 Hz, 2H), 3.87 (s, 3H), 3.96 (s, 2H), 4.22 (t, J=4.4
Hz, 2H), 5.42 (br s, 1H), 6.26 (d, J=6.0 Hz, 1H), 7.15-7.22 (m,
4H), 7.26-7.30 (m, 1H), 7.70 (d, J=6.0 Hz, 1H), 7.89 (d, J=8.4 Hz,
2H).
[0759] The compounds of Examples A5-A35 were synthesized in a
similar manner to that of Examples A1-A4.
TABLE-US-00002 TABLE 2 Ex. MS(ESI)m/z: No. Structure IUPAC Name (M
+ 1) A5 ##STR00037## methyl 4-[(1S)-1-[[4-[[4-
(trifluoromethyl)phenyl] methyl]-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]ethyl]benzoate 472.2 A6 ##STR00038##
methyl 4-[(1S)-1-[[4- [(3,4- difluorophenyl)methyl]-
2,3-dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate
440.2 A7 ##STR00039## methyl 4-[(1S)-1-[[4-[(4-
chlorophenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoate 438.2 A8 ##STR00040## methyl
4-[(1S)-1-[[4-[(3- fluorophenyl)methyl]-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]ethyl]benzoate 422.2 A9 ##STR00041##
methyl 4-[(1S)-1-[[4-[(4- fluorophenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 422.2
A10 ##STR00042## methyl 4-[(1S)-1-[[4-(m- tolylmethyl)-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 418.3
A11 ##STR00043## methyl 4-[(1S)-1-[[4-(p- tolylmethyl)-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 418.3
A12 ##STR00044## methyl 4-[(1S)-1-[[4-[(3-
methoxyphenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoate 434.3 A13 ##STR00045## methyl
4-[(1S)-1-[[4- [(3,5- difluorophenyl)methyl]-
2,3-dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate
440.2 A14 ##STR00046## methyl 4-[(1S)-1-[[4-[[3-
(trifluoromethyl)phenyl] methyl]-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]ethyl]benzoate 472.3 A15 ##STR00047##
methyl 4-[(1S)-1-[[4-[(4- methoxyphenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 434.2
A16 ##STR00048## methyl 4-[1-[[4-[(3- fluorophenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]cyclopropyl] benzoate
433.9 A17 ##STR00049## methyl 4-[1-[[4-[(3,5-
difluorophenyl)methyl]- 2,3-dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl] benzoate 451.9 A18 ##STR00050## methyl
4-[1-[[4-[(4- fluorophenyl)methyl]-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]cyclopropyl] benzoate 433.9 A19
##STR00051## methyl 4-[1-[[4-[(4- chlorophenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]cyclopropyl] benzoate
449.9 A20 ##STR00052## methyl 4-[1-[[4-[[4-
(trifluoromethyl)phenyl] methyl]-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]cyclopropyl] benzoate 484.2 A21
##STR00053## methyl 4-[1-[[4-[(4- methoxyphenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]cyclopropyl] benzoate
445.9 A22 ##STR00054## methyl 4-[1-[(4-benzyl-
2,3-dihydropyrido[4,3- b][1,4]oxazin-5- yl)amino]cyclopropyl]
benzoate 416.0 A23 ##STR00055## methyl 4-[1-[[4-[(3-
methoxyphenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl] benzoate 445.9 A24 ##STR00056## methyl
4-[1-[[4-[(3- chlorophenyl)methyl]-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]cyclopropyl] benzoate 449.9 A25
##STR00057## methyl 4-[1-[[4-(m- tolylmethyl)-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]cyclopropyl] benzoate
430.0 A26 ##STR00058## methyl 4-[1-[[4-(p- tolylmethyl)-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]cyclopropyl] benzoate
430.0 A27 ##STR00059## methyl 4-[(1S)-1-[[4-(2- pyridylmethyl)-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 405.0
A28 ##STR00060## methyl 4-[(1S)-1-[[4-(3- pyridylmethyl)-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 404.9
A29 ##STR00061## methyl 4-[(1S)-1-[[4-(2- naphthylmethyl)-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 453.9
A30 ##STR00062## methyl 4-[(1S)-1-[[4-[(4-
phenylphenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoate 479.9 A31 ##STR00063## methyl
4-[(1S)-1-[[4-[[5- (trifluoromethyl)-2- furyl]methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 461.9
A32 ##STR00064## methyl 4-[(1R)-1-[[4-[[4- (trifluoromethyl)phenyl]
methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl[benzoate 472.0 A33 ##STR00065## methyl
4-[(1R)-1-[[4-[(3- chlorophenyl)methyl]-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]ethyl]benzoate 438.0 A34 ##STR00066##
methyl 4-[(1S)-1-[[4-[(3- chlorophenyl)methyl]-1- methyl-2,3-
dihydropyrido[3,4- b]pyrazin-5- yl]amino]ethyl]benzoate 450.9 A35
##STR00067## methyl 4-[(1S)-1-[[1- methyl-4-[[4-
(trifluoromethyl)phenyl] methyl]-2,3- dihydropyrido[3,4-
b]pyrazin-5- yl]amino]ethyl]benzoate 485.0
Example A36: Methyl
4-[(1S)-1-[[3-oxo-4-[[4-(trifluoromethyl)phenyl]methyl]pyrido[4,3-b][1,4]-
thiazin-5-yl]amino]ethyl]benzoate]
##STR00068##
[0761] To a solution of methyl
4-[(1S)-1-[(3-oxo-4H-pyrido[4,3-b][1,4]thiazin-5-yl)amino]ethyl]benzoate
(Preparation 9, 0.3 g, 0.87 mmol) in DMF (15 mL) were added
potassium carbonate (0.24 g, 1.74 mmol) and 4-trifluoromethylbenzyl
bromide (0.250 g, 1.05 mmol). The reaction mixture was heated at
120-130.degree. C. under nitrogen atmosphere for 16 hours and the
product formation was confirmed by TLC. The reaction mixture was
diluted with water (25 mL) and extracted with ethyl acetate
(2.times.15 mL). The combined organic layers were washed with brine
and dried over sodium sulfate. The organic layer was evaporated
under vacuo, and the obtained crude material was purified by by
combiflash column chromatography using 10-15% ethyl acetate in
hexane as a mobile phase to give the title compound (0.2 g,
46%).
[0762] MS (EI) m/z: 502.3 (M+1); .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 1.37 (d, J=6.8 Hz, 3H), 3.32-3.42 (m, 2H), 3.90 (s, 3H),
4.32 (d, J=6.8 Hz, 1H), 5.07-5.09 (m, 2H), 5.19-5.21 (m, 1H), 6.63
(d, J=5.6 Hz, 1H), 7.23-7.27 (m, 3H), 7.46-7.51 (m, 3H), 7.71-7.75
(m, 1H), 7.93-7.95 (m, 2H).
Example A37: Methyl
4-[(1S)-1-[[1-[[4-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-1,7-naph-
thyridin-8-yl]amino]ethyl]benzoate
##STR00069##
[0764] The title compound was obtained (0.120 g, 40%) in a similar
manner to that of Example A36 using the compound obtained in
Preparation 10 (0.2 g, 0.64 mmol) and 4-trifluoromethylbenzyl
bromide (0.184 g, 0.77 mmol).
[0765] MS(ESI) m/z: 470.3 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.41 (d, J=6.8 Hz, 3H), 1.84-1.86 (m, 2H),
2.71 (t, J=6.0 Hz, 2H), 3.01 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 4.06
(s, 2H), 5.19-5.23 (m, 1H), 6.34 (d, J=5.2 Hz, 1H), 7.22-7.25 (m,
2H), 7.49 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.61-7.65 (m,
2H), 7.69 (d, J=5.6 Hz, 1H), 7.86-7.88 (m, 2H)
Example A38: Methyl
4-[(1S)-1-[[5-[(3-chlorophenyl)methyl]-6,7-dihydropyrimido[4,5-b][1,4]oxa-
zin-4-yl]amino]ethyl]benzoate
##STR00070##
[0767] A suspension of
4-chloro-5-[(3-chlorophenyl)methyl]-6,7-dihydropyrimido[4,5-b][1,4]oxazin-
e (Preparation 12, 0.05 g, 0.17 mmol), methyl
4-[(1S)-1-aminoethyl]benzoate (0.045 g, 0.25 mmol) and cesium
carbonate (0.08 g, 0.25 mmol) in 1,4-dioxane (2 mL) was degassed
with argon for 30 min. To above suspension were added
Pd.sub.2(dba).sub.3-CHCl.sub.3 (0.008 g, 0.008 mmol) and BINAP
(0.016 g, 0.025 mmol). Degassing was continued for another 20 min.
The resulting mixture was heated at 100.degree. C. for 18 hours
under argon atmosphere. Progress of the reaction was monitored by
TLC. After completion of the reaction, the reaction mixture was
diluted with water (10 mL). The aqueous layer was extracted with
ethyl acetate (3.times.15 mL). The combined organic layers were
washed and brine (15 mL), and dried over sodium sulfate. The
organic layer was evaporated under vacuum, and the residue was
purified by preparative TLC to give the title compound as solid
(0.05 g, 67%).
[0768] MS(ESI) m/z: (M+1) 439.3 [M(.sup.35Cl)+1], 441.2
[M(.sup.37Cl)+1]; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 1.47 (d,
J=6.8 Hz, 3H), 3.03-2.99 (t, J 25=4.0 Hz, 2H), 3.83 (s, 3H), 4.01
(s, 2H), 4.27 (t, J=4.0 Hz, 2H), 5.24-5.28 (m, 1H), 6.09 (d, J=7.2
Hz, 1H), 7.38-7.48 (m. 5H), 7.57 (s, 1H), 7.87-7.89 (m, 3H)
[0769] The compounds of Examples A39-A51 were synthesized in a
similar manner to that of Examples A1-A4 and A36-A38.
TABLE-US-00003 TABLE 3 Ex. MS(ESI)m/z: No. Structure IUPAC Name (M
+ 1) A39 ##STR00071## methyl 4-[(1S)-1-[[4- (cyclohexylmethyl)-2,3-
dihydropyrido [4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 410.3
A40 ##STR00072## methyl 4-[(1S)-1-[[4-[2-(3-
chlorophenyl)ethyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoate 452.3 A41 ##STR00073## methyl
4-[(1S)-1-[[4-[(3,5- dimethylisoxazol-4- yl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate 423.3
A42 ##STR00074## methyl 4-[(1S)-1-[[4-[(3,4-
difluorophenyl)methyl]-3- oxopyrido[4,3- b][1,4]thiazin-5-
yl]amino]ethyl]benzoate 470.2 A43 ##STR00075## methyl
4-[(1S)-1-[[4-[(3- chlorophenyl)methyl]-3- oxopyrido[4,3-
b][1,4]thiazin-5- yl]amino]ethyl]benzoate 468.2 A44 ##STR00076##
methyl 4-[(1S)-1-[[1- [(3,4- difluorophenyl)methyl]-
3,4-dihydro-2H-1,7- naphthyridin-8- yl]amino]ethyl]benzoate 438.3
A45 ##STR00077## methyl 4-[(1S)-1-[[1-[(3-
chlorophenyl)methyl]-3,4- dihydro-2H-1,7- naphthyridin-8-
yl]amino]ethyl]benzoate 436.3 A46 ##STR00078## methyl
4-[(1S)-1-[[5-[(3- chlorophenyl)methyl]-6- oxo-pyrimido[4,5-
b][1,4]oxazin-4- yl]amino]ethyl]benzoate 453.2 A47 ##STR00079##
methyl 4-[1-[[4-[(3, 4- difluorophenyl)methyl]-3- oxopyrido[4,3-
b][1,4]oxazin-5- yl]amino]cyclopropyl] benzoate 466.1 A48
##STR00080## methyl 4-[(1S)-1-[[4-[4- (trifluoromethyl)benzoyl]-
2,3-dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoate
486.2 A49 ##STR00081## 4-[(3,4- difluorophenyl)methyl]-N-
[(4-methoxyphenyl)methyl]- 2,3-dihydropyrido[4,3-
b][1,4]oxazin-5-amine 398.2 A50 ##STR00082## 4-[(3,4-
difluorophenyl)methyl]-N- [(3-methyl-2- pyridyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5-amine 383.3 A51 ##STR00083##
N-(cyclohexylmethyl)-4- [(3,4- difluorophenyl)methyl]-
2,3-dihydropyrido[4,3- b][1,4]oxazin-5-amine 374.2
Example B1:
4-[(1S)-1-[(4-Benzyl-2,3-dihydropyrido[4,3-b][1,4]oxazin-5-yl)amino]ethyl-
]benzoic acid
##STR00084##
[0771] To a solution of methyl
4-[(1S)-1-[(4-benzyl-2,3-dihydropyrido[4,3-b][1,4]oxazin-5-yl)amino]ethyl-
]benzoate (Example A1, 0.1 g, 0.25 mmol) in ethanol:water (10:1, 6
mL) was added potassium hydroxide (0.042 g, 0.74 mmol). The mixture
was stirred at 100.degree. C. for 2 hours. The reaction completion
was confirmed by TLC, then the mixture was cooled to room
temperature and evaporated to dryness. The residue was dissolved in
water (10 mL), and the solution was acidified by 5% aqueous citric
acid solution to pH 4-5, and stirred for 30 min. The resulting
solid was collected by filtration, washed with water and dried
under vacuum to give the title compound as a pale yellow solid
(0.023 g, 24%).
[0772] MS(ESI) m/z: 390.1 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.54 (d, J=5.6 Hz, 3H), 3.12 (s, 2H), 4.05
(s, 2H), 4.22 (s, 2H), 5.15-5.25 (m, 1H), 6.57 (s, 1H), 7.34-7.41
(m, 5H), 7.48 (d, J=8.8 Hz, 2H), 7.59 (d, J=6.8 Hz, 1H), 7.89 (d,
J=8 Hz, 2H), 13.00 (br s, 1H).
Example B2:
4-[(1S)-1-[[4-[(3-Chlorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazi-
n-5-yl]amino]ethyl]benzoic acid
##STR00085##
[0774] The title compound was obtained as an off-white solid (0.68
g, 88%) in a similar manner to that of Example B1 using the
compound obtained in Example A2 (0.8 g, 1.82 mmol) and potassium
hydroxide (0.3 g, 5.48 mmol).
[0775] MS(ESI) m/z: 423.6 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.41 (d, J=6.8 Hz, 3H), 2.98 (d, J=3.2 Hz,
2H), 4.01 (d, J=6.8 Hz, 2H), 4.19 (t, J=4.4 HZ, 2H), 5.12-5.15 (m,
1H), 5.29 (d, J=6.8 Hz, 1H), 6.18 (d, J=5.6 Hz, 1H), 7.39-7.52 (m,
6H), 7.57 (br s, 1H), 7.83 (d, J=8.0 Hz, 2H), 12.75 (br s, 1H).
Example B3:
4-[(1S)-1-[[4-[2-(4-Fluorophenoxy)ethyl]-2,3-dihydropyrido[4,3-b][1,4]oxa-
zin-5-yl]amino]ethyl]benzoic acid
##STR00086##
[0777] The title compound was obtained as brown solid (0.021 g,
14%) in a similar manner to that of Example B1 using the compound
obtained in Example A3 (0.15 g, 0.33 mmol) and potassium hydroxide
(0.056 g, 0.99 mmol).
[0778] MS(ESI) m/z: 438.1 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.56 (s, 3H), 3.18 (br s, 4H), 4.22 (s, 2H),
4.32 (s, 2H), 5.26 (s, 1H), 6.82-6.96 (m, 2H), 7.10 (t, J=8.8 Hz,
2H), 7.49-7.51 (m, 4H), 7.89 (d, J=8 Hz, 2H), 12.90 (br s, 1H).
Example B4:
4-[1-[[4-[(3,4-Difluorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazin-
-5-yl]amino]cyclopropyl]benzoic acid
##STR00087##
[0780] The title compound was obtained as an off-white solid (5.2
g, 82%) in a similar manner to that of Example B1 using the
compound obtained in Example A4 (6.0 g, 13 mmol) and potassium
hydroxide (2.2 g, 40 mmol).
[0781] MS(ESI) m/z: 438.1 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.60 (br s, 4H), 3.06 (s, 2H), 4.02 (s, 2H),
4.26 (s, 2H), 6.66 (s, 1H), 7.22 (d, J=8 Hz, 2H), 7.36 (br s, 1H),
7.41-7.45 (m, 1H), 7.53-7.58 (m, 1H), 7.79 (t, J=9.2 Hz, 1H), 7.89
(d, J=6.4 Hz, 2H), 8.55 (s, 1H), 12.40 (s, 1H).
[0782] The compounds of Examples B5-B35 were synthesized in a
similar manner to that of Examples B1-B4.
TABLE-US-00004 TABLE 4 Ex. IUPAC Name and MS(ESI)m/z: No. Structure
.sup.1H NMR data (M + 1) B5 ##STR00088## 4-[(1S)-1-[[4-[[4-
(trifluoromethyl)phenyl]methyl]- 2,3-dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid .sup.1H NMR
DMSO-d.sub.6: .delta. 1.38 (d, J = 6.8 Hz, 3H), 3.00 (br s, 2H),
4.11 (d, J = 5.2 Hz, 2H), 4.21 (br s, 2H), 5.10- 5.20 (br s, 1H),
5.20-5.30 (br s, 1H), 6.19 (d, J = 5.6 Hz, 1H), 7.37 (d, J = 8 Hz,
2H), 7.52 (d, J = 6.0 Hz, 1H), 7.74-7.82 (m, 6H), 12.80 (br s, 1H).
458.1 B6 ##STR00089## 4-[(1S)-1-[[4-[(3,4-
difluorophenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.44
(d, J = 6.8 Hz, 3H); 2.98 (s, 2H); 3.97-4.01 (m, 2H); 4.19 (s, 2H);
5.12-5.60 (m, 1H); 5.40 (br s, 1H); 6.19 (br s, 1H); 7.30-7.64 (m,
7H); 7.83 (d, J = 8 Hz, 1H); 12.80 (br s, 1H). 426.2 B7
##STR00090## 4-[(1S)-1-[[4-[(4- chlorophenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid
.sup.1H NMR DMSO-d.sub.6 (for K-slat): .delta. 1.40 (d, J = 6.0 Hz,
3H), 2.96 (s, 2H), 3.95 (s, 2H), 4.19 (s, 2H), 5.12-5.14 (m, 2H),
6.16 (d, J = 6.0 Hz, 1H), 7.10 (d, J = 7.2 Hz, 2H), 7.45-7.50 (m,
4H), 7.56 (d, J = 6.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H). 424.2 B8
##STR00091## 4-[(1S)-1-[[4-[(3- fluorophenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid
.sup.1H NMR DMSO-d.sub.6: .delta. 1.54 (s, 3H), 3.10 (s, 2H), 4.05
(s, 2H), 4.23 (s, 2H), 5.16-5.19 (m, 1H), 6.50 (br s, 1H), 7.17 (t,
J = 6.4 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 9.6 Hz,
1H), 7.41-7.48 (m, 3H), 7.58 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 8
Hz, 2H), 13.00 (br s, 1H). 408.1 B9 ##STR00092## 4-[(1S)-1-[[4-[(4-
fluorophenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.57
(d, J = 6 Hz, 3H), 3.10 (br s, 2H), 4.03 (s, 2H), 4.23 (s, 2H),
5.25 (s, 1H), 6.55 (br s, 1H), 7.22 (t, J = 8.4 Hz, 2H), 7.46-7.52
(m, 4H), 7.59 (d, J = 7.2 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 13.20
(br s, 1H). 408.1 B10 ##STR00093## 4-[(1S)-1-[[4-(m-
tolylmethyl)-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.55
(d, J = 6.4 Hz, 3H), 2.28 (s, 3H), 3.11 (s, 2H), 4.00 (s, 2H), 4.25
(s, 2H), 5.20-5.30 (m, 1H), 6.55 (br s, 1H), 7.15 (d, J = 7.6 Hz,
2H), 7.19- 7.20 (m, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.49 (d, J = 7.2
Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 8 Hz, 2H), 13.00
(br s, 1H). 404.1 B11 ##STR00094## 4-[(1S)-1-[[4-(p-
tolylmethyl)-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.55
(d, J = 7.2 Hz, 3H), 2.30 (s, 3H), 3.11 (br s. 2H), 4.00-4.04 (m,
2H), 4.16-4.22 (m, 2H), 5.30 (br s, 1H), 6.54 (br s, 1H), 7.18 (d,
J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz,
2H), 7.58 (d, J = 6.8 Hz, 1H), 7.89 (d, J = 8.0 Hz, 2H), 13.40 (br
s, 1H). 404.1 B12 ##STR00095## 4-[(1S)-1-[[4-[(3-
methoxyphenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.54
(d, J = 6.4 Hz, 3H), 3.15 (s, 2H), 3.72 (s, 3H), 4.09 (s, 2H), 4.22
(s. 2H), 5.33-5.36 (m, 1H), 6.58 (d, J = 6.4 Hz, 1H), 6.86-6.97 (m,
3H), 7.30 (t, J = 7.6 Hz 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.60 (d, J
= 6.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 13.40 (br s, 1H). 420.1
B13 ##STR00096## 4-[(1S)-1-[[4-[(3,5- difluorophenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid
.sup.1H NMR DMSO-d.sub.6: .delta. 1.57 (d, J = 6.8 Hz, 3H), 3.11
(s, 2H), 4.03-4.09 (m, 2H), 4.27-4.28 (m, 2H), 5.24(br s, 1H), 6.57
(br s, 1H), 7.18-7.27 (m, 3H), 7.50 (d, J = 8 Hz, 2H), 7.61 (d, J =
7.2 Hz, 1H), 7.89 (d, J = 8.0 Hz, 2H), 13.00 (br s, 1H). 426.1 B14
##STR00097## 4-[(1S)-1-[[4-[[3- (trifluoromethyl)phenyl]
methyl]-2,3-dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.55
(d, J = 6.4 Hz, 3H), 3.13 (s, 2H), 4.14 (dd, J = 19.6, 15.2 Hz,
2H), 4.26 (s, 2H), 5.25 (s, 1H), 6.56 (s, 1H), 7.20 (br s, 1H),
7.50 (d, J = 8 Hz, 2H), 7.61-7.79 (m, 5H), 7.87 (d, J = 8.4 Hz,
2H), 13.20 (br s, 1H). 458.2 B15 ##STR00098## 4-[(1S)-1-[[4-[(4-
methoxyphenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.45
(d, J = 6.4 Hz, 3H), 2.94-2.95 (m, 2H), 3.76 (s, 3H), 3.92 (q, J =
14.2 Hz, 2H), 4.18 (s, 2H), 5.15-5.18 (m, 1H), 5.37-5.38 (m, 1H),
6.17 (d, J = 5.2 Hz, 1H) , 6.96 (d, J = 8.4 Hz, 2H), 7.38-7.44 (m,
4H), 7.50 (d, J = 5.6 Hz, 1H), 7.84 (d, J = 8 Hz, 2H), 12.8 (br s,
1H). 420.1 B16 ##STR00099## 4-[1-[[4-[(3- fluorophenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]cyclopropyl]benzoic
acid .sup.1H NMR DMSO-d.sub.6: 1.24-1.27 (m, 2H); 1.35 (br s, 2H),
2.98 (br s, 2H), 4.03 (s, 2H), 4.17 (s, 2H), 6.11 (s, 1H), 6.19 (d,
J = 5.6 Hz, 1H), 7.13-7.15 (m, 1H), 7.19 (d, J = 8.0 Hz, 2H) , 7.36
(d, J = 7.6 Hz, 1H), 7.43-7.50 (m, 3H), 7.77 (d, J = 8.4 Hz, 2H),
12.70 (br s, 1H). 420.3 B17 ##STR00100## 4-[1-[[4-[(3,5-
difluorophenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl]benzoic acid .sup.1H NMR DMSO-d.sub.6:
1.19-1.24 (m, 2H), 1.36 (br s, 2H), 2.97 (s, 2H), 4.02 (s, 2H),
4.18 (s, 2H), 6.21 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.36 (d, J =
6.8 Hz, 2H), 7.49 (d, J = 5.2 Hz, 2H), 7.78 (d, J = 7.6 Hz, 2H),
12.60 (br s, 1H). 438.2 B18 ##STR00101## 4-[1-[[4-[(4-
fluorophenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta.
1.23-1.38 (m, 4H); 2.95-2.97 (m, 2H), 3.99 (s, 2H), 4.15-4.17 (m,
2H), 6.09 (s, 1H), 6.19 (d, J = 5.2 Hz, 1H), 7.18-7.25 (m, 4H),
7.49 (d, J = 6.0 Hz, 1H), 7.57-7.59 (m, 2H), 7.78 (d, J = 8.4 Hz,
2H), 12.70 (br s, 1H). 420.3 B19 ##STR00102## 4-[1-[[4-[(4-
chlorophenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta.
1.28 (br s, 2H), 1.36 (s, 2H), 2.96 (t, J = 4.4 Hz, 2H), 4.00 (s,
2H), 4.16 (t, J = 4.4 Hz, 2H), 6.06 (s, 1H), 6.19 (d, J = 6 Hz,
1H), 7.19 (d, J = 8.4 Hz, 2H), 7.45-7.50 (m, 3H), 7.56 (d, J = 8.4
Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 12.70 (br s, 1H). 436.2 B20
##STR00103## 4-[1-[[4-[[4- (trifluoromethyl)phenyl]methyl]-
2,3-dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta.
1.27 (s, 2H), 1.35 (s, 2H), 2.98 (t, J = 4.4 Hz, 2H), 4.11 (s, 2H),
4.18 (t, J = 4.4 Hz, 2H), 6.06 (br s, 1H), 6.21 (d, J = 5.6 Hz,
1H), 7.19 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 6 Hz, 1H), 7.75-7.79
(m, 6H), 12.70 (br s, 1H). 470.3 B21 ##STR00104## 4-[1-[[4-[(4-
methoxyphenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta.
1.30 (s, 2H), 1.37 (s, 2H), 2.96-2.97 (m, 2H); 3.75 (s, 3H), 3.94
(s, 2H), 4.15 (t, J = 4 Hz, 2H), 6.07 (br s, 1H), 6.21 (d, J = 5.2
Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.41
(d, J = 8.0 Hz, 2H), 7.48 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 8.4 Hz,
2H), 12.70 (br s, 1H). 432.3 B22 ##STR00105## 4-[1-[(4-benzyl-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl)amino]cyclopropyl]benzoic
acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.29 (s, 2H), 1.37 (s, 2H),
2.99 (s, 2H), 4.02 (s, 2H), 4.16 (t, J = 4.4 Hz, 2H), 6.01 (br s,
1H), 6.22 (s, 1H), 7.19 (d, J = 8 Hz, 2H), 7.32 (t, J = 7.2 Hz,
1H), 7.40 (t, J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 3H), 7.78 (d, J
= 8.4 Hz, 2H), 12.70 (br s, 1H) 402.3 B23 ##STR00106##
4-[1-[[4-[(3- methoxyphenyl)methyl]-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]cyclopropy1]benzoic acid .sup.1H NMR
DMSO-d.sub.6: .delta. 1.27 (s, 2H), 1.36 (s, 2H), 3.01 (s, 2H),
3.70 (s, 3H), 4.00 (s, 2H), 4.15 (t, J = 4.0 Hz, 2H), 6.01 (br s,
1H), 6.19 (d, J = 5.2 Hz, 1H), 6.88- 6.90 (m, 1H), 7.04 (s, 1H),
7.09 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.32 (t, J =
8.0 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H),
12.60 (br s, 1H). 432.3 B24 ##STR00107## 4-[1-[[4-[(3-
chlorophenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl]benzoic acid acid .sup.1H NMR DMSO-d.sub.6:
.delta. 1.27 (s, 2H), 1.36 (s, 2H), 2.98- 2.99 (m, 2H), 4.02 (s,
2H), 4.17 (t, J = 4 .0 Hz, 2H), 6.13 (br s, 1H), 6.19 (d, J = 5.2
Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.37-7.52 (m, 4H), 7.65 (s, 1H),
7.78 (d, J = 8.4 Hz, 2H), 12.70 (br s, 1H). 436.3 B25 ##STR00108##
4-[1-[[4-(m-tolylmethyl)- 2,3-dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta.
1.28-1.29 (m, 2H), 1.35-1.36 (m, 2H), 2.33 (s, 3H), 2.97 (t, J =
3.6 Hz, 2H), 3.97 (s, 2H), 4.17 (t, J = 3.6 Hz, 2H), 5.99 (s, 1H),
6.19 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.19 (d, J =
8.0 Hz, 2H), 7.29-7.32 (m, 3H), 7.49 (d, J = 5.2 Hz, 1H), 7.78 (d,
J = 8.0 Hz, 2H), 12.70 (s, 1H). 416.3 B26 ##STR00109##
4-[1-[[4-(p-tolylmethyl)- 2,3-dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]cyclopropyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta.
1.28-1.29 (m, 2H), 1.35-1.36 (m, 2H), 2.31 (s, 3H), 2.96 (t, J =
4.0 Hz, 2H), 3.96 (s, 2H), 4.15 (t, J = 4 .4 Hz, 2H), 6.01 (s, 1H),
6.19 (d, J = 5.6 Hz, 1H), 7.18-7.21 (m, 4H), 7.38 (d, J = 8.0 Hz,
2H), 7.48 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 12.70 (br
s, 1H). 416.3 B27 ##STR00110## 4-[(1S)-1-[[4-(2-
pyridylmethyl)-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.58
(d, J = 6.8 Hz, 3H), 2.84-2.88 (m, 2H), 3.91-3.92 (m, 2H), 4.26 (s,
2H), 5.28-5.32 (m, 1H), 6.09 (d, J = 5.2 Hz, 1H), 7.40-7.45 (m,
2H), 7.48-7.52 (m, 3H), 7.84-7.86 (m, 3H), 7.99 (d, J = 6.8 Hz,
1H), 8.65-8.66 (m, 1H), 12.80 (br s, 1H). 391.3 B28 ##STR00111##
4-[(1S)-1-[[4-(3- pyridylmethyl)-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid .sup.1H NMR
DMSO-d.sub.6: .delta. 1.44 (d, J = 6.8 Hz, 3H), 2.97-2.98 (m, 2H),
4.03-4.05 (m, 2H), 4.21 (s, 2H), 5.14-5.18 (m, 1H), 5.41 (d, J =
6.4 Hz, 1H), 6.18 (d, J = 5.6 Hz, 1H), 7.43-7.46 (m, 2H), 7.52 (d,
J = 5.6 Hz, 1H), 7.83 (d, J = 8 Hz, 2H), 7.94 (d, J = 8 Hz, 1H),
8.40 (s, 1H), 8.55 (d, J = 4.4 Hz, 1H), 8.67 (s, 1H), 12.80 (br s,
1H). 391.3 B29 ##STR00112## 4-[(1S)-1-[[4-(2- naphthylmethyl)-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid
.sup.1H NMR DMSO-d.sub.6: 1.38 (d, J = 6.4 Hz, 3H), 3.03-3.05 (m.
2H), 4.15-4.18 (m, 2H), 4.23-4.25 (m, 2H), 5.17-5.14 (m, 1H), 5.41
(d, J = 6.4 Hz, 1H), 6.20 (d, J = 6 Hz, 1H), 7.38 (d, J = 8 Hz,
2H), 7.54-7.52 (m, 3H), 7.63 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.6
Hz, 2H), 7.98-7.91 (m, 3H), 8.05 (s, 1H), 12.80 (br s, 1H). 440.4
B30 ##STR00113## 4-[(1S)-1-[[4-[(4- phenylphenyl)methyl]-2,3-
dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid
.sup.1H NMR DMSO-d.sub.6: 1.44 (d, J= 6.8 Hz, 3H), 3.02-3.01 (m.
2H), 4.06-4.04 (m, 2H), 4.23 (s, 2H), 5.40 (br s, 1H), 5.15-5.19
(m, 1H), 6.20 (d, J = 5.2 Hz, 1H), 7.37-7.53 (m, 6H), 7.59 (d, J =
8.4 Hz, 2H), 7.68-7.70 (m, 4H), 7.84 (d, J = 8.4 Hz, 2H), 12.50 (br
s, 1H). 446.3 B31 ##STR00114## 4-[(1S)-1-[[4-[[5-
(trifluoromethyl)-2- furyl]methyl]-2,3- dihydropyrido[4,3-
b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid .sup.1H NMR
DMSO-d.sub.6: .delta.: 1.51 (d, J = 6.8 Hz, 3H), 2.95-3.05 (m, 2H),
3.99 (s, 2H), 4.22 (s, 2H), 5.22 (m, 1H), 5.59 (d, J = 6.8 Hz, 1H),
6.16 (d, J = 5.2 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 7.25 (d, J =
2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 6.0 Hz, 1H),
7.85 (d, J = 8.4 Hz, 2H), 12.80 (br s, 1H). 448.3 B32 ##STR00115##
4-[(1R)-1-[[4-[[4- (trifluoromethyl)phenyl]methyl]-
2,3-dihydropyrido[4,3- b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid
.sup.1H NMR DMSO-d.sub.6: .delta. 1.38 (d, J = 3.2 Hz, 3H), 2.99
(s, 2H), 4.09-4.15 (m, 2H), 4.19-5.22 (m, 2H), 5.10-5.19 (m, 1H),
5.21 (d, J = 6.8 Hz, 1H), 6.19 (d, J = 5.6 Hz, 1H), 7.32 (d, J =
7.6 Hz, 1H), 7.53 (d, J = 6 Hz, 1H), 7.73-7.80 (m, 6H), 12.90 (br
s, 1H). 458.0 B33 ##STR00116## 4-[(1R)-1-[[4-[(3-
chlorophenyl)methyl]-2,3- dihydropyrido[4,3- b][1,4]oxazin-5-
yl]amino]ethyl]benzoic acid 1H NMR DMSO-d.sub.6: .delta. 1.41 (d, J
= 6.8 Hz, 3H), 2.99 (d, J = 3.2 Hz, 2H), 4.00-4.02 (m, 2H), 4.20
(t, J = 4.4 Hz, 2H), 5.12-5.16 (m, 1H), 5.30 (d, J = 6.4 Hz, 1H),
6.18 (d, J = 5.6 Hz, 1H), 7.39- 7.52 (m, 6H), 7.58 (s, 1H), 7.83
(d, J = 8.4 Hz, 2H), 12.90 (s, 1H). 424.3 B34 ##STR00117##
4-[(1S)-1-[[4-[(3- chlorophenyl)methyl]-1- methyl-2,3-
dihydropyrido[3,4-b]pyrazin- 5-yl]amino]ethyl]benzoic acid .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 1.38 (d, J = 6.8 Hz, 3H),
2.86-2.89 (m, 2H), 2.91 (s, 3H); 3.26 (br s, 2H), 3.82 (br s, 2H),
5.09-5.13 (m, 1H), 5.23 (d, J = 7.6 Hz, 1H), 6.12 (d, J = 6.0 Hz,
1H), 7.35-7.48 (m, 6H), 7.53 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H),
12.76 (br s, 1H). 437.3 B35 ##STR00118##
4-[(1S)-1-[[1-methyl-4-[[4- (trifluoromethyl)phenyl]methyl]-
2,3-dihydropyrido[3,4- b]pyrazin-5- yl]amino]ethyl]benzoic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.36 (d, J = 6.8 Hz,
3H), 2.85-2.88 (m, 2H), 2.92 (s, 3H), 3.27 (br s, 2H), 3.92 (br s,
2H), 5.09-5.21 (m, 2H), 6.14 (d, J = 6.0 Hz, 1H), 7.34 (d, J = 7.6
Hz, 2H), 7.43 (d, J = 5.6 Hz, 1H), 7.68-7.80 (m, 6H), 12.70 (brs,
1H). 471.3
Example B36:
4-[(1S)-1-[[3-oxo-4-[[4-(trifluoromethyl)phenyl]methyl]pyrido[4,3-b][1,4]-
thiazin-5-yl]amino]ethyl]benzoic acid
##STR00119##
[0784] To a solution of methyl
4-[(1S)-1-[[3-oxo-4-[[4-(trifluoromethyl)phenyl]methyl]pyrido[4,3-b][1,4]-
thiazin-5-yl]amino]ethyl]benzoate (Example A36, 0.2 g, 0.40 mmol)
in THF:MeOH:H.sub.2O (3:2:1; 18 mL) was added lithium hydroxide
monohydrate (0.049 g, 1.20 mmol), and the mixture was stirred at
room temperature for 2 days, and the product formation was
confirmed by TLC. The reaction mixture was evaporated under vacuo,
diluted with water (5 mL), and then acidified by using 1N HCl to pH
4-5. The obtained solid was collected by filtration, washed with
water, n-hexane, dried, and then purified by cobiflash column
chromatography using 20-25% ethyl acetate in hexane as a mobile
phase to give the title compound (0.11 g, 57%).
[0785] MS(EI) m/z: 488.1 (M+1); .sup.1H NMR DMSO-d.sub.6: .delta.
1.48 (br s, 3H), 3.50-3.58 (m, 2H), 5.23-5.45 (m, 3H), 6.64 (d,
J=5.2 Hz, 1H), 6.72-6.80 (m, 1H), 7.18-7.26 (m, 2H), 7.48-7.52 (m,
2H), 7.55-7.58 (m, 3H), 7.86 (d, J=8.0 Hz, 2H), 12.78 (br s,
1H)
Example B37:
4-[(1S)-1-[[1-[[4-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-1,7-naph-
thyridin-8-yl]amino]ethyl]benzoic acid
##STR00120##
[0787] The title compound was obtained as an light brown solid
(0.035 g, 30%) in a similar manner to that of Example B36 using the
compound obtained in Example A37 (0.12 g, 0.26 mmol) and lithium
hydroxide (0.031 g, 0.77 mmol).
[0788] MS(EI) m/z: 456.2 (M+1).sup.1H NMR DMSO-d.sub.6: .delta.
1.32 (d, J=6.8 Hz, 3H), 1.77-1.82 (m, 2H), 2.65 (t, J=6.4 Hz, 2H),
2.94 (t, J=4.8 Hz, 2H), 4.07 (s, 2H), 5.08-5.11 (m, 1H), 5.17 (d,
J=6.4 Hz, 1H), 6.36 (d, J=4.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.54
(d, J=5.2 Hz, 1H), 7.72-7.79 (m, 6H), 12.78 (br s, 1H).
Example B38:
4-[(1S)-1-[[5-[(3-chlorophenyl)methyl]-6,7-dihydropyrimido[4,5-b][1,4]oxa-
zin-4-yl]amino]ethyl]benzoic acid
##STR00121##
[0790] The title compound was obtained as an off-white solid (0.03
g, 62%) in a similar manner to that of Example B1 or B36 using the
compound obtained in Example A38 (0.05 g, 0.11 mmol) and lithium
hydroxide (0.023 g, 0.56 mmol).
[0791] MS(ESI) m/z: 424.8 [M(.sup.35Cl)+1], 426.8 [M(.sup.37Cl)+1];
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.46 (d, J=6.8 Hz,
3H), 3.00 (d, J=3.6 Hz, 2H), 4.00 (s, 2H), 4.27 (t, J=4.8 HZ, 2H),
5.20-5.25 (m, 1H), 6.04 (d, J=7.6 Hz, 1H), 7.39-7.45 (m, 5H), 7.57
(s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 12.80 (br s,
1H).
[0792] The compounds of Examples B39-B45 were synthesized in a
similar manner to that of Examples B1-B4 and B36-B38.
TABLE-US-00005 TABLE 5 Ex. MS (ESI) m/z: No. Structure IUPAC Name
and 1H NMR data (M + 1) B39 ##STR00122##
4-[(1S)-1-[[4-(cyclohexylmethyl)-2,3-
dihydropyrido[4,3-b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.86- 0.94 (m, 2H),
1.10-1.30 (m, 3H), 1.49 (d, J = 6.4 Hz, 3H), 1.60-1.75 (m, 4H),
1.83-1.92 (m, 2H), 2.54 (s, 2H), 2.98- 3.09 (m, 2H), 4.15 (t, J =
4.0 Hz, 2H), 5.11-5.15 (m, 2H), 6.11 (d, J = 5.6 Hz, 1H), 7.45 (m,
3H), 7.87 (m, 2H), 12.45 (brs, 1H). 396.3 B40 ##STR00123##
4-[(1S)-1-[[4-[2-(3-chlorophenyl)ethyl]-2,3-
dihydropyrido[4,3-b][1,4]oxazin-5- yl]amino]ethyl]benzoic acid
.sup.1H NMR DMSO-d.sub.6: .delta. 1.18 (d, J = 7.6 Hz, 3H),
2.93-2.95 (m, 4H), 3.15-3.25 (m, 2H), 4.22 (t, J = 4.4 Hz, 2H),
4.74 (d, J = 8.0 Hz, 1H), 5.12-5.16 (m, 1H), 6.10 (d, J = 6.0 Hz,
1H), 7.26-7.32 (m, 5H), 7.41-7.43 (m, 2H), 7.84 (d, J = 8.4 Hz,
2H), 12.70 (s, 1H). 438.2 B41 ##STR00124##
4-[(1S)-1-[[4-[(3,5-dimethylisoxazol-4-
yl)methyl]-2,3-dihydropyrido[4,3-b]
[1,4]oxazin-5-yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6:
.delta. 1.50 (d, J = 6.8 Hz, 3H), 2.19 (s, 3H), 2.32 (s, 3H), 2.95-
2.98 (m, 2H), 3.80-3.95 (m, 2H), 4.17 (t, J = 4.6 Hz, 2H),
5.15-5.18 (m, 1H), 5.42 (d, J = 6.4 Hz, 1H), 6.17 (d, J = 6.0 Hz,
1H), 7.48 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 5.6 Hz, 1H), 7.86 (d, J
= 8.4 Hz, 2H), 12.80 (s, 1H). 409.2 B42 ##STR00125##
4-[(1S)-1-[[4-[(3,4-difluorophenyl)methyl]-
3-oxopyrido[4,3-b][1,4]thiazin-5-yl] amino]ethyl]benzoic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.50 (br s, 3H),
3.49-3.57 (m, 2H), 4.80-5.27 (m, 3H), 6.40 (br s, 1H), 6.74-7.02
(m, 3H), 7.24-7.26 (m, 1H), 7.46-7.54 (m, 2H), 7.56-7.62 (m, 1H),
7.86 (d, J = 7.6 Hz, 2H), 12.78 (br s, 1H) 456.2 B43 ##STR00126##
4-[(1S)-1-[[4-[(3-chlorophenyl)methyl]-3-
oxopyrido[4,3-b][1,4]thiazin-5-yl]amino] ethyl]benzoic acid .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 1.49 (d, J = 5.2 Hz, 3H),
3.50-3.58 (m, 2H), 4.80-5.27 (m, 3H), 6.63 (d, J = 4.8 Hz, 1H),
6.72-6.78 (m, 1H), 6.90-7.06 (m, 2H), 7.20 (br s, 2H), 7.50 (d, J =
5.6 Hz, 2H), 7.59 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H),
12.76 (br s, 1H). 454.1 B44 ##STR00127##
4-[(1S)-1-[[1-[(3,4-difluorophenyl)methyl]-
3,4-dihydro-2H-1,7-naphthyridin-8-yl] amino]ethyl]benzoic acid
.sup.1H NMR DMSO-d.sub.6: .delta. 1.37 (d, J = 6.8 Hz, 3H),
1.75-1.79 (m, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 4.4 Hz,
2H), 3.95 (s, 2H), 5.08-5.12 (m, 1H), 5.30-5.40 (m, 1H), 6.35 (d, J
= 5.6 Hz, 1H), 7.35-7.37 (m, 3H), 7.42-7.49 (m, 1H), 7.53-7.59 (m,
2H), 7.81 (d, J = 8.4 Hz, 2H), 12.78 (br s, 1H) 424.3 B45
##STR00128## 4-[(1S)-1-[[1-[(3-chlorophenyl)methyl]-3,4-
dihydro-2H-1,7-naphthyridin-8-yl]amino] ethyl]benzoic acid .sup.1H
NMR DMSO-d.sub.6: .delta. 1.34 (d, J = 6.8 Hz, 3H), 1.76-1.81 (m,
2H), 1.76-1.81 (m, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.92-2.94 (m,
2H), 3.98 (s, 2H), 5.08-5.12 (m, 1H), 5.24 (d, J = 6.0 Hz, 1H),
6.35 (d, J = 5.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.37-7.40 (m,
1H), 7.42-7.49 (m, 2H), 7.54 (d, J = 5.2 Hz, 2H), 7.81 (d, J = 8.4
Hz, 2H), 12.78 (br s, 1H) 422.2
Example B46:
4-[(1S)-1-[[8-Methyl-4-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyr-
ido[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoic acid
##STR00129##
[0793] Step 1:
4-[(1S)-1-[[8-Bromo-4-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyri-
do[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoic acid
[0794] To a mixture of
4-[(1S)-1-[[4-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyrido[4,3-b-
][1,4]oxazin-5-yl]amino]ethyl]benzoic acid (Example B14, 2.0 g,
4.37 mmol) in acetonitrile (50 mL) was added and N-bromosuccinimide
(0.93 g, 5.20 mmol) at room temperature, and the mixture was
stirred for 2 hours. The reaction completion was confirmed by TLC.
To the resulting residue was added water (50 mL), and the mixture
was extracted with ethyl acetate (3.times.50 mL). The combined
organic layers were washed with brine (50 mL) and dried over sodium
sulfate. The organic layer was evaporated under vacuum, and the
residue was purified by combiflash with 50% ethyl acetate in hexane
as a mobile phase to give the title compound as solid (1.1 g,
47%).
[0795] MS(ESI) m/z: 536.0 [M(.sup.79Br)+1], 538.0 [M(.sup.81Br)+1];
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.38 (d, J=6.8 Hz,
3H), 3.05 (s, 2H), 4.13 (s, .sup.2H), 4.31-4.32 (m, 2H), 5.08-5.11
(m, 1H), 5.33 (d, J=6.8 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.73-7.81
(m, 7H), 12.75 (s, 1H).
Step 2: Methyl
4-[(1S)-1-[[8-bromo-4-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyri-
do[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoate
[0796] To a solution of
4-[(1S)-1-[[8-bromo-4-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyri-
do[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoic acid (1.0 g, 1.86
mmol) in N,N-dimethylformamide (10 mL) was cooled to 0.degree. C.,
potassium carbonate (0.52 g, 3.72 mmol) and methyl iodide (0.14 mL,
0.22 mmol) were added thereto. The reaction mixture was stirred at
room temperature for 2.0 hours. Progress of the reaction was
monitored by TLC. After completion of the reaction, water (50 mL)
was added thereto. The mixture was extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were washed with water
(50 mL) and brine (50 mL), and dried over sodium sulfate. The
organic layer was evaporated under vacuum, and the residue was
purified by combiflash with 20% ethyl acetate in hexane as a mobile
phase to give the title compound as solid (0.78 g, 76%).
[0797] MS(ESI) m/z: (M+1) 550.2 [M(.sup.79Br)+1], 552.2
[M(.sup.81Br)+1] .sup.1H NMR CDCL.sub.3: .delta. 1.46 (d, J=6.8 Hz,
3H), 3.07 (t, J=4.4 Hz, 2H), 3.89 (s, 3H), 4.07 (s, 2H), 4.33 (m,
2H), 4.90 (d, J=6.4 Hz, 1H), 5.18-5.30 (m, 1H), 7.28 (d, J=8.4 Hz,
2H), 7.54 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.6 Hz, 2H), 7.84 (s. 1H),
7.91 (d, J=8.0 Hz, 2H)
Step 3: Methyl
4-[(1S)-1-[[8-methyl-4-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyr-
ido[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoate
[0798] A mixture of methyl
4-[(1S)-1-[[8-bromo-4-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyri-
do[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoate (0.2 g, 0.36 mmol),
methyl boronic acid (0.108 g, 1.81 mmol), potassium phosphate
(0.269 g, 1.27 mmol), water (0.2 mL) and toluene (4 mL) was
degassed with argon for 30 min. To the mixture were added palladium
acetate (0.008 g, 0.036 mmol) and tricyclohexylphosphine (0.020 g,
0.073 mmol). Degassing was continued for another 20 min. The
resulting mixture was heated at 100.degree. C. for 3 hours under
argon atmosphere. The reaction mixture was cooled to room
temperature, filtered through celite pad, and washed with ethyl
acetate. The filtrate was evaporated under vacuum, and the residue
was purified by combiflash with 10-15% ethyl acetate in hexane as a
mobile phase to give the title compound (0.09 g. 75,%).
[0799] MS(ESI) m/z: 486.3 [M+1]; .sup.1H NMR CDCl.sub.3: 1.46 (d,
J=6.8 Hz, 3H), 2.02 (s, 3H), 3.01-3.03 (m, 2H), 3.88 (s, 3H), 4.07
(m, 2H), 4.24-4.26 (m, 2H), 4.79 (d, J=6.8 Hz, 1H), 5.20-5.24 (m,
1H), 7.30 (d, J=8.0 Hz, 2H), 7.54-7.56 (m, 3H), 7.65 (d, J=8.4 Hz,
2H), 7.90 (d, J=8.4 Hz, 2H).
Step 4:
4-[(1S)-1-[[8-Methyl-4-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dih-
ydropyrido[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoic acid
[0800] To a solution of methyl
4-[(1S)-1-[[8-methyl-4-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyr-
ido[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoate (0.09 g, 0.18 mmol)
in THF:water:methanol (3:2:2, 6 mL) was added lithium hydroxide
monohydrate (0.039 g, 0.92 mmol). The mixture was stirred at room
temperature for 18 hours. The reaction completion was confirmed by
TLC, and then the mixture was evaporated to dryness. The residue
was dissolved in water (10 mL), and the solution was acidified by
5% aqueous citric acid solution to pH 4-5, and stirred for 30 min.
The resulting solid was collected by filtration, washed with water
and dried under vacuum to give the title compound as a pale yellow
solid (0.065 g, 74%).
[0801] MS(ESI) m/z: 472.1 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.36 (d, J=6.8 Hz, 3H), 1.95 (s, 3H), 2.98
(t, J=3.2 Hz, 2H), 4.09-4.11 (m, 2H), 4.26 (t, J=3.6 Hz, 2H),
5.02-5.15 (m, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.40 (s, 1H), 7.77-7.81
(m, 6H), 12.85 (br S, 1H)
[0802] The compounds of Example B47 was synthesized in a similar
manner to that of Example B46.
TABLE-US-00006 TABLE 6 Ex. IUPAC Name MS (ESI) m/z: No. Structure
.sup.1H NMR data (M + 1) B47 ##STR00130##
4-[(1S)-1-[[8-cyclopropyl- 4-[[3-(trifluoromethyl)
phenyl]methyl]-2,3- dihydropyrido[4,3-b][1,4]
oxazin-5-yl]amino]ethyl] benzoic acid .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 0.50-0.54 (m, 2H), 0.73-0.75 (m, 2H), 1.35
(d, J = 6.0 Hz, 3H), 1.70- 1.74 (m, 1H), 2.99 (s, 2H), 4.05- 4.16
(m, 2H), 4.29 (s, 2H), 5.02- 5.15 (m, 2H), 7.26 (s, 1H), 7.33 (d, J
= 8.0 Hz, 2H), , 7.75-7.80 (m, 6H), 12.85 (br s, 1H). 498.1
Example C1: Potassium salt of
4-[(1S)-1-[[4-[(4-methoxyphenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxaz-
in-5-yl]amino]ethyl]benzoic acid
##STR00131##
[0804] To a solution of methyl
4-[(1S)-1-[[4-[(4-methoxyphenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxaz-
in-5-yl]amino]ethyl]benzoate (Example A15, 0.43 g, 0.99 mmol) in
mixture of solvent ethanol:H.sub.2O (9:1, 10 mL) was added
potassium hydroxide (0.167 g, 2.97 mmol). The mixture was stirred
at 100.degree. C. for 2 hours. The reaction completion was
confirmed by TLC then, the mixture was cooled to room temperature
and evaporated to dryness, and the residue was purified by
preparative HPLC using acetonitrile:water to give the title
compound as an off-white solid (0.24 g, 53%).
[0805] MS(ESI) m/z: 420.1 (M+1); .sup.1H NMR DMSO-d.sub.6: .delta.
1.44 (d, J=6.4 Hz, 3H), 2.93-2.94 (m, 2H), 3.76 (s, 3H), 3.88 (s,
2H), 4.18 (s. 2H), 5.13-5.16 (m, 1H), 5.28 (d, J=6.8 Hz, 1H), 6.16
(d, J=5.2 Hz, 1H), 6.95 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H),
7.35 (d, J=8.0 Hz, 2H), 7.54 (d, J=5.6 Hz, 1H), 7.76 (d, J=8.0 Hz,
1H).
[0806] The compounds of Examples C2-C7 were synthesized in a
similar manner to that of Example Cl.
TABLE-US-00007 TABLE 7 Ex. IUPAC Name MS (ESI) m/z: No. Structure
.sup.1H NMR data (M + 1) C2 ##STR00132## Potassium salt of
4-[(1S)-1- [[4-[(3-chlorophenyl)methyl]-
2,3-dihydropyrido[4,3-b][1,4] oxazin-5-yl]amino]ethyl]benzoic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 1.35 (d, J = 6.4 Hz,
3H), 2.94 (t, J = 4.0 Hz, 2H), 3.95 (s, 2H), 4.17 (t, J = 4.0 Hz,
2H), 5.05-5.16 (m, 2H), 6.15 (d, J = 6.0 Hz, 1H), 7.10 (d, J = 7.2
Hz, 2H), 7.38-7.42 (m, 3H), 7.53-7.55 (m, 2H), 7.67 (d, J = 8.0 Hz,
2H). 424.2 C3 ##STR00133## Potassium salt of 4-[(1S)-1-
[[4-[[4-(trifluoromethyl)phenyl] methyl]-2,3-dihydopyrido[4,3-b]
[1,4]oxazin-5-yl]amino]ethyl] benzoic acid .sup.1H NMR
DMSO-d.sub.6: .delta. 1.36 (d, J = 6 Hz, 3H), 2.96-2.98 (m, 2H),
4.06 (s, 2H), 4.19-4.21 (m. 2H), 5.12-5.13 (m, 1H), 6.18 (d, J =
5.6 Hz, 1H), 7.08 (d, J = 8 Hz, 2H), 7.56 (d, J = 6 Hz, 2H), 7.67
(d, J = 8 Hz, 2H), 7.72 (d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H).
458.2 C4 ##STR00134## Potassium salt of 4-[(1S)-1-
[[4-[(3,4-difluorophenyl)methyl]- 2,3-dihydropyrido[4,3-b][1,4]
oxazin-5-yl]amino]ethyl]benzoic acid .sup.1H NMR DMSO-d.sub.6:
.delta. 1.40 (d, J = 4.4 Hz, 3H), 2.96 (s, 2H), 3.95 (s, 2H), 4.18
(s, 2H), 5.12 (br s, 1H), 5.21 (br s, 1H), 6.16 (br s, 1H), 7.18
(d, J = 6.4 Hz, 2 H), 7.33 (s, 1H), 7.43-7.62 (br s, 3H), 7.73 (d,
J = 6.8 Hz, 2 H). 426.1 C5 ##STR00135## Potassium salt of
4-[1-[[4-[(3,4- difluorophenyl)methyl]-2,3-
dihydropyrido[4,3-b][1,4]oxazin- 5-yl]amino]cyclopropyl]benzoic
acid .sup.1H NMR DMSO-d.sub.6: .delta. 1.23-1.29 (m, 4H), 2.95 (t,
J = 4.0 Hz, 2H), 3.77 (s, 2H), 4.16 (t, J = 4.0 Hz, 1H), 6.12 (s,
1H), 6.17 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.37-7.46
(m, 2H), 7.50 (d, J = 5.6 Hz, 2H), 7.70 (d, J = 8.4 Hz, 3H). 438.3
C6 ##STR00136## Potassium salt of 4-[1-[[4-[[3-
(trifluoromethyl)phenyl]methyl]- 2,3-dihydropyrido[4,3-b][1,4]
oxazin-5-yl]amino]cyclopropyl] benzoic acid .sup.1H NMR
DMSO-d.sub.6: .delta. 1.15-1.65 (m, 2H), 1.21-1.24 (m, 2H),
2.97-2.99 (m, 2H), 4.10 (s, 2H), 4.17 (t, J = 4.4 Hz, 2 H), 5.94
(s, 1H), 6.17 (d, J = 5.2 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.51
(d, J = 5.2 Hz, 1H), 7.61-7.69 (m, 4H), 7.85-7.88 (m, 2H). 471.1 C7
##STR00137## Potassium salt of 4-[1-[[4-[[4-
(trifluoromethyl)phenyl]methyl]- 2,3-dihydropyrido[4,3-b][1,4]
oxazin-5-yl]amino]cyclopropyl] benzoic acid .sup.1H NMR
DMSO-d.sub.6: .delta. 1.18 (s, 2H), 1.25 (s, 2H), 2.98 (s, 2H),
4.09 (s, 2H), 4.18 (s, 2H), 5.91 (s, 1H), 6.19 (d, J = 6 Hz, 1H),
6.99 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 6 Hz, 1H), 7.65 (d, J = 8.4
Hz, 2H), 7.7 (s, 4H). 470.3
Example D1:
4-[(1S)-1-[[4-[[4-(Trifluoromethyl)phenyl]methyl]-2,3-dihydropyrido[4,3-b-
][1,4]oxazin-5-yl]amino]ethyl]benzamide
##STR00138##
[0808] To a solution of
4-[(1S)-1-[[4-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyrido[4,3-b-
][1,4]oxazin-5-yl]amino]ethyl]benzoic acid (Example B5, 1.0 g, 2.18
mmol) in THF (10 mL) were added triethylamine (0.61 mL, 4.37 mmol)
and ethyl chloroformate (0.31 mL, 3.28 mmol). The reaction mixture
was stirred at 0.degree. C. under argon atmosphere. After 15 min
stirring at 0.degree. C., 7N ammonia solution in 1.4-dioxane was
added thereto, and the mixture was continued to stir for 1 hour.
The reaction mixture was concentrated under vacuum, and the residue
was obtained was purified by silica gel (100-200) column
chromatography with 35% ethyl acetate in hexane to give the title
compound as a white solid (0.75 g, 75%).
[0809] MS(ESI) m/z: 457.1 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.38 (d, J=6.4 Hz, 3H), 2.99 (s, 2H), 4.10
(d, J=3.2 Hz, 2H), 4.19-4.21 (m, 2H), 5.12-5.15 (m, 1H), 5.24 (d,
J=7.2 Hz, 2H), 6.18 (d, J=5.2 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.52
(d, J=6.0 Hz, 1H), 7.73-7.78 (m, 6H), 7.79-7.85 (m, 1H).
Example D2:
N-Methoxy-4-[(1S)-1-[[4-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydropy-
rido[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzamide
##STR00139##
[0811] To a solution of
4-[(1S)-1-[[4-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyrido[4,3-b-
][1,4]oxazin-5-yl]amino]ethyl]benzoic acid (Example B5, 0.1 g, 0.21
mmol), methoxylamine hydrochloride (0.033 g, 0.40 mmol) and HATU
(0.114 g, 0.30 mmol) in DMF (5 mL) was added DIPEA (0.18 mL, 1.0
mmol). The reaction mixture was stirred at room temperature for 18
hours. The reaction mixture was quenched with water (20 mL), and
extracted with ethyl acetate (3.times.20 mL). The combined organic
layers were washed successively with water (20 mL) and brine (20
mL), dried over sodium sulfate and concentrated under vacuum. The
crude mixture thus obtained was purified by flash column
chromatography using silica gel and 30% ethyl acetate in hexane to
give the title compound as an off-white solid (0.08 g, 75%).
[0812] MS(ESI) m/z: 487.1 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.38 (d, J=7.2 Hz, 3H), 2.99 (s, 2H), 3.68
(s, 3H), 4.10 (d, J=4.8 Hz, 2H), 4.20-4.21 (m, 2H), 5.10-5.13 (m,
1H), 5.25 (s, 1H), 6.19 (d, J=5.6 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H),
7.51 (d, J=5.2 Hz, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.74-7.79 (m, 4H),
11.6 (s, 1H).
[0813] The compounds of Examples D3-D5 were synthesized in a
similar manner to that of Example D2.
TABLE-US-00008 TABLE 8 Ex. IUPAC Name MS (ESI) m/z: No. Structure
.sup.1H NMR data (M + 1) D3 ##STR00140##
N-methyl-4-[(1S)-1-[[4-[[4- (trifluoromethyl)phenyl]
methyl]-2,3-dihydropyrido[4,3- b][1,4]oxazin-5-yl]amino]ethyl]
benzamide .sup.1H NMR DMSO-d.sub.6: .delta. 1.38 (d, J = 6.3 Hz,
3H), 2.75 (d, J = 4.8 Hz, 3H), 2.99 (s, 2H), 4.10 (d, J = 4.0 Hz,
2H), 4.21 (d, J = 4.0 Hz, 2H), 5.12-5.15 (m, 1H), 5.24 (d, J = 7.2
Hz, 1H), 6.19 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.52
(d, J = 5.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.74-7.79 (m, 4H),
8.31-8.30 (m, 1H). 471.1 D4 ##STR00141##
N-ethoxy-4-[(1S)-1-[[4-[[4- (trifluoromethyl)phenyl]
methyl]-2,3-dihydropyrido[4,3- b][1,4]oxazin-5-yl]amino]ethyl]
benzamide .sup.1H NMR DMSO-d.sub.6: .delta. 1.17-1.29 (m, 3H), 1.38
(d, J = 6.8 Hz, 3H), 2.99 (s, 2H), 3.90 (q, J = 6.8 Hz, 2H), 4.10
(d, J = 3.6 Hz, 2H), 4.20 (s, 2H), 5.09-5.13 (m, 1H), 5.25 (s, 1H),
6.19 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.52 (d, J =
5.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.73-7.79 (m, 4H). 501.1 D5
##STR00142## N-benzyloxy-4-[(1S)-1-[[4-[[4-
(trifluoromethyl)phenyl]methyl]- 2,3-dihydropyrido[4,3-b][1,4]
oxazin-5-yl]amino]ethyl]benzamide .sup.1H NMR DMSO-d.sub.6: .delta.
1.37 (d, J = 6.4 Hz, 3H); 2.99 (s, 2H), 4.10 (dd, J = 5.6, 15.6 Hz,
2H), 4.20 (s, 2H), 4.89 (s, 2H), 5.10-5.13 (m, 1H), 5.25 (d, J =
6.4 Hz, 1H), 6.19 (d, J = 5.6 Hz, 1H), 7.34-7.45 (m, 7H), 7.51 (d,
J = 5.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.75-7.8 (m, 4H).
563.2
Example E1:
4-[(1S)-1-[[4-[[4-(Trifluoromethyl)phenyl]methyl]-2,3-dihydropyrido[4,3-b-
][1,4]oxazin-5-yl]amino]ethyl]benzonitrile
##STR00143##
[0815] To a solution of
4-[(1S)-1-[[4-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyrido[4,3-b-
][1,4]oxazin-5-yl]amino]ethyl]benzamide (Example D1, 0.4 g, 0.87
mmol) in THF (10 mL) were added pyridine (0.18 mL, 2.19 mmol) and
trifluoroacetic anhydride (0.3 mL, 2.19 mmol). The reaction mixture
was stirred at 0.degree. C. under argon atmosphere for 2 hours. The
reaction was quenched with water (20 mL) and extracted with ethyl
acetate (3.times.20 mL). The combined organic layers were washed
successively with water (20 mL) and brine (20 mL), dried over
sodium sulfate and concentrated under vacuum. The residue was
purified by silica gel (100-200) column chromatography with 20-30%
ethyl acetate in hexane to give the title compound as an off-white
solid (0.335 g, 87%). MS(ESI) m/z: 439.1 (M+1); .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 1.39 (d, J=7.2 Hz, 3H), 2.99 (d, J=3.6
Hz, 2H), 4.12 (dd, J=10.0, 15.6 Hz, 2H), 4.21 (d, J=5.4 Hz, 2H),
5.09-5.12 (m, 1H), 5.32 (d, J=6.4 Hz, 1H), 6.20 (d, J=5.6 Hz, 1H),
7.48-7.50 (m, 3H), 7.70 (d, J=8.4 Hz, 2H), 7.77-7.80 (m, 4H).
Example F1:
N-[(1S)-1-[4-(1H-Tetrazol-5-yl)phenyl]ethyl]-4-[[4-(trifluoromethyl)pheny-
l]methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazin-5-amine
##STR00144##
[0817] A mixture of
4-[(1S)-1-[[4-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyrido[4,3-b-
][1,4]oxazin-5-yl]amino]ethyl]benzonitrile (Example E1, 0.1 g, 0.23
mmol) and trimethylsilylazide (0.039 g, 0.34 mmol) was heated at
100.degree. C. under argon atmosphere for 4 hours. After cooling at
room temperature, the reaction mixture was diluted with water (10
mL) and extracted with ethyl acetate (3.times.20 mL). The combined
organic layers were washed successively with water (20 mL) and
brine (20 mL), dried over sodium sulfate and concentrated under
vacuum. The residue was purified by silica gel (100-200) column
chromatography with 60-70% ethyl acetate in hexane as a mobile
phase to give the title compound as an off-white solid (0.035 g,
32%).
[0818] MS(ESI) m/z: 482.1 (M+1
[0819] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.43 (d, J=6.4
Hz, 3H), 3.00 (s, 2H), 4.13 (dd, J=16.0, 8.2 Hz, 2H), 4.20-4.22 (m,
2H), 5.13-5.17 (m, 1H), 5.34 (s, 1H), 6.21 (d, J=6 Hz, 1H),
7.49-7.54 (m, 3H), 7.75-7.79 (m, 4H), 7.91 (d, J=8.8 Hz, 2H), 16.6
(br s, 1H).
Example G1:
4-[(1S)-1-[[8-Chloro-4-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyr-
ido[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoic acid
##STR00145##
[0821] A mixture of
4-[(1S)-1-[[4-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydropyrido[4,3-b-
][1,4]oxazin-5-yl]amino]ethyl]benzoic acid (Example B5, 0.2 g, 0.44
mmol) in acetonitrile (10 mL) and N-chlorosuccinimide (0.058 g,
0.44 mmol) was heated at 70.degree. C. for 2 hours. The reaction
completion was confirmed by TLC. To the resulting residue was added
water (15 mL), and the mixture was extracted with ethyl acetate
(3.times.15 mL). The combined organic layers were washed with brine
(20 mL) and dried over sodium sulfate. The organic layer was
evaporated under vacuum, and the residue was purified by LCMS
purification technique to give the title compound (0.11 g,
51%).
[0822] MS(ESI) m/z: 492.2 (M+1); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.38 (d, J=6.8 Hz, 3H), 3.05 (s, 2H), 4.13
(s, 2H), 4.31-4.32 (m, 2H), 5.09-5.12 (m, 1H), 5.32 (d, J=6.8 Hz,
1H), 7.36 (d, J=8.4 Hz, 2H), 7.66 (s, 1H), 7.74-7.82 (m, 6H), 12.75
(s, 1H).
TABLE-US-00009 Formulation Example 1 (production of capsule) 1)
compound of Example 1 30 mg 2) fine powder cellulose 10 mg 3)
lactose 19 mg 4) magnesium stearate 1 mg Total 60 mg
[0823] 1), 2), 3) and 4) are mixed and filled in a gelatin
capsule.
TABLE-US-00010 Formulation Example 2 (production of tablet) 1)
compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 4)
calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000
tablets total 140 g
[0824] The total amount of 1), 2) and 3) and 4) (30 g) is kneaded
with water, vacuum dried, and sieved. The sieved powder is mixed
with 4) (14 g) and 5) (1 g), and the mixture is punched by a
tableting machine, whereby 1000 tablets containing 30 mg of the
compound of Example 1 per tablet are obtained.
Experimental Example 1
[0825] Membrane Preparation:
[0826] The full-length coding sequences for human EP1 (NM_000955),
human EP2 (NM_000956), human EP3 (NM_198717) and human EP4
(NM_000958) were cloned into pcDNA3.1(+) vector (Life Technologies,
CA, USA). In order to prepare overexpressed EP 1-4 membrane in
Freestyle293 cells (Life Technologies, CA, USA), the pcDNA3.1(+)
vector encoding a cDNA of the relevant gene was transiently
transfected into FreeStyle293 cells using 293Fectin (Life
Technologies, CA, USA) according to the manufacturer instruction
manual. After 2 days, cultured cells were centrifuged
(1,000.times.g, 10 min, 4.degree. C.) and pellets homogenized by a
probe sonicator (Sonics vibracell, Sonics and Materials Inc., USA;
31% Amp, 5 sec pulse, 1 min interval, 4 cycles) in ice-cold 50 mM
Tris-HCl buffer (pH 7.5 at 25.degree. C.) containing 0.5 mM EDTA,
250 mM Sucrose and 10 mM MgCl.sub.2. Cell homogenates were
centrifuged (890.times.g, 10 min, 4.degree. C.), and the
supernatant was recovered. Total membrane fractions were isolated
by ultracentrifugation (140,000.times.g, 60 min, 4.degree. C.)
Pellets were re-suspended in the same buffer, and stored at
-80.degree. C. until use. The protein concentration in homogenate
was determined with the BCA Protein Assay Kit (Pierce
Biotechnology, Inc., IL, USA) according to the manufacturer
protocol.
[0827] Primary In Vitro Binding Assay:
[0828] The binding affinity of the compounds was evaluated using a
competitive radioligand binding assay which measured the specific
binding of [3H] PGE2 to the human EP4 receptor. Briefly, varying
concentrations of NCEs were incubated with cell membrane fractions
generated HEK293F cells transiently transfected with human EP4
receptor as described above. Each reaction consisted of 10 .mu.g
membrane protein and NCE in 50 mM Tris-HCl, pH-6.0 by NaOH, 10 mM
MgCl.sub.2 and 0.5 mM EDTA assay buffer. Radioligand, [3H] PGE2
(American Radiochemicals Inc. Specific Activity 180 Ci/mmol), at a
final of 1 nM was added to each reaction where the final assay
volume was 200 .mu.L and concentration of DMSO was adjusted to 1%.
Appropriate controls included total binding in the assay (vehicle
control) and control for non-specific binding. Non-specific binding
was evaluated by incubating the hEP4 protein with 10 .mu.M
unlabeled PGE2 under the same assay conditions as NCEs. The
reaction was incubated at room temperature for 2 hours and
terminated by harvesting the reaction contents to a PEI coated GF/C
filter plate (PerkinElmer). The plate was washed four times with
cold 50 mM Tris-HCl, pH-7.5 wash buffer and dried at 50.degree. C.
for 2 hours or at 37.degree. C. overnight. [3H] PGE2 bound to the
protein was quantified by the addition of 25 .mu.L of Microscint PS
(PerkinElmer) and plate was read on MicroBeta2 liquid Scintillation
and luminescence counter (PerkinElmer). Data was analyzed using
GraphPad Prism 5 (GraphPad Software Inc., San Diego, Calif.) where
non-specific binding was normalized to 0% specific binding of
[3]PGE2 and vehicle control (DMSO) was normalized to 100% specific
binding of [3]PGE2. Binding affinity of NCEs, Ki, was generated
using One site--Fit Ki equation in GraphPad Prism 5.
[0829] Functional Assay:
[0830] The functional assay for hEP4 activation and inhibition was
carried out via the quantitative determination of agonist, PGE2,
induced cAMP response using HTRF in a competitive immunoassay
(Cisbio dynamic 2 kit). NCEs at varying concentrations were
evaluated for inhibition of PGE2 induced increase in cAMP. Briefly,
C6 glioma cells overexpressing hEP4 (Takeda) were cultured in DMEM
(low glucose, pyruvate), 10% FBS (Gibco) and PenStep. The cells
were harvested on the day of the assay, washed with HBSS+10 mM
HEPES (pH 7.4)+0.1% BSA buffer and pre-incubated with varying
concentrations of NCE. Each reaction contained 7000 cells and NCEs
in HBSS+10 mM HEPES+0.1% BSA assay buffer along with PDE inhibitors
IBMX and Ro 20-1724 (final concentration of each inhibitor 200 mM).
Following 15 min pre-incubation, the cells were treated with EC80
concentration of agonist PGE2 for 30 min to induce cAMP. Final
volume of the assay was 6 .mu.L and DMSO concentration was
maintained at 1%. The reaction was terminated with the addition of
cAMP labeled with the dye d2 in lysis buffer according to
manufacturers' protocol. This was followed by the addition of the
anti-cAMP antibody labeled with Cryptate according to the
manufacturers' protocol. The reaction was incubated at room
temperature in dark for 45 min and the plate was evaluated for
fluorescence at 665 nm (FRET) and 620 nm (cryptate emission) on a
Flexstation III microplate reader (Molecular Devices, Sunnyvale,
Calif.) Ex max: 313 nm; Em1: 620 nm; Em2: 665 nm. Data was analyzed
using GraphPad Prism 5 (GraphPad Software Inc., San Diego, Calif.)
where cells treated with agonist (EC.sub.80) was normalized to 0%
inhibition of hEP4 and cells treated with buffer (no agonist) was
normalized to 100% inhibition of hEP4. IC.sub.50 of NCEs was
generated using non-linear regression--Log(inhibitor) vs. response
equation in GraphPad Prism 5.
[0831] Table 9: Potency of compound in hEP4 radioligand binding
assay at 300 nM and cell based assay (cAMP) at 1 .mu.M
TABLE-US-00011 TABLE 9 hEP4 radioligand hEP4 cell based binding
assay assay (cAMP) Example % Inhibition at 300 nM % Inhibition at 1
.mu.M Example A46 12 ND* Example A47 12 ND* Example A48 28 ND*
Example A49 17 ND* Example A50 26 ND* Example A51 ND* (300 nM) ND*
29 (1 .mu.M) Example B1 93 100 Example B2 98 100 Example B3 81 90
Example B4 83 97 Example B5 74 100 Example B6 89 100 Example B7 99
100 Example B8 97 100 Example B9 97 100 Example B10 97 100 Example
B11 95 100 Example B12 98 100 Example B13 92 100 Example B14 93 100
Example B15 98 99 Example B16 93 88 Example B17 96 86 Example B18
93 79 Example B19 92 81 Example B20 92 92 Example B21 87 87 Example
B22 80 90 Example B23 100 74 Example B24 100 71 Example B25 98 79
Example B26 93 87 Example B27 42 ND* Example B28 49 ND* Example B29
100 96 Example B30 87 77 Example B31 92 98 Example B32 53 47
Example B33 66 36 Example B34 42.5 ND* Example B35 42.4 ND* Example
B36 49 ND* Example B37 97 97 Example B38 88 ND* Example B39 100 93
Example B40 80 85 Example B41 47 ND* Example B42 0.3 (300 nM) ND*
26 (1 .mu.M) Example B43 10 ND* Example B44 93 92 Example B45 100
98 Example B46 87 95 Example B47 60 ND* Example D1 85 98 Example D2
87 92 Example D3 73 84 Example D4 92 93 Example D5 88 90 Example E1
92 91 Example F1 100 90 Example G1 100 92 *ND: Not determined
Experimental Example 2
[0832] Suppression of Arthritis Development in Adjuvant Induced
Arthritis (AIA) model in female Lewis rats
[0833] Adjuvant arthritis was induced on day 1 in female Lewis rats
(10-12 weeks) by intradermal injection of heat killed Mycobacterium
tuberculosis in complete freund's adjuvant (CFA)intradermally
(Mycobacterium tuberculosis 100 mg in 5 mL incomplete freunds
adjuvant, 200 .mu.L per rat). Animals were randomized into
different treatment groups, each group consist of 8 animals based
on clinical scores on day 14. The animals in control group were
given CFA and in second control group were administered with CFA
and vehicle (1% Tween-80+0.5% CMC, quantity sufficient, 3 ml/kg,
PO), where as animals in experimental groups were treated with CFA
and EP4 antagonist (Example B2 and Example B4) in therapeutic
fashion orally twice a day (BID) from day 14 to day 23 at 0.1, 0.3,
1, 3, 10 and 30 mg/kg doses.
[0834] Evaluation of disease severity (Arthritis Score)
[0835] Animals were evaluated for clinical symptoms and scored
accordingly for inflamed paws and erythema. The scorer was blind to
the treatment groups. Key findings for example B2 (Refer FIG. 1)
and B4 (Refer FIG. 2) in rat arthritis model are as follows.
[0836] Rats treated with Example B2 showed 23, 45, 46, 67, 68 and
71% reduction in arthritis score at 0.1, 0.3, 1, 3, 10 and 30 mg/kg
BID, doses respectively compared to vehicle treatment at the end of
study period. ED.sub.50 was 0.76 mg/kg, PO, BID.
[0837] Rats treated with Example B4 showed 3, 4, 27, 39, 51 and 55%
reduction in arthritis score at 0.1, 0.3, 1, 3, 10 and 30 mg/kg
BID, doses respectively compared to vehicle treatment at the end of
study period. ED.sub.50 was 8.8 mg/kg, PO, BID.
INDUSTRIAL APPLICABILITY
[0838] Compound (I) has a superior EP4 receptor antagonistic
action, which may be useful as an agent for the prophylaxis or
treatment of EP4 receptor associated diseases (e.g., rheumatoid
arthritis, aortic aneurysm (e.g. abdominal aortic aneurysm,
thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.),
endometriosis, ankylosing spondylitis, inflammatory breast cancer
etc.) and the like.
[0839] This application is based on patent application No.
2244/DEL/2015 filed on Jul. 23, 2015 in India, the contents of
which are encompassed in full herein.
* * * * *