U.S. patent application number 17/002603 was filed with the patent office on 2020-12-10 for substituted pyridazines and 1,2,4-triazines as prostacyclin receptor modulators.
The applicant listed for this patent is Arena Pharmaceuticals, Inc.. Invention is credited to Rena HAYASHI, Jason B. IBARRA, Thuy-Anh TRAN, Brett ULLMAN, Ning ZOU.
Application Number | 20200385357 17/002603 |
Document ID | / |
Family ID | 1000005050199 |
Filed Date | 2020-12-10 |
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United States Patent
Application |
20200385357 |
Kind Code |
A1 |
TRAN; Thuy-Anh ; et
al. |
December 10, 2020 |
SUBSTITUTED PYRIDAZINES AND 1,2,4-TRIAZINES AS PROSTACYCLIN
RECEPTOR MODULATORS
Abstract
Cyclohexane derivatives of Formula Ia and pharmaceutical
compositions thereof that modulate the activity of the PGI2
receptor. ##STR00001## Compounds of the present invention and
pharmaceutical compositions thereof are directed to methods useful
in the treatment of: pulmonary arterial hypertension (PAH) and
related disorders; platelet aggregation; coronary artery disease;
myocardial infarction; transient ischemic attack; angina; stroke;
ischemia-reperfusion injury; restenosis; atrial fibrillation; blood
clot formation in an angioplasty or coronary bypass surgery
individual or in an individual suffering from atrial fibrillation;
atherosclerosis; atherothrombosis; asthma or a symptom thereof; a
diabetic-related disorder such as diabetic peripheral neuropathy,
diabetic nephropathy or diabetic retinopathy; glaucoma or other
disease of the eye with abnormal intraocular pressure;
hypertension; inflammation; psoriasis; psoriatic arthritis;
rheumatoid arthritis; Crohn's disease; transplant rejection;
multiple sclerosis; systemic lupus erythematosus (SLE); ulcerative
colitis; ischemia-reperfusion injury; restenosis; atherosclerosis;
acne; type 1 diabetes; type 2 diabetes; sepsis; and chronic
obstructive pulmonary disorder (COPD).
Inventors: |
TRAN; Thuy-Anh; (San Diego,
CA) ; HAYASHI; Rena; (Hacienda Heights, CA) ;
IBARRA; Jason B.; (Las Vegas, NV) ; ULLMAN;
Brett; (San Diego, CA) ; ZOU; Ning; (San
Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Arena Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000005050199 |
Appl. No.: |
17/002603 |
Filed: |
August 25, 2020 |
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Application
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16159971 |
Oct 15, 2018 |
10793529 |
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17002603 |
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15230825 |
Aug 8, 2016 |
10138210 |
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16159971 |
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14566019 |
Dec 10, 2014 |
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15230825 |
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13133036 |
Jun 6, 2011 |
8940891 |
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PCT/US2009/006408 |
Dec 7, 2009 |
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14566019 |
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61205726 |
Jan 22, 2009 |
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61201150 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 409/04 20130101;
C07D 403/04 20130101; C07D 401/04 20130101; C07D 237/14 20130101;
C07D 253/07 20130101 |
International
Class: |
C07D 237/14 20060101
C07D237/14; C07D 253/07 20060101 C07D253/07; C07D 401/04 20060101
C07D401/04; C07D 403/04 20060101 C07D403/04; C07D 409/04 20060101
C07D409/04 |
Claims
1. A compound selected from compounds of Formula Ia and
pharmaceutically acceptable salts, solvates and hydrates thereof:
##STR00102## wherein: R.sup.1 is selected from: H and
C.sub.1-C.sub.8 alkyl; R.sup.2 and R.sup.3 are each independently
selected from: H, C.sub.1-C.sub.8 alkyl, aryl and heteroaryl;
wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each
optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl
and halogen; and X is selected from: N and CH.
2. The compound according to claim 1, wherein R.sup.1 is H.
3. The compound according to claim 1, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl.
4. The compound according to any one of claims 1 to 3, wherein
R.sup.2 and R.sup.3 are each independently selected from: H,
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: chloro, ethyl, fluoro, isopropyl, methoxy, methyl,
methylthio, phenyl and trifluoromethyl.
5. The compound according to any one of claims 1 to 3, wherein
R.sup.2 and R.sup.3 are each independently selected from: H,
1H-pyrazol-4-yl, methyl, phenyl, pyridinyl, thiophen-2-yl and
thiophen-3-yl; wherein said methyl, phenyl, pyridinyl,
thiophen-2-yl and thiophen-3-yl are each optionally substituted
with one or more substituents each independently selected from:
chloro, ethyl, fluoro, isopropyl, methoxy, methyl, methylthio,
phenyl and trifluoromethyl.
6. The compound according to any one of claims 1 to 3, wherein
R.sup.2 and R.sup.3 are each independently selected from: H,
1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl,
2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,
2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-fluoropyridin-3-yl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl,
3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,
3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-chloropyridin-3-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl.
7. The compound according to any one of claims 1 to 3, wherein
R.sup.2 is selected from: C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl
and halogen.
8. The compound according to any one of claims 1 to 3, wherein
R.sup.2 is selected from: C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: chloro, ethyl, fluoro, isopropyl,
methoxy, methyl, methylthio, phenyl and trifluoromethyl.
9. The compound according to any one of claims 1 to 3, wherein
R.sup.2 is selected from: methyl, phenyl, pyridinyl, thiophen-2-yl
and thiophen-3-yl; wherein said methyl, phenyl, pyridinyl,
thiophen-2-yl and thiophen-3-yl are each optionally substituted
with one or more substituents each independently selected from:
chloro, ethyl, fluoro, isopropyl, methoxy, methyl, methylthio,
phenyl and trifluoromethyl.
10. The compound according to any one of claims 1 to 3, wherein
R.sup.2 is selected from: 2,3-difluorophenyl, 2-chlorophenyl,
2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,
3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl,
3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl,
4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl,
4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl.
11. The compound according to any one of claims 1 to 3, wherein
R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy and halogen.
12. The compound according to any one of claims 1 to 3, wherein
R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: chloro, fluoro, methoxy and
methyl.
13. The compound according to any one of claims 1 to 3, wherein
R.sup.3 is selected from: H, 1H-pyrazol-4-yl, phenyl, pyridinyl and
thiophen-2-yl; wherein said phenyl, pyridinyl and thiophen-2-yl are
each optionally substituted with one or more substituents each
independently selected from: chloro, fluoro, methoxy and
methyl.
14. The compound according to any one of claims 1 to 3, wherein
R.sup.3 is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl,
2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,
2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,
2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,
4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
15. The compound according to any one of claims 1 to 14, wherein X
is N.
16. The compound according to any one of claims 1 to 14, wherein X
is CH.
17. The compound according to claim 1, selected from compounds of
Formula Ic and pharmaceutically acceptable salts, solvates and
hydrates thereof: ##STR00103## wherein: R.sup.2 is selected from:
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen; and R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl,
aryl and heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl are each optionally substituted with one or more
substituents each independently selected from: C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 alkoxy and halogen.
18. The compound according to claim 1, selected from compounds of
Formula Ic and pharmaceutically acceptable salts, solvates and
hydrates thereof: ##STR00104## wherein: R.sup.2 is selected from:
2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl,
2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl,
3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,
3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl; and R.sup.3 is selected from: H,
1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl,
2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,
2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,
2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,
4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
19. The compound according to claim 1, selected from compounds of
Formula Ie and pharmaceutically acceptable salts, solvates and
hydrates thereof: ##STR00105## wherein: R.sup.2 is selected from:
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen; and R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl,
aryl and heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl are each optionally substituted with one or more
substituents each independently selected from: C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 alkoxy and halogen.
20. The compound according to claim 1, selected from compounds of
Formula Ie and pharmaceutically acceptable salts, solvates and
hydrates thereof: ##STR00106## wherein: R.sup.2 is selected from:
2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl,
2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl,
3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,
3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl; and R.sup.3 is selected from: H,
1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl,
2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,
2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,
2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,
4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
21. The compound according to claim 1, selected from compounds of
Formula Ig and pharmaceutically acceptable salts, solvates and
hydrates thereof: ##STR00107## wherein: R.sup.2 is selected from:
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen; and R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl,
aryl and heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl are each optionally substituted with one or more
substituents each independently selected from: C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 alkoxy and halogen.
22. The compound according to claim 1, selected from compounds of
Formula Ig and pharmaceutically acceptable salts, solvates and
hydrates thereof: ##STR00108## wherein: R.sup.2 is selected from:
2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl,
2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl,
3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,
3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl; and R.sup.3 is selected from: H,
1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl,
2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,
2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,
2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,
4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
23. The compound according to claim 1, selected from compounds of
Formula Ii and pharmaceutically acceptable salts, solvates and
hydrates thereof: ##STR00109## wherein: R.sup.2 is selected from:
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen; and R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl,
aryl and heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl are each optionally substituted with one or more
substituents each independently selected from: C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 alkoxy and halogen.
24. The compound according to claim 1, selected from compounds of
Formula Ii and pharmaceutically acceptable salts, solvates and
hydrates thereof: ##STR00110## wherein: R.sup.2 is selected from:
2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl,
2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl,
3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,
3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl; and R.sup.3 is selected from: H,
1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl,
2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,
2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,
2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,
4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
25. A compound according to claim 1 selected from the following
compounds and pharmaceutically acceptable salts, solvates and
hydrates thereof:
2-(((1r,4r)-4-((4-(3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-oxo-3,4-diphenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-benzhydryl-6-oxopyridazin-1(6H)yl)-methyl)cyclohexyl)me-
thoxy)acetic acid;
2-(((1s,4s)-4-((3-(4-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(3-chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1r,4r)-4-((3-benzhydryl-6-oxopyridazin-(6H)yl)methyl)cyclohexyl)meth-
oxy)acetic acid;
2-(((1s,4s)-4-((4-(2,3-difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)me-
thyl) cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-oxo-3-phenyl-4-m-tolylpyridazin-1(6H)yl)methyl)cyclohex-
yl)methoxy) acetic acid;
2-(((1s,4s)-4-((6-oxo-3-phenyl-4-p-tolylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(3-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(4-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(2-chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(4-chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(2-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(4-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(2-fluoro-3-methoxyphenyl)-6-oxo-3-phenylpyridazin-(6H)-
-yl)methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(3-fluoro-5-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H-
)yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1r,4r)-4-((6-oxo-3,4-diphenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-oxo-4-phenyl-3-p-tolylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(3-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(4-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(2-chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(4-chlorophenyl)-6-oxo-4-phenylpyridazin-1(6)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(2-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(3-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(3-fluoro-5-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H-
)yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(2,3-difluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(3-chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(5-chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-
yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(3-chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-
yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(3-chloro-4-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-
yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(3,5-dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(3,4-dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(2-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(4-ethylphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(4-(trifluoromethyl)phenyl)
pyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(3-fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-
yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(4-isopropylphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-
yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(4-(methylthio)phenyl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-oxo-5,6-di-p-tolyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-oxo-3-phenyl-4-(pyridin-3-yl)pyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(5-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)yl-
) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-oxo-3-phenyl-4-(1H-pyrazol-4-yl)pyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(3-chlorophenyl)-6-oxo-3-p-tolylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((5,6-bis(4-fluorophenyl)-3-oxo-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(4-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)yl-
) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(2-methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(4-chloro-2-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-
yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(4-chloro-3-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-
yl) methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(2-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(6-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(2-chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(2-fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(5-methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(5-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(6-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-(4-fluorophenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-(6-chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((4-(5-chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((5-(3-chlorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-(4-methoxyphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((5-(3-methoxyphenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-(2-fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin--
2(3H)-yl)methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((6-(4-chlorophenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((5-(3-fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1r,4r)-4-((6-(2-fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin--
2(3H)-yl)methyl)cyclohexyl)methoxy)acetic acid;
2-(((1r,4r)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-oxo-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-oxo-5-(pyridin-4-yl)-6-p-tolyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1s,4s)-4-((3-oxo-5-n-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1r,4r)-4-((3-oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)yl)methyl)cyc-
lohexyl)methoxy)acetic acid;
2-(((1r,4r)-4-((5-(3-fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3)yl)
methyl)cyclohexyl)methoxy)acetic acid;
2-(((1r,4r)-4-((3-oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid; and
2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)yl)
methyl)cyclohexyl)methoxy)acetic acid.
26. A pro-drug of compound according to anyone of claims 1 to 25
selected from compounds of Formula Ha and pharmaceutically
acceptable salts, solvates and hydrates thereof: ##STR00111##
wherein: R.sup.2 and R.sup.3 are each independently selected from:
H, C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen; R.sup.5 is selected from: H and carboxyl; and R.sup.6 is
selected from: H and C.sub.1-C.sub.6 alkyl; wherein C.sub.1-C.sub.6
alkyl is optionally substituted with 4-hydroxyphenyl, amino,
carboxamide, carboxyl, guanidine, hydroxyl, imidazolyl, indolyl,
methylthio, phenyl, pyrrolidinyl, sulfo and thiol.
27. A pro-drug of compound according to any one of claims 1 to 25
selected from compounds of Formula Ha and pharmaceutically
acceptable salts, solvates and hydrates thereof: ##STR00112##
wherein: R.sup.2 is selected from: C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl
and halogen. R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl,
aryl and heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl are each optionally substituted with one or more
substituents each independently selected from: C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 alkoxy and halogen. R.sup.5 is H or
carboxyl; and R.sup.6 is H or --CH.sub.2SO.sub.3H.
28. A pro-drug according claim 26, selected from
2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl-
)cyclohexyl)methoxy)acetamido)acetic acid and pharmaceutically
acceptable salts, solvates and hydrates thereof.
29. A pro-drug according claim 26, selected from:
2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl-
)cyclohexyl)methoxy)acetamide)ethanesulfonic acid and
pharmaceutically acceptable salts, solvates and hydrates
thereof.
30. A pharmaceutical composition comprising a compound according to
any one of claims 1 to 25, or a pro-drug according to any one of
claims 26 to 29, and a pharmaceutically acceptable carrier.
31. A method of modulating the activity of a PGI2 receptor by
contacting the receptor with a compound according to any one of
claims 1 to 25, a pro-drug according to any one of claims 26 to 29,
or a pharmaceutical composition according to claim 30.
32. A method of agonizing a PGI2 receptor by contacting the
receptor with a compound according to any one of claims 1 to 25, a
pro-drug according to any one of claims 26 to 29, or a
pharmaceutical composition according to claim 30.
33. A method for the treatment of a PGI2 receptor mediated disorder
in an individual, comprising administering to said individual in
need thereof, a therapeutically effective amount of a compound
according to any one of claims 1 to 25, a pro-drug according to any
one of claims 26 to 29, or a pharmaceutical composition according
to claim 30.
34. A method for the treatment of PAH in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound according to any one of claims 1 to
25, a pro-drug according to any one of claims 26 to 29, or a
pharmaceutical composition according to claim 30.
35. The method according to claim 34, wherein said PAH is selected
from: idiopathic PAH; familial PAH; PAH associated with a collagen
vascular disease selected from: scleroderma, CREST syndrome,
systemic lupus erythematosus (SLE), rheumatoid arthritis,
Takayasu's arteritis, polymyositis, and dermatomyositis; PAH
associated with a congenital heart disease selected from: atrial
septic defect (ASD), ventricular septic defect (VSD) and patent
ductus arteriosus in an individual; PAH associated with portal
hypertension; PAH associated with HIV infection; PAH associated
with ingestion of a drug or toxin; PAH associated with hereditary
hemorrhagic telangiectasia; PAH associated with splenectomy; PAH
associated with significant venous or capillary involvement; PAH
associated with pulmonary veno-occlusive disease (PVOD); and PAH
associated with pulmonary capillary hemangiomatosis (PCH) in an
individual.
36. A method for the treatment of a disorder selected from:
platelet aggregation, coronary artery disease, myocardial
infarction, transient ischemic attack, angina, stroke,
ischemia-reperfusion injury, restenosis, atrial fibrillation, blood
clot formation, atherosclerosis, atherothrombosis, asthma, a
symptom of asthma, a diabetic-related disorder, diabetic peripheral
neuropathy, diabetic nephropathy, diabetic retinopathy, glaucoma or
other disease of the eye with abnormal intraocular pressure,
hypertension, inflammation, psoriasis, psoriatic arthritis,
rheumatoid arthritis, Crohn's disease, transplant rejection,
multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative
colitis, ischemia-reperfusion injury, restenosis, atherosclerosis,
acne, type 1 diabetes, type 2 diabetes, sepsis and chronic
obstructive pulmonary disorder (COPD) in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound according to any one of claims 1 to
25, a pro-drug according to any one of claims 26 to 29, or a
pharmaceutical composition according to claim 30.
37. Use of a compound according to any one of claims 1 to 25 or a
pro-drug according to any one of claims 26 to 29, in the
manufacture of a medicament for modulating the activity of a PGI2
receptor.
38. Use of a compound according to any one of claims 1 to 25 or a
pro-drug according to any one of claims 26 to 29, in the
manufacture of a medicament for agonizing a PGI2 receptor.
39. Use of a compound according to any one of claims 1 to 25 or a
pro-drug according to any one of claims 26 to 29, in the
manufacture of a medicament for the treatment of a PGI2 receptor
mediated disorder.
40. Use of a compound according to any one of claims 1 to 25 or a
pro-drug according to any one of claims 26 to 29, in the
manufacture of a medicament for the treatment of PAH.
41. The use according to claim 40, wherein said PAH is selected
from: idiopathic PAH; familial PAH; PAH associated with a collagen
vascular disease selected from: scleroderma, CREST syndrome,
systemic lupus erythematosus (SLE), rheumatoid arthritis,
Takayasu's arteritis, polymyositis, and dermatomyositis; PAH
associated with a congenital heart disease selected from: atrial
septic defect (ASD), ventricular septic defect (VSD) and patent
ductus arteriosus in an individual; PAH associated with portal
hypertension; PAH associated with HIV infection; PAH associated
with ingestion of a drug or toxin; PAH associated with hereditary
hemorrhagic telangiectasia; PAH associated with splenectomy; PAH
associated with significant venous or capillary involvement; PAH
associated with pulmonary vena-occlusive disease (PVOD); and PAH
associated with pulmonary capillary hemangiomatosis (PCH) in an
individual.
42. Use of a compound according to any one of claims 1 to 25 or a
pro-drug according to any one of claims 26 to 29, in the
manufacture of a medicament for the treatment of a disorder
selected from: platelet aggregation, coronary artery disease,
myocardial infarction, transient ischemic attack, angina, stroke,
ischemia-reperfusion injury, restenosis, atrial fibrillation, blood
clot formation, atherosclerosis, atherothrombosis, asthma, a
symptom of asthma, a diabetic-related disorder, diabetic peripheral
neuropathy, diabetic nephropathy, diabetic retinopathy, glaucoma or
other disease of the eye with abnormal intraocular pressure,
hypertension, inflammation, psoriasis, psoriatic arthritis,
rheumatoid arthritis, Crohn's disease, transplant rejection,
multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative
colitis, ischemia-reperfusion injury, restenosis, atherosclerosis,
acne, type 1 diabetes, type 2 diabetes, sepsis and chronic
obstructive pulmonary disorder (COPD).
43. A compound according to any one of claims 1 to 25, a pro-drug
according to any one of claims 26 to 29, or a pharmaceutical
composition according to claim 30, for use in a method of treatment
of the human or animal body by therapy.
44. A compound according to any one of claims 1 to 25, a pro-drug
according to any one of claims 26 to 29, or a pharmaceutical
composition according to claim 30, for use in a method of
modulating the activity of a PGI2 receptor.
45. A compound according to any one of claims 1 to 25, a pro-drug
according to any one of claims 26 to 29, or a pharmaceutical
composition according to claim 30, for use in a method of agonizing
a PGI2 receptor.
46. A compound according to any one of claims 1 to 25, a pro-drug
according to any one of claims 26 to 29, or a pharmaceutical
composition according to claim 30, for use in a method of treatment
of a PGI2 receptor mediated disorder.
47. A compound according to any one of claims 1 to 25, a pro-drug
according to any one of claims 26 to 29, or a pharmaceutical
composition according to claim 30, for use in a method of treatment
of PAH.
48. A compound according to claim 47, wherein said PAH is selected
from: idiopathic PAH; familial PAH; PAH associated with a collagen
vascular disease selected from: scleroderma, CREST syndrome,
systemic lupus erythematosus (SLE), rheumatoid arthritis,
Takayasu's arteritis, polymyositis, and dermatomyositis; PAH
associated with a congenital heart disease selected from: atrial
septic defect (ASD), ventricular septic defect (VSD) and patent
ductus arteriosus in an individual; PAH associated with portal
hypertension; PAH associated with HIV infection; PAH associated
with ingestion of a drug or toxin; PAH associated with hereditary
hemorrhagic telangiectasia; PAH associated with splenectomy; PAH
associated with significant venous or capillary involvement; PAH
associated with pulmonary vena-occlusive disease (PVOD); and PAH
associated with pulmonary capillary hemangiomatosis (PCH).
49. A compound according to any one of claims 1 to 25, a pro-drug
according to any one of claims 26 to 29, or a pharmaceutical
composition according to claim 30, for use in a method of treatment
of a disorder selected from: platelet aggregation, coronary artery
disease, myocardial infarction, transient ischemic attack, angina,
stroke, ischemia-reperfusion injury, restenosis, atrial
fibrillation, blood clot formation, atherosclerosis,
atherothrombosis, asthma, a symptom of asthma, a diabetic-related
disorder, diabetic peripheral neuropathy, diabetic nephropathy,
diabetic retinopathy, glaucoma or other disease of the eye with
abnormal intraocular pressure, hypertension, inflammation,
psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's
disease, transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis and chronic obstructive pulmonary disorder
(COPD).
50. A process for preparing a composition comprising admixing a
compound according to any one of claims 1 to 25 or a pro-drug
according to any one of claims 26 to 29, and a pharmaceutically
acceptable carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/159,971, filed Oct. 15, 2018, which is a continuation of
U.S. application Ser. No. 15/230,825, filed Aug. 8, 2016, now U.S.
Pat. No. 10,138,210, issued Nov. 27, 2018, which is a divisional of
U.S. application Ser. No. 14/566,019, filed Dec. 10, 2014, now
abandoned, which is a divisional of U.S. application Ser. No.
13/133,036, filed Jun. 6, 2011, now U.S. Pat. No. 8,940,891, issued
Jan. 27, 2015, which is a U.S. National Stage entry of
International Application No. PCT/US2009/006408, filed Dec. 7,
2009, which claims the benefit of priority from U.S. Provisional
Application No. 61/205,726, filed Jan. 22, 2009, and U.S.
Provisional Application No. 61/201,150, filed Dec. 8, 2008, all of
which are hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to certain compounds of
Formula Ia and pharmaceutical compositions thereof that modulate
the activity of the PGI2 receptor. Compounds of the present
invention and pharmaceutical compositions thereof are directed to
methods useful in the treatment of: pulmonary arterial hypertension
(PAH); idiopathic PAH; familial PAH; PAH associated with: a
collagen vascular disease, a congenital heart disease, portal
hypertension, HIV infection, ingestion of a drug or toxin,
hereditary hemorrhagic telangiectasia, splenectomy, pulmonary
veno-occlusive disease (PVOD) or pulmonary capillary
hemangiomatosis (PCH); PAH with significant venous or capillary
involvement; platelet aggregation; coronary artery disease;
myocardial infarction; transient ischemic attack; angina; stroke;
ischemia-reperfusion injury; restenosis; atrial fibrillation; blood
clot formation in an angioplasty or coronary bypass surgery
individual or in an individual suffering from atrial fibrillation;
atherothrombosis; asthma or a symptom thereof; a diabetic-related
disorder such as diabetic peripheral neuropathy, diabetic
nephropathy or diabetic retinopathy; glaucoma or other disease of
the eye with abnormal intraocular pressure; hypertension;
inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis;
Crohn's disease; transplant rejection; multiple sclerosis; systemic
lupus erythematosus (SLE); ulcerative colitis; atherosclerosis;
acne; type 1 diabetes; type 2 diabetes; sepsis; and chronic
obstructive pulmonary disorder (COPD).
BACKGROUND OF THE INVENTION
[0003] Prostacyclin (PGI2) is a lipid molecule derived from
arachidonic acid through the cyclooxygenase pathway. It is a potent
vasodilator, antiproliferative, anti-thrombotic and antiplatelet
agent that mediates its effects as an agonist of a G
protein-coupled receptor (PGI2 receptor e.g., human PGI2 receptor,
GenBank.RTM. Accession No. NP_000951 and alleles thereof). It is
known that the binding of PGI2 (or other such agonist) to the PGI2
receptor leads to coupling with the Gs protein and increases
intracellular cAMP levels. (See. e.g., Zhang et al., Arch. Biochem.
Biophys., 2006, 454:80-88.)
[0004] Pulmonary arterial hypertension (PAH) is a life-threatening
disease characterized by a progressive pulmonary vasculopathy
leading to right ventricular hypertrophy. Right heart failure
occurs if left untreated. Prostacyclin, which has vasodilatory and
antiproliferative effects on the pulmonary vasculature has been
found to be low in patients with PAH compared with normal controls.
Exogenous administration of prostacyclin or an analog of
prostacyclin (i.e., an agonist of the PGI2 receptor) has become an
important strategy in the treatment of PAH. (See, e.g., Tuder et
al., Am. J. Respir. Crit. Care. Med., 1999, 159:1925-1932; Humbert
et al., J. Am. Coll. Cardiol., 2004, 43:13S-24S; Rosenzweig. Expert
Opin. Emerging Drugs, 2006, 11:609-619; McLaughlin et al.,
Circulation, 2006, 114:1417-1431; Rosenkranz, Clin. Res. Cardiol.,
2007, 96:527-541; Driscoll et al., Expert Opin. Pharmacother.,
2008, 9:65-81.)
[0005] Trepostinil and iloprost are FDA-approved analogs of
prostacyclin which, like prostacyclin, are not orally-active.
Beraprost is an orally-active analog of prostacyclin approved for
the treatment of PAH in Japan, but it has failed registration for
the treatment of PAH in Europe and in the US. Of the three
FDA-approved drugs, prostacyclin is the best studied in PAH
patients. The approximate annual cost of treating PAH with these
drugs is $25,000 to $200,000 depending on the dose. At present,
many experts consider intravenous prostacyclin to be the most
reliable agent for managing the sickest PAH patients. Due to the
short half-life of prostacyclin, intravenous treatment is
complicated by the need for a continuous infusion. Patients are at
risk for potentially fatal rebound pulmonary hypertension if the
infusion is abruptly disrupted, as well as significant risk of
catheter-related complications including sepsis. (See, e.g.,
Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11:609-619; Naeije
et a., Expert Opin. Pharmacother., 2007, 8:2247-2265: Strauss et
al., Clin. Chest. Med., 2007, 28:127-142; Driscoll et al., Expert
Opin. Pharmacother., 2008, 9:65-81.)
[0006] There is considerable interest in developing prostacyclin
analogs (i.e., agonists of the PGI2 receptor) for use in the
treatment of other diseases, such as atherothrombosis. Developing
stable, orally-active analogs of prostacyclin (i.e., stable,
orally-active agonists of the PGI2 receptor) is a rate-limiting
step in achieving this goal (see. e.g., Arehart et al., Cuff. Med.
Chem., 2007, 14:2161-2169; Arehart et al., Circ. Res., 2008,
102(8), 986-93), as well as in the improved management of PAH.
SUMMARY OF THE INVENTION
[0007] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula Ia and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00002##
[0008] wherein:
[0009] R.sup.1 is selected from: H and C.sub.1-C.sub.8 alkyl;
[0010] R.sup.2 and R.sup.3 are each independently selected from: H,
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen; and
[0011] X is selected from: N and CH.
[0012] One aspect of the present invention pertains to
pharmaceutical compositions comprising a compound of the present
invention and a pharmaceutically acceptable carrier.
[0013] One aspect of the present invention pertains to methods for
the treatment of a PGI2 receptor mediated disorder in an
individual, comprising administering to the individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0014] One aspect of the present invention pertains to methods for
the treatment of PAH in an individual, comprising administering to
the individual in need thereof, a therapeutically effective amount
of a compound of the present invention or a pharmaceutical
composition thereof.
[0015] One aspect of the present invention pertains to methods for
the treatment of idiopathic PAH in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0016] One aspect of the present invention pertains to methods for
the treatment of familial PAH in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0017] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a collagen vascular disease in
an individual, comprising administering to the individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0018] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a collagen vascular disease
selected from: scleroderma, CREST syndrome, systemic lupus
erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,
polymyositis, and dermatomyositis in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0019] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a congenital heart disease in
an individual, comprising administering to the individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0020] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a congenital heart disease
selected from: atrial septic defect (ASD), ventricular septic
defect (VSD) and patent ductus arteriosus in an individual,
comprising administering to the individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0021] One aspect of the present invention pertains to methods for
the treatment of PAH associated with portal hypertension in an
individual, comprising administering to the individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0022] One aspect of the present invention pertains to methods for
the treatment of PAH associated with HIV infection in an
individual, comprising administering to the individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0023] One aspect of the present invention pertains to methods for
the treatment of PAH associated with ingestion of a drug or toxin
an individual, comprising administering to the individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0024] One aspect of the present invention pertains to methods for
the treatment of PAH associated with hereditary hemorrhagic
telangiectasia in an individual, comprising administering to the
individual in need thereof, a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition
thereof.
[0025] One aspect of the present invention pertains to methods for
the treatment of PAH associated with splenectomy in an individual,
comprising administering to the individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0026] One aspect of the present invention pertains to methods for
the treatment of PAH associated with significant venous or
capillary involvement in an individual, comprising administering to
the individual in need thereof, a therapeutically effective amount
of a compound of the present invention or a pharmaceutical
composition thereof.
[0027] One aspect of the present invention pertains to methods for
the treatment of PAH associated with pulmonary veno-occlusive
disease (PVOD) in an individual, comprising administering to the
individual in need thereof, a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition
thereof.
[0028] One aspect of the present invention pertains to methods for
the treatment of PAH associated with pulmonary capillary
hemangiomatosis (PCH) in an individual, comprising administering to
the individual in need thereof, a therapeutically effective amount
of a compound of the present invention or a pharmaceutical
composition thereof.
[0029] One aspect of the present invention pertains to methods for
the treatment of platelet aggregation in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0030] One aspect of the present invention pertains to methods for
the treatment of: coronary artery disease, myocardial infarction,
transient ischemic attack, angina, stroke, ischemia-reperfusion
injury, restenosis or atrial fibrillation in an individual,
comprising administering to the individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0031] One aspect of the present invention pertains to methods for
the treatment of blood clot formation in an angioplasty or coronary
bypass surgery individual comprising administering to the
individual in need thereof, a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition
thereof.
[0032] One aspect of the present invention pertains to methods for
the treatment of blood clot formation in an individual suffering
from atrial fibrillation comprising administering to the individual
in need thereof, a therapeutically effective amount of a compound
of the present invention or a pharmaceutical composition
thereof.
[0033] One aspect of the present invention pertains to methods for
the treatment of atherosclerosis in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0034] One aspect of the present invention pertains to methods for
the treatment of atherothrombosis in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0035] One aspect of the present invention pertains to methods for
the treatment of asthma in an individual, comprising administering
to the individual in need thereof, a therapeutically effective
amount of a compound of the present invention or a pharmaceutical
composition thereof.
[0036] One aspect of the present invention pertains to methods for
the treatment of a symptom of asthma in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0037] One aspect of the present invention pertains to methods for
the treatment of a diabetic-related disorder in an individual,
comprising administering to the individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0038] One aspect of the present invention pertains to methods for
the treatment of diabetic peripheral neuropathy in an individual,
comprising administering to the individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0039] One aspect of the present invention pertains to methods for
the treatment of diabetic nephropathy in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0040] One aspect of the present invention pertains to methods for
the treatment of diabetic retinopathy in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0041] One aspect of the present invention pertains to methods for
the treatment of glaucoma or other disease of the eye with abnormal
intraocular pressure in an individual, comprising administering to
the individual in need thereof, a therapeutically effective amount
of a compound of the present invention or a pharmaceutical
composition thereof. In some embodiments the abnormal intraocular
pressure is increased intraocular pressure.
[0042] One aspect of the present invention pertains to methods for
the treatment of hypertension in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0043] One aspect of the present invention pertains to methods for
the treatment of hypertension intended to confer protection against
cerebral ischemia in an individual, comprising administering to the
individual in need thereof, a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition
thereof.
[0044] One aspect of the present invention pertains to methods for
the treatment of inflammation in an individual, comprising
administering to the individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0045] One aspect of the present invention pertains to methods for
the treatment of an inflammatory disease in an individual,
comprising administering to the individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0046] One aspect of the present invention pertains to methods for
the treatment of an inflammatory disease selected from: psoriasis,
psoriatic arthritis, rheumatoid arthritis, Crohn's disease,
transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis, chronic obstructive pulmonary disorder (COPD) and
asthma in an individual, comprising administering to the individual
in need thereof, a therapeutically effective amount of a compound
of the present invention or a pharmaceutical composition
thereof.
[0047] One aspect of the present invention pertains to methods of
modulating the activity of a PGI2 receptor by contacting the
receptor with a compound of the present invention.
[0048] One aspect of the present invention pertains to methods of
agonizing a PGI2 receptor by contacting the receptor with a
compound of the present invention.
[0049] One aspect of the present invention pertains to methods for
the treatment of PAH selected from: idiopathic PAH; familial PAH;
PAH associated with a collagen vascular disease selected from:
scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),
rheumatoid arthritis, Takayasu's arteritis, polymyositis, and
dermatomyositis; PAH associated with a congenital heart disease
selected from: atrial septic defect (ASD), ventricular septic
defect (VSD) and patent ductus arteriosus in an individual; PAH
associated with portal hypertension; PAH associated with HIV
infection; PAH associated with ingestion of a drug or toxin; PAH
associated with hereditary hemorrhagic telangiectasia; PAH
associated with splenectomy; PAH associated with significant venous
or capillary involvement; PAH associated with pulmonary
veno-occlusive disease (PVOD); and PAH associated with pulmonary
capillary hemangiomatosis (PCH) in an individual comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0050] One aspect of the present invention pertains to methods for
the treatment of a disorder selected from: platelet aggregation,
coronary artery disease, myocardial infarction, transient ischemic
attack, angina, stroke, ischemia-reperfusion injury, restenosis,
atrial fibrillation, blood clot formation, atherosclerosis,
atherothrombosis, asthma, a symptom of asthma, a diabetic-related
disorder, diabetic peripheral neuropathy, diabetic nephropathy,
diabetic retinopathy, glaucoma or other disease of the eye with
abnormal intraocular pressure, hypertension, inflammation,
psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's
disease, transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type I diabetes, type 2
diabetes, sepsis and chronic obstructive pulmonary disorder (COPD)
in an individual comprising administering to said individual in
need thereof, a therapeutically effective amount of a compound of
the present invention or a pharmaceutical composition thereof.
[0051] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of a PGI2 receptor mediated
disorder.
[0052] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH.
[0053] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of idiopathic PAH.
[0054] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of familial PAH.
[0055] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with collagen
vascular disease.
[0056] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with a collagen
vascular disease selected from: scleroderma, CREST syndrome,
systemic lupus erythematosus (SLE), rheumatoid arthritis.
Takayasu's arteritis, polymyositis, and dermatomyositis.
[0057] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with a congenital
heart disease.
[0058] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with a congenital
heart disease selected from: atrial septic defect (ASD),
ventricular septic defect (VSD) and patent ductus arteriosus.
[0059] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with portal
hypertension.
[0060] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with HIV
infection.
[0061] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with ingestion of a
drug or toxin.
[0062] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with hereditary
hemorrhagic telangiectasia.
[0063] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with
splenectomy.
[0064] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with significant
venous or capillary involvement.
[0065] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with pulmonary
veno-occlusive disease (PVOD).
[0066] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with pulmonary
capillary hemangiomatosis (PCH).
[0067] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of platelet aggregation.
[0068] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of a PGI2 receptor mediated disorder
selected from: coronary artery disease, myocardial infarction,
transient ischemic attack, angina, stroke, ischemia-reperfusion
injury, restenosis and atrial fibrillation.
[0069] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of blood clot formation in an
angioplasty or coronary bypass surgery individual.
[0070] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of blood clot formation in an
individual suffering from atrial fibrillation.
[0071] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of atherosclerosis.
[0072] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of atherothrombosis.
[0073] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of asthma.
[0074] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of a symptom of asthma.
[0075] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of a diabetic-related disorder.
[0076] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of diabetic peripheral neuropathy.
[0077] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of diabetic nephropathy.
[0078] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of diabetic retinopathy.
[0079] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of glaucoma or other disease of the
eye with abnormal intraocular pressure. In some embodiments the
abnormal intraocular pressure is increased intraocular
pressure.
[0080] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of hypertension.
[0081] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of hypertension intended to confer
protection against cerebral ischemia.
[0082] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of inflammation.
[0083] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of an inflammatory disease.
[0084] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of an inflammatory disease selected
from: psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's
disease, transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis, chronic obstructive pulmonary disorder (COPD) and
asthma.
[0085] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for modulating the activity of a PGI2 receptor.
[0086] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for agonizing a PGI2 receptor.
[0087] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH selected from: idiopathic PAH;
familial PAH; PAH associated with a collagen vascular disease
selected from: scleroderma, CREST syndrome, systemic lupus
erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,
polymyositis, and dermatomyositis; PAH associated with a congenital
heart disease selected from: atrial septic defect (ASD),
ventricular septic defect (VSD) and patent ductus arteriosus in an
individual; PAH associated with portal hypertension; PAH associated
with HIV infection; PAH associated with ingestion of a drug or
toxin; PAH associated with hereditary hemorrhagic telangiectasia;
PAH associated with splenectomy; PAH associated with significant
venous or capillary involvement; PAH associated with pulmonary
veno-occlusive disease (PVOD); and PAH associated with pulmonary
capillary hemangiomatosis (PCH).
[0088] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of a disorder selected from: platelet
aggregation, coronary artery disease, myocardial infarction,
transient ischemic attack, angina, stroke, ischemia-reperfusion
injury, restenosis, atrial fibrillation, blood clot formation,
atherosclerosis, atherothrombosis, asthma, a symptom of asthma, a
diabetic-related disorder, diabetic peripheral neuropathy, diabetic
nephropathy, diabetic retinopathy, glaucoma or other disease of the
eye with abnormal intraocular pressure, hypertension, inflammation,
psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's
disease, transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis and chronic obstructive pulmonary disorder
(COPD).
[0089] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of the human
or animal body by therapy.
[0090] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of a PGI2
receptor mediated disorder.
[0091] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH.
[0092] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
idiopathic PAH.
[0093] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of familial
PAH
[0094] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with a collagen vascular disease.
[0095] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with a collagen vascular disease selected from:
scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),
rheumatoid arthritis, Takayasu's arteritis, polymyositis, and
dermatomyositis.
[0096] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with a congenital heart disease.
[0097] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with a congenital heart disease selected from: atrial
septic defect (ASD), ventricular septic defect (VSD) and patent
ductus arteriosus.
[0098] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with portal hypertension.
[0099] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with HIV infection.
[0100] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with ingestion of a drug or toxin.
[0101] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with hereditary hemorrhagic telangiectasia.
[0102] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with splenectomy.
[0103] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with significant venous or capillary involvement.
[0104] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with pulmonary veno-occlusive disease (PVOD).
[0105] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with pulmonary capillary hemangiomatosis (PCH).
[0106] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of platelet
aggregation.
[0107] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of: coronary
artery disease, myocardial infarction, transient ischemic attack,
angina, stroke, ischemia-reperfusion injury, restenosis or atrial
fibrillation.
[0108] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of blood
clot formation in an angioplasty or coronary bypass surgery
individual.
[0109] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of blood
clot formation in an individual suffering from atrial
fibrillation.
[0110] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
atherosclerosis.
[0111] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
atherothrombosis.
[0112] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
asthma.
[0113] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of a symptom
of asthma.
[0114] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of a
diabetic-related disorder.
[0115] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of diabetic
peripheral neuropathy.
[0116] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of diabetic
nephropathy.
[0117] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of diabetic
retinopathy.
[0118] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of glaucoma
or other disease of the eye with abnormal intraocular pressure. In
some embodiments the abnormal intraocular pressure is increased
intraocular pressure.
[0119] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
hypertension.
[0120] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
hypertension intended to confer protection against cerebral
ischemia.
[0121] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
inflammation.
[0122] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of an
inflammatory disease.
[0123] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of an
inflammatory disease selected from: psoriasis, psoriatic arthritis,
rheumatoid arthritis, Crohn's disease, transplant rejection,
multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative
colitis, ischemia-reperfusion injury, restenosis, atherosclerosis,
acne, type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive
pulmonary disorder (COPD) and asthma.
[0124] One aspect of the present invention pertains to compounds of
the present invention for use in a method of modulating the
activity of a PGI2 receptor.
[0125] One aspect of the present invention pertains to compounds of
the present invention for use in a method of agonizing a PGI2
receptor.
[0126] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
selected from: idiopathic PAH; familial PAH; PAH associated with a
collagen vascular disease selected from: scleroderma, CREST
syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis,
Takayasu's arteritis, polymyositis, and dermatomyositis; PAH
associated with a congenital heart disease selected from: atrial
septic defect (ASD), ventricular septic defect (VSD) and patent
ductus arteriosus in an individual; PAH associated with portal
hypertension; PAH associated with HIV infection; PAH associated
with ingestion of a drug or toxin; PAH associated with hereditary
hemorrhagic telangiectasia; PAH associated with splenectomy; PAH
associated with significant venous or capillary involvement; PAH
associated with pulmonary veno-occlusive disease (PVOD); and PAH
associated with pulmonary capillary hemangiomatosis (PCH).
[0127] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of a
disorder selected from: platelet aggregation, coronary artery
disease, myocardial infarction, transient ischemic attack, angina,
stroke, ischemia-reperfusion injury, restenosis, atrial
fibrillation, blood clot formation, atherosclerosis,
atherothrombosis, asthma, a symptom of asthma, a diabetic-related
disorder, diabetic peripheral neuropathy, diabetic nephropathy,
diabetic retinopathy, glaucoma or other disease of the eye with
abnormal intraocular pressure, hypertension, inflammation,
psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's
disease, transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type I diabetes, type 2
diabetes, sepsis and chronic obstructive pulmonary disorder
(COPD).
[0128] One aspect of the present invention pertains to compounds
for preparing a composition comprising admixing a compound of the
present invention and a pharmaceutically acceptable carrier.
[0129] These and other aspects of the invention disclosed herein
will be set forth in greater detail as the patent disclosure
proceeds.
BRIEF DESCRIPTION OF THE DRAWINGS
[0130] FIG. 1 shows the results of an experiment which measured the
ability of Compound 68 to inhibit the right ventricle hypertrophic
response to MCT-induced pulmonary arterial hypertension in rat at
30 mg/kg.
[0131] FIG. 2 depicts a general method for preparing intermediates
useful in the synthesis of compounds of the present invention.
Cyclohexane-1,4-dicarboxylic acid is first converted to the diol
either directly or via an ester. The diol is then converted to a
sulfonate ester intermediate by either by alkylation with
tert-butyl bromoacetate followed activation with a sulfonyl
chloride or alternatively by treatment first with a sulfonyl
chloride followed by alkylation with tert-butyl 2-diazoacetate in
the presence of diacetoxyrhodium.
[0132] FIG. 3 depicts a general method for preparing
1,2,4-triazin-3(2H)-ones of the present invention. In the first
step, an acetic acid derivative is reacted with an acid chloride in
the presence of base to give a .beta.-ketoester derivative. This
undergoes acid mediated hydrolysis/decarboxylation to give an
ethanone derivative. Reaction with tert-butyl nitrite in the
presence of base gives an oxime which is reacted with
hydrazinecarbothioamide followed by iodomethane to give a
3-(methylthio)-1,2,4-triazine intermediate. This is converted to
the triazinone by treatment with MCPBA and then base. The
triazinone is coupled to the sulfonate ester intermediate described
in FIG. 2 to give an ester of Formula Ia which is hydrolyzed with
acid to give a carboxylic acid of Formula Ia.
[0133] FIG. 4 depicts another general method for preparing
compounds of the present invention. In this method, a
5-halo-1,2,4-triazin-3(2H)-ones or a 5-halopyridazin-3(2H)-one
intermediate is reacted with the sulfonate ester described in FIG.
2 in the presence of potassium tert-butoxide and 18-crown-6 in DMF.
The product undergoes a palladium catalyzed coupling to an aryl or
heteroaryl boronic acid derivative to give an ester of Formula Ia
which is hydrolyzed with acid to give a carboxylic acid of Formula
Ia.
[0134] FIG. 5 depicts another general method for preparing
compounds of the present invention. Certain pyridazinone
intermediates are prepared by reaction of
3,4-dibromo-5-hydroxyfuran-2(5H)-one with an aryl or heteroaryl
derivative in the presence of a Lewis acid followed by treatment
with hydrazine. The resulting pyridazinone is reacted with a
boronic acid derivative in the presence of a palladium catalyst.
The product of that reaction is coupled to the sulfonate ester
intermediate described in FIG. 2 to give an ester of Formula Ia.
This is hydrolyzed with acid to give a carboxylic acid of Formula
Ia. Alternatively, the order in which the pyridazinone is coupled
to the boronic acid and the sulfonate ester may be reversed.
[0135] FIG. 6 depicts another general method for preparing
compounds of the present invention. Certain furan-2,5-dione
derivatives may be converted to hydroxypyridazinone intermediates
by reaction with benzylhydrazine in acetic acid. Subsequent
conversion to the chloride and removal of the benzyl group is
achieved by treatment with phosphorous oxychloride followed by
aluminum chloride. The resulting chloropyridazinone intermediate is
coupled to the sulfonate ester intermediate described in FIG. 2 and
treated with a boronic acid in the presence of a palladium catalyst
to give an ester of Formula Ia. This is hydrolyzed with acid to
give a carboxylic acid of Formula Ia.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0136] For clarity and consistency, the following definitions will
be used throughout this patent document.
[0137] The term "agonists" is intended to mean moieties that
interact and activate the receptor, such as, the PGI2 receptor and
initiate a physiological or pharmacological response characteristic
of that receptor. For example, when moieties activate the
intracellular response upon binding to the receptor, or enhance GTP
binding to membranes.
[0138] The term "contact or contacting" is intended to mean
bringing the indicated moieties together, whether in an in vitro
system or an in vivo system. Thus, "contacting" a PGI2 receptor
with a compound of the invention includes the administration of a
compound of the present invention to an individual, preferably a
human, having a PGI2 receptor, as well as, for example, introducing
a compound of the invention into a sample containing a cellular or
more purified preparation containing a PGI2 receptor.
[0139] The term "hydrate" as used herein means a compound of the
invention or a salt thereof, that further includes a stoichiometric
or non-stoichiometric amount of water bound by non-covalent
intermolecular forces.
[0140] The terms "including" and "such as" are illustrative and not
limitative.
[0141] The term "in need of treatment" and the term "in need
thereof," when referring to treatment are used interchangeably to
mean a judgment made by a caregiver (e.g. physician, nurse, nurse
practitioner, etc. in the case of humans; veterinarian in the case
of animals, including non-human mammals) that an individual or
animal requires or will benefit from treatment. This judgment is
made based on a variety of factors that are in the realm of a
caregiver's expertise, but that includes the knowledge that the
individual or animal is ill, or will become ill, as the result of a
disease, condition or disorder that is treatable by the compounds
of the invention. Accordingly, the compounds of the invention can
be used in a protective or preventive manner; or compounds of the
invention can be used to alleviate, inhibit or ameliorate the
disease, condition or disorder.
[0142] The term "individual" is intended to mean any animal,
including mammals, preferably mice, rats, other rodents, rabbits,
dogs, cats, swine, cattle, sheep, horses, or primates and most
preferably humans.
[0143] The term "modulate or modulating" is intended to mean an
increase or decrease in the amount, quality, response or effect of
a particular activity, function or molecule.
[0144] The term "pharmaceutical composition" is intended to mean a
composition comprising at least one active ingredient; including
but not limited to, salts, solvates and hydrates of compounds of
the present invention; whereby the composition is amenable to
investigation for a specified, efficacious outcome in a mammal (for
example, without limitation, a human). Those of ordinary skill in
the art will understand and appreciate the techniques appropriate
for determining whether an active ingredient has a desired
efficacious outcome based upon the needs of the artisan.
[0145] The term "solvate" as used herein means a compound of the
invention or a salt, thereof, that further includes a
stoichiometric or non-stoichiometric amount of a solvent bound by
non-covalent intermolecular forces. Preferred solvents are
volatile, non-toxic, and/or acceptable for administration to humans
in trace amounts.
[0146] The term "therapeutically effective amount" is intended to
mean the amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue, system,
animal, individual or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician or caregiver; or in
an individual, which includes one or more of the following:
[0147] (1) Preventing the disease; for example, preventing a
disease, condition or disorder in an individual that may be
predisposed to the disease, condition or disorder but does not yet
experience or display the pathology or symptomatology of the
disease;
[0148] (2) Inhibiting the disease; for example, inhibiting a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., arresting further development
of the pathology and/or symptomatology); and
[0149] (3) Ameliorating the disease; for example, ameliorating a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., reversing the pathology
and/or symptomatology).
Chemical Group, Moiety or Radical
[0150] The term "C.sub.1-C.sub.6 alkoxy" is intended to mean a
C.sub.1-C.sub.6 alkyl radical, as defined herein, attached directly
to an oxygen atom. Some embodiments are 1 to 5 carbons; some
embodiments are 1 to 4 carbons; some embodiments are 1 to 3
carbons; and some embodiments are 1 or 2 carbons. Examples include
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy,
isobutoxy, sec-butoxy and the like.
[0151] The term "C.sub.1-C.sub.6 alkyl" is intended to mean a
straight or branched carbon radical containing 1 to 6 carbons. Some
embodiments are 1 to 5 carbons. Some embodiments are 1 to 4
carbons. Some embodiments are 1 to 3 carbons. Some embodiments are
1 or 2 carbons. Some embodiments are 1 carbon. Examples of an alkyl
include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl,
isopentyl, i-pentyl, neo-pentyl, 1-methylbutyl [i.e.,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3], 2-methylbutyl [i.e.,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3], n-hexyl and the like.
[0152] The term "C.sub.1-C.sub.6 alkylthio" is intended to mean a
C.sub.1-C.sub.6 alkyl radical attached to a sulfur atom (i.e.,
--S--) wherein the alkyl radical has the same definition as
described herein. Examples include, but are not limited to,
methylsulfanyl (i.e., CH.sub.3S--), ethylsulfanyl,
n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl,
sec-butylsulfanyl, iso-butylsulfanyl, t-butylsulfanyl, and the
like.
[0153] The term "aryl" is intended to mean an aromatic ring radical
containing 6 to 10 ring carbons. Examples include phenyl and
naphthyl. In some embodiments aryl is intended to mean phenyl.
[0154] The term "18-crown-6" is intended to mean
1,4,7,10,13,16-hexaoxacyclooctadecane.
[0155] The term "C.sub.1-C.sub.6 haloalkyl" is intended to mean a
C.sub.1-C.sub.6 alkyl group, defined herein, wherein the alkyl is
substituted with one halogen up to fully substituted and a fully
substituted C.sub.1-C.sub.6 haloalkyl can be represented by the
formula C.sub.nL.sub.2n+1 wherein L is a halogen and "n" is 1, 2,
3, 4, 5 or 6. When more than one halogen is present then they may
be the same or different and selected from the group consisting of
F, Cl, Br and I, preferably F. Some embodiments are 1 to 5 carbons,
some embodiments are 1 to 4 carbons, some embodiments are 1 to 3
carbons, and some embodiments are 1 or 2 carbons. Examples of
haloalkyl groups include, but are not limited to, fluoromethyl,
difluoromethyl, trifluoromethyl, chlorodifluoromethyl,
2,2,2-trifluoroethyl, pentafluoroethyl and the like.
[0156] The term "halogen" or "halo" is intended to mean to a
fluoro, chloro, bromo or iodo group.
[0157] The term "heteroaryl" is intended to mean an aromatic ring
system containing 5 to 14 aromatic ring atoms that may be a single
ring, two fused rings or three fused rings wherein at least one
aromatic ring atom is a heteroatom selected from, but not limited
to, the group consisting of O, S and N wherein the N can be
optionally substituted with H, C.sub.1-C.sub.4 acyl or
C.sub.1-C.sub.4 alkyl. Some embodiments contain 5 to 6 ring atoms
for example furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl,
thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, triazinyl and the like. Some embodiments contain 8 to
14 ring atoms for example carbazolyl, quinolizinyl, quinolinyl,
isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl,
indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl,
acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl,
benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothienyl,
benzofuranyl, isobenzofuran and the like.
COMPOUNDS OF THE INVENTION
[0158] One aspect of the present invention pertains to certain
compounds as shown in Formula Ia:
##STR00003##
and pharmaceutically acceptable salts, solvates and hydrates
thereof wherein R.sup.1, R.sup.2, R.sup.3 and X have the same
definitions as described herein, supra and infra.
[0159] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination.
All combinations of the embodiments pertaining to the chemical
groups represented by the variables (e.g., R.sup.1, R.sup.2,
R.sup.3 and X) contained within the generic chemical formulae
described herein, for example, Ia, Ic, Ie, Ig, Ii, etc., are
specifically embraced by the present invention just as if each and
every combination was individually explicitly recited, to the
extent that such combinations embrace compounds that result in
stable compounds (i.e., compounds that can be isolated,
characterized and tested for biological activity). In addition, all
subcombinations of the chemical groups listed in the embodiments
describing such variables, as well as all subcombinations of uses
and medical indications described herein, are also specifically
embraced by the present invention just as if each and every
subcombination of chemical groups and subcombination of uses and
medical indications was individually and explicitly recited
herein.
[0160] As used herein, "substituted" indicates that at least one
hydrogen atom of the chemical group is replaced by a non-hydrogen
substituent or group, the non-hydrogen substituent or group can be
monovalent or divalent. When the substituent or group is divalent,
then it is understood that this group is further substituted with
another substituent or group. When a chemical group herein is
"substituted" it may have up to the full valance of substitution;
for example, a methyl group can be substituted by 1, 2, or 3
substituents, a methylene group can be substituted by 1 or 2
substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5
substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5,
6, or 7 substituents and the like. Likewise, "substituted with one
or more substituents" refers to the substitution of a group with
one substituent up to the total number of substituents physically
allowed by the group. Further, when a group is substituted with
more than one group they can be identical or they can be
different.
[0161] Compounds of the invention can also include tautomeric
forms, such as keto-enol tautomers and the like. Tautomeric forms
can be in equilibrium or sterically locked into one form by
appropriate substitution. It is understood that the various
tautomeric forms are within the scope of the compounds of the
present invention.
[0162] Compounds of the invention can also include all isotopes of
atoms occurring in the intermediates and/or final compounds.
Isotopes include those atoms having the same atomic number but
different mass numbers. For example, isotopes of hydrogen include
deuterium and tritium.
[0163] It is understood and appreciated that compounds of Formula
Ia and formulae related thereto may have one or more chiral centers
and therefore can exist as enantiomers and/or diastereoisomers. The
invention is understood to extend to and embrace all such
enantiomers, diastereoisomers and mixtures thereof, including but
not limited to racemates. It is understood that compounds of
Formula Ia and formulae used throughout this disclosure are
intended to represent all individual enantiomers and mixtures
thereof, unless stated or shown otherwise.
[0164] It is understood and appreciated that compounds of Formula
Ia exist as meso isomers. Such meso isomers may be referred to as
cis and trans. Certain cis meso isomers of compounds of Formula Ia
are named herein using the prefix (1s,4s) and certain trans meso
isomers of compounds of Formula Ia are named herein using the
prefix (1r,4r) as shown below.
##STR00004##
[0165] The Group R.sup.1:
[0166] In some embodiments, R.sup.1 is selected from: H and
C.sub.1-C.sub.6 alkyl.
[0167] In some embodiments, R.sup.1 is H.
[0168] In some embodiments, R.sup.1 is C.sub.1-C.sub.6 alkyl.
[0169] In some embodiments, R.sup.1 is tert-butyl.
[0170] The Group R.sup.2:
[0171] In some embodiments, R.sup.2 is selected from: H,
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen.
[0172] In some embodiments, R.sup.2 is selected from:
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen.
[0173] In some embodiments, R.sup.2 is selected from:
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: chloro, ethyl, fluoro, isopropyl, methoxy, methyl,
methylthio, phenyl and trifluoromethyl.
[0174] In some embodiments, R.sup.2 is selected from: methyl,
phenyl, pyridinyl, thiophen-2-yl and thiophen-3-yl; wherein said
methyl, phenyl, pyridinyl, thiophen-2-yl and thiophen-3-yl are each
optionally substituted with one or more substituents each
independently selected from: chloro, ethyl, fluoro, isopropyl,
methoxy, methyl, methylthio, phenyl and trifluoromethyl.
[0175] In some embodiments, R.sup.2 is selected from:
2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl,
2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl,
3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,
3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl.
[0176] In some embodiments, R.sup.2 is 2,3-difluorophenyl.
[0177] In some embodiments, R.sup.2 is 2-chlorophenyl.
[0178] In some embodiments, R.sup.2 is 2-fluoro-4-methylphenyl.
[0179] In some embodiments, R.sup.2 is 2-fluorophenyl.
[0180] In some embodiments, R.sup.2 is 2-methoxyphenyl.
[0181] In some embodiments, R.sup.2 is 3-chlorophenyl.
[0182] In some embodiments, R.sup.2 is 3-fluoro-4-methylphenyl.
[0183] In some embodiments, R.sup.2 is
3-fluoro-5-methoxyphenyl.
[0184] In some embodiments, R.sup.2 is 3-fluorophenyl.
[0185] In some embodiments, R.sup.2 is 3-methoxyphenyl.
[0186] In some embodiments, R.sup.2 is 4-(methylthio)phenyl.
[0187] In some embodiments, R.sup.2 is
4-(trifluoromethyl)phenyl.
[0188] In some embodiments, R.sup.2 is 4-chloro-2-fluorophenyl.
[0189] In some embodiments, R.sup.2 is 4-chloro-3-fluorophenyl.
[0190] In some embodiments, R.sup.2 is 4-chlorophenyl.
[0191] In some embodiments, R.sup.2 is 4-ethylphenyl.
[0192] In some embodiments, R.sup.2 is 4-fluorophenyl.
[0193] In some embodiments, R.sup.2 is 4-isopropylphenyl.
[0194] In some embodiments, R.sup.2 is 4-methoxyphenyl.
[0195] In some embodiments, R.sup.2 is 5-methylpyridin-3-yl.
[0196] In some embodiments, R.sup.2 is 6-chloropyridin-3-yl.
[0197] In some embodiments, R.sup.2 is 6-methylpyridin-3-yl.
[0198] In some embodiments, R.sup.2 is benzhydryl.
[0199] In some embodiments, R.sup.2 is phenyl.
[0200] In some embodiments, R.sup.2 is p-tolyl.
[0201] In some embodiments, R.sup.2 is pyridin-3-yl.
[0202] In some embodiments, R.sup.2 is pyridin-4-yl.
[0203] In some embodiments, R.sup.2 is thiophen-2-yl.
[0204] In some embodiments, R.sup.2 is thiophen-3-yl.
[0205] The Group R.sup.3:
[0206] In some embodiments, R.sup.3 is selected from: H,
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen.
[0207] In some embodiments, R.sup.3 is selected from: H,
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy and
halogen.
[0208] In some embodiments, R.sup.3 is selected from: H,
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: chloro, fluoro, methoxy and methyl.
[0209] In some embodiments, R.sup.3 is selected from: H,
1H-pyrazol-4-yl, phenyl, pyridinyl and thiophen-2-yl; wherein said
phenyl, pyridinyl and thiophen-2-yl are each optionally substituted
with one or more substituents each independently selected from:
chloro, fluoro, methoxy and methyl.
[0210] In some embodiments, R.sup.3 is selected from: H,
1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl,
2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,
2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,
2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,
4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
[0211] In some embodiments, R.sup.3 is H.
[0212] In some embodiments, R.sup.3 is 1H-pyrazol-4-yl.
[0213] In some embodiments, R.sup.3 is 2,3-difluorophenyl.
[0214] In some embodiments, R.sup.3 is 2-chlorophenyl.
[0215] In some embodiments, R.sup.3 is 2-chloropyridin-4-yl.
[0216] In some embodiments, R.sup.3 is
2-fluoro-3-methoxyphenyl.
[0217] In some embodiments, R.sup.3 is 2-fluoropyridin-3-yl.
[0218] In some embodiments, R.sup.3 is 2-fluoropyridin-4-yl.
[0219] In some embodiments, R.sup.3 is 2-methoxyphenyl.
[0220] In some embodiments, R.sup.3 is 2-methylpyridin-4-yl.
[0221] In some embodiments, R.sup.3 is 3,4-dichlorophenyl.
[0222] In some embodiments, R.sup.3 is 3,5-dichlorophenyl.
[0223] In some embodiments, R.sup.3 is 3-chloro-2-fluorophenyl.
[0224] In some embodiments, R.sup.3 is 3-chloro-4-fluorophenyl.
[0225] In some embodiments, R.sup.3 is 3-chlorophenyl.
[0226] In some embodiments, R.sup.3 is
3-fluoro-5-methoxyphenyl.
[0227] In some embodiments, R.sup.3 is 3-fluorophenyl.
[0228] In some embodiments, R.sup.3 is 3-methoxyphenyl.
[0229] In some embodiments, R.sup.3 is 4-chlorophenyl.
[0230] In some embodiments, R.sup.3 is 4-fluorophenyl.
[0231] In some embodiments, R.sup.3 is 4-methoxyphenyl.
[0232] In some embodiments, R.sup.3 is 4-methylthiophen-2-yl.
[0233] In some embodiments, R.sup.3 is 5-chloro-2-fluorophenyl.
[0234] In some embodiments, R.sup.3 is 5-chloro-pyridin-3-yl.
[0235] In some embodiments, R.sup.3 is 5-methylpyridin-3-yl.
[0236] In some embodiments, R.sup.3 is 5-methylthiophen-2-yl.
[0237] In some embodiments, R.sup.3 is 6-fluoropyridin-3-yl.
[0238] In some embodiments, R.sup.3 is m-tolyl.
[0239] In some embodiments, R.sup.3 is phenyl.
[0240] In some embodiments, R.sup.3 is p-tolyl.
[0241] In some embodiments, R.sup.3 is pyridin-3-yl.
[0242] In some embodiments, R.sup.3 is pyridin-4-yl.
[0243] In some embodiments, R.sup.3 is thiophen-2-yl.
[0244] The Group X:
[0245] In some embodiments, X is selected from: N and CH.
[0246] In some embodiments, X is N.
[0247] In some embodiments, X is CH.
[0248] Certain Combinations of the Present Invention:
[0249] In some embodiments, R.sup.2 and R.sup.3 are each
independently selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl
and halogen.
[0250] In some embodiments, R.sup.2 and R.sup.3 are each
independently selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one, two, three, four or five
substituents each independently selected from: C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 alkylthio, aryl,
C.sub.1-C.sub.8 haloalkyl and halogen.
[0251] In some embodiments, R.sup.2 and R.sup.3 are each
independently selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one, two, three or four
substituents each independently selected from: C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 alkylthio, aryl,
C.sub.1-C.sub.8 haloalkyl and halogen.
[0252] In some embodiments, R.sup.2 and R.sup.3 are each
independently selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one, two or three substituents
each independently selected from: C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 alkylthio, aryl,
C.sub.1-C.sub.8 haloalkyl and halogen.
[0253] In some embodiments, R.sup.2 and R.sup.3 are each
independently selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or two substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl
and halogen.
[0254] In some embodiments, R.sup.2 and R.sup.3 are each
independently selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one substituent selected from:
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and halogen.
[0255] In some embodiments, R.sup.2 and R.sup.3 are each
independently selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: chloro, ethyl, fluoro, isopropyl,
methoxy, methyl, methylthio, phenyl and trifluoromethyl.
[0256] In some embodiments, R.sup.2 and R.sup.3 are each
independently selected from: H, 1H-pyrazol-4-yl, methyl, phenyl,
pyridinyl, thiophen-2-yl and thiophen-3-yl; wherein said methyl,
phenyl, pyridinyl, thiophen-2-yl and thiophen-3-yl are each
optionally substituted with one or more substituents each
independently selected from: chloro, ethyl, fluoro, isopropyl,
methoxy, methyl, methylthio, phenyl and trifluoromethyl.
[0257] In some embodiments, R.sup.2 and R.sup.3 are each
independently selected from: H, 1H-pyrazol-4-yl,
2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl,
2-fluoro-3-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,
2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,
2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,
3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,
3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-chloropyridin-3-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl.
[0258] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula Ic and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00005##
[0259] wherein:
[0260] R.sup.2 is selected from: C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl
and halogen; and
[0261] R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy and halogen.
[0262] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula Ic and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00006##
[0263] wherein:
[0264] R.sup.2 is selected from: 2,3-difluorophenyl,
2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,
2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl; and
[0265] R.sup.3 is selected from: H, 1H-pyrazol-4-yl,
2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl,
2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl,
3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,
3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl,
3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl,
4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
[0266] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula Ie and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00007##
[0267] wherein:
[0268] R.sup.2 is selected from: C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl
and halogen; and
[0269] R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy and halogen.
[0270] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula Ie and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00008##
[0271] wherein:
[0272] R.sup.2 is selected from: 2,3-difluorophenyl,
2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,
2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl; and
[0273] R.sup.3 is selected from: H, 1H-pyrazol-4-yl,
2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl,
2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl,
3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,
3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl,
3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl,
4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
[0274] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula Ig and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00009##
[0275] wherein:
[0276] R.sup.2 is selected from: C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl
and halogen; and
[0277] R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy and halogen.
[0278] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula Ig and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00010##
[0279] wherein:
[0280] R.sup.2 is selected from: 2,3-difluorophenyl,
2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,
2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl; and
[0281] R.sup.3 is selected from: H, 1H-pyrazol-4-yl,
2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl,
2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl,
3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,
3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl,
3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl,
4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
[0282] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula Ii and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00011##
[0283] wherein:
[0284] R.sup.2 is selected from: C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl
and halogen; and
[0285] R.sup.3 is selected from: H, C.sub.1-C.sub.8 alkyl, aryl and
heteroaryl; wherein said C.sub.1-C.sub.8 alkyl, aryl and heteroaryl
are each optionally substituted with one or more substituents each
independently selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
alkoxy and halogen.
[0286] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula Ii and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00012##
[0287] wherein:
[0288] R.sup.2 is selected from: 2,3-difluorophenyl,
2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,
2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,
4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,
5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl,
thiophen-2-yl and thiophen-3-yl; and
[0289] R.sup.3 is selected from: H, 1H-pyrazol-4-yl,
2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl,
2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl,
3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,
3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl,
3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl,
4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl,
5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl,
pyridin-4-yl and thiophen-2-yl.
[0290] Some embodiments of the present invention include every
combination of one or more compounds selected from the following
group shown in TABLE A.
TABLE-US-00001 TABLE A Cpd No. Chemical Structure Chemical Name 1
##STR00013## 2-(((1r,4r)-4-((4-(3- methoxyphenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 2
##STR00014## 2-(((1s,4s)-4-((4-(3- methoxyphenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 3
##STR00015## 2-(((1s,4s)-4-((6-oxo-3,4- diphenylpyridazin-1(6H)
yl)methyl)cyclohexyl) methoxy)acetic acid 4 ##STR00016##
2-(((1s,4s)-4-((3- benzhydryl-6-oxopyridazin- 1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 5 ##STR00017##
2-(((1s,4s)-4-((3-(4- methoxyphenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 6
##STR00018## 2-(((1s,4s)-4-((4-(3- chlorophenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 7
##STR00019## 2-(((1r,4r)-4-((3- benzhydryl-6-oxopyridazin- 1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 8 ##STR00020##
2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 9
##STR00021## 2-(((1s,4s)-4-((6-oxo-3- phenyl-4-m-tolylpyridazin-
1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 10 ##STR00022##
2-(((1s,4s)-4-((6-oxo-3- phenyl-4-p-tolylpyridazin- 1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 11 ##STR00023##
2-(((1s,4s)-4-((4-(3- fluorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 12 ##STR00024##
2-(((1s,4s)-4-((4-(4- fluorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 13 ##STR00025##
2-(((1s,4s)-4-((4-(2- chlorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 14 ##STR00026##
2-(((1s,4s)-4-((4-(4- chlorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 15 ##STR00027##
2-(((1s,4s)-4-((4-(2- methoxyphenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 16
##STR00028## 2-(((1s,4s)-4-((4-(4- methoxyphenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 17
##STR00029## 2-(((1s,4s)-4-((4-(2-fluoro- 3-methoxyphenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 18
##STR00030## 2-(((1s,4s)-4-((4-(3-fluoro- 5-methoxyphenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 19
##STR00031## 2-(((1r,4r)-4-((6-oxo-3,4- diphenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 20 ##STR00032##
2-(((1s,4s)-4-((6-oxo-4- phenyl-3-p-tolylpyridazin- 1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 21 ##STR00033##
2-(((1s,4s)-4-((3-(3- fluorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 22 ##STR00034##
2-(((1s,4s)-4-((3-(4- fluorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 23 ##STR00035##
2-(((1s,4s)-4-((3-(2- chlorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 24 ##STR00036##
2-(((1s,4s)-4-((3-(4- chlorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 25 ##STR00037##
2-(((1s,4s)-4-((3-(2- methoxyphenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 26
##STR00038## 2-(((1s,4s)-4-((3-(3- methoxyphenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 27
##STR00039## 2-(((1s,4s)-4-((3-(3-fluoro- 5-methoxyphenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 28
##STR00040## 2-(((1s,4s)-4-((3-(2,3- difluorophenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 29
##STR00041## 2-(((1s,4s)-4-((3-(3- chlorophenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 30
##STR00042## 2-(((1s,4s)-4-((4-(5-chloro- 2-fluorophenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 31
##STR00043## 2-(((1s,4s)-4-((4-(3-chloro- 2-fluorophenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 32
##STR00044## 2-(((1s,4s)-4-((4-(3-chloro- 4-fluorophenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxyl)acetic acid
33 ##STR00045## 2-(((1s,4s)-4-((4-(3,5- dichlorophenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 34
##STR00046## 2-(((1s,4s)-4-((4-(3,4- dichlorophenyl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 35
##STR00047## 2-(((1s,4s)-4-((3-(2- fluorophenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 36
##STR00048## 2-(((1s,4s)-4-((3-(4- ethylphenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 37
##STR00049## 2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(4-
(trifluoromethyl)phenyl) pyridazin-1(6H)- yl)methyl)cyclohexyl)
methoxy)acetic acid 38 ##STR00050## 2-(((1s,4s)-4-((3-(3-fluoro-
4-methylphenyl)-6-oxo-4- phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 39 ##STR00051##
2-(((1s,4s)-4-((3-(4- isopropylphenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 40
##STR00052## 2-(((1s,4s)-4-((3-(2-fluoro- 4-methylphenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy(acetic acid 41
##STR00053## 2-(((1s,4s)-4-((3-(4- (methylthio)phenyl)-6-oxo-
4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid
42 ##STR00054## 2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(pyridin-3-
yl)pyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 43
##STR00055## 2-(((1s,4s)-4-((3-oxo-5,6-di-
p-tolyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 44 ##STR00056## 2-(((1s,4s)-4-((6-oxo-3- phenyl-4-(pyridin-3-
yl)pyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 45
##STR00057## 2-(((1s,4s)-4-((4-(5- methylthiophen-2-yl)-6-
oxo-3-phenylpyridazin- 1(6H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 46 ##STR00058## 2-(((1s,4s)-4-((6-oxo-3-
phenyl-4-(1H-pyrazol-4- yl)pyridazin-1(6H)- yl)methyl)cyclohexyl)
methoxy)acetic acid 47 ##STR00059## 2-(((1s,4s)-4-((4-(3-
chlorophenyl)-6-oxo-3-p- tolylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 48 ##STR00060##
2-(((1s,4s)-4-((3-oxo-5,6- diphenyl-1,2,4-triazin- 2(3H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 49 ##STR00061##
2-(((1s,4s)-4-((5,6-bis(4- fluorophenyl)-3-oxo-1,2,4-
triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic acid 50
##STR00062## 2-(((1s,4s)-4-((4-(4- methylthiophen-2-yl)-6-
oxo-3-phenylpyridazin- 1(6H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 51 ##STR00063## 2-(((1s,4s)-4-((4-(2-
methylpyridin-4-yl)-6-oxo- 3-phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 52 ##STR00064##
2-(((1s,4s)-4-((3-(4-chloro- 2-fIuorophenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 53
##STR00065## 2-(((1s,4s)-4-((3-(4-chloro- 3-fluorophenyl)-6-oxo-4-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 54
##STR00066## 2-(((1s,4s)-4-((4-(2- fluoropyridin-3-yl)-6-oxo-3-
phenylpyndazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 55
##STR00067## 2-(((1s,4s)-4-((4-(6- fluoropyridin-3-yl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 56
##STR00068## 2-(((1s,4s)-4-((4-(2- chloropyridin-4-yl)-6-oxo-
3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid
57 ##STR00069## 2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(pyridin-4-
yl)pyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 58
##STR00070## 2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(thiophen-2-
yl)pyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 59
##STR00071## 2-(((1s,4s)-4-((4-(2- fluoropyridin-4-yl)-6-oxo-3-
phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 60
##STR00072## 2-(((1s,4s)-4-((4-(5- methylpyridin-3-yl)-6-oxo-
3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid
61 ##STR00073## 2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(thiophen-3-
yl)pyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 62
##STR00074## 2-(((1s,4s)-4-((3-(5- methylpyridin-3-yl)-6-oxo-
4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid
63 ##STR00075## 2-(((1s,4s)-4-((3-(6- methylpyridin-3-yl)-6-oxo-
4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid
64 ##STR00076## 2-(((1s,4s)-4-((6-(4- fluorophenyl)-3-oxo-5-
phenyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 65 ##STR00077## 2-(((1s,4s)-4-((3-(6-
chloropyridin-3-yl)-6-oxo- 4-phenylpyridazin-1(6H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 66 ##STR00078##
2-(((1s,4s)-4-((4-(5- chloropyridin-3-yl)-6-oxo-
3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid
67 ##STR00079## 2-(((1s,4s)-4-((5-(3- chlorophenyl)-3-oxo-6-
phenyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 68 ##STR00080## 2-(((1s,4s)-4-((3-oxo-5-
phenyl-6-p-tolyl-1,2,4- triazin-2(3H)- yl)methyl)cyclohexyl)
methoxy)acetic acid 69 ##STR00081## 2-(((1s,4s)-4-((6-(4-
methoxyphenyl)-3-oxo-5- phenyl-1,2,4-triazin-2(3H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 70 ##STR00082##
2-(((1s,4s)-4-((5-(3- methoxyphenyl)-3-oxo-6-
phenyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 71 ##STR00083## 2-(((1s,4s)-4-((6-(2-fluoro-
4-methylphenyl)-3-oxo-5- phenyl-1,2,4-triazin-2(3H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 72 ##STR00084##
2-(((1s,4s)-4-((6-(4- chlorophenyl)-3-oxo-5-
phenyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 73 ##STR00085## 2-(((1s,4s)-4-((3-oxo-6-
phenyl-5-m-tolyl-1,2,4- triazin-2(3H)- yl)methyl)cyclohexyl)
methoxy)acetic acid 74 ##STR00086## 2-(((1s,4s)-4-((5-(3-
fluorophenyl)-3-oxo-6- phenyl-1,2,4-triazin-2(3H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 75 ##STR00087##
2-(((1r,4r)-4-((6-(2-f1uoro- 4-methylphenyl)-3-oxo-5-
phenyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 76 ##STR00088## 2-(((1r,4r)-4-((3-oxo-5-
phenyl-6-p-tolyl-1,2,4- triazin-2(3H)- yl)methyl)cyclohexyl)
methoxy)acetic acid 77 ##STR00089## 2-(((1s,4s)-4-((3-oxo-6-
phenyl-5-(pyridin-3-yl)- 1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl)
methoxy)acetic acid 78 ##STR00090## 2-(((1s,4s)-4-((3-oxo-6-
(pyridin-3-yl)-5-p-tolyl- 1,2,4-triazin-2(3H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 79 ##STR00091##
2-(((1s,4s)-4-((3-oxo-5- (pyridin-4-yl)-6-p-tolyl-
1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic acid 80
##STR00092## 2-(((1s,4s)-4-((3-oxo-5-m-
tolyl-6-p-tolyl-1,2,4-triazin- 2(3H)- yl)methyl)cyclohexyl)
methoxy)acetic acid 81 ##STR00093## 2-(((1r,4r)-4-((3-oxo-6-
phenyl-5-m-tolyl-1,2,4- triazin-2(3H)- yl)methyl)cyclohexyl)
methoxy)acetic acid
82 ##STR00094## 2-(((1r,4r)-4-((5-(3- fluorophenyl)-3-oxo-6-
phenyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 83 ##STR00095## 2-(((1r,4r)-4-((3-oxo-5-m-
tolyl-6-p-tolyl-1,2,4-triazin- 2(3H)- yl)methyl)cyclohexyl)
methoxy)acetic acid 84 ##STR00096## 2-(((1s,4s)-4-((3-oxo-6-
phenyl-5-(thiophen-2-yl)- 1,2,4-triazin-2(3H)-
yl)methyl)cyclohexyl) methoxy)acetic acid 85 ##STR00097##
2-(((1s,4s)-4-((5-(3- chlorophenyl)-3-oxo-6-p-
tolyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic
acid 86 ##STR00098## 2-(2-(((1s,4s)-4-((3-oxo-5-
phenyl-6-p-tolyl-1,2,4- triazin-2(3H)-yl)methyl)
cyclohexyl)methoxy) acetamido) acetic acid 87 ##STR00099##
2-(2-(((1s,4s)-4-((3-oxo-5- phenyl-6-p-tolyl- 1,2,4-triazin-2(3H)-
yl)methyl)cyclohexyl) methoxy)acetamido) ethanesulfonic acid
[0291] Additionally, individual compounds and chemical genera of
the present invention, for example those compounds found in TABLE A
including diastereoisomers and enantiomers thereof, encompass all
pharmaceutically acceptable salts, solvates and particularly
hydrates, thereof.
[0292] The compounds of the Formula Ia of the present invention may
be prepared according to relevant published literature procedures
that are used by one skilled in the art. Exemplary reagents and
procedures for these reactions appear hereinafter in the working
Examples. Protection and deprotection may be carried out by
procedures generally known in the art (see, for example, Greene, T.
W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis,
3.sup.rd Edition, 1999 [Wiley]; incorporated herein by reference in
its entirety).
[0293] It is understood that the present invention embraces each
diastereoisomer, each enantiomer and mixtures thereof of each
compound and generic formulae disclosed herein just as if they were
each individually disclosed with the specific stereochemical
designation for each chiral carbon. Separation of the individual
isomers (such as, by chiral HPLC, recrystallization of
diastereoisomeric mixtures and the like) or selective synthesis
(such as, by enantiomeric selective syntheses and the like) of the
individual isomers is accomplished by application of various
methods which are well known to practitioners in the art.
Indications and Methods of Prophylaxis and/or Treatment
[0294] In addition to the foregoing beneficial uses for the
modulators of PGI2 receptor activity disclosed herein, the
compounds disclosed herein are useful in the treatment of several
additional diseases and disorders, and in the amelioration of
symptoms thereof. Without limitation, these include the
following:
[0295] 1. Pulmonary Arterial Hypertension (PAH)
[0296] Pulmonary arterial hypertension (PAH) has a multifactorial
pathobiology. Vasoconstriction, remodeling of the pulmonary vessel
wall, and thrombosis contribute to increased pulmonary vascular
resistance in PAH (Humbert et al., J. Am. Coll. Cardiol., 2004,
43:13S-24S.)
[0297] The compounds of the present invention disclosed herein are
useful in the treatment of pulmonary arterial hypertension (PAH)
and symptoms thereof. PAH shall be understood to encompass the
following forms of pulmonary arterial hypertension described in the
2003 World Health Organization (WHO) clinical classification of
pulmonary arterial hypertension: idiopathic PAH (IPAH); familial
PAH (FPAH); PAH associated with other conditions (APAH), such as
PAH associated with collagen vascular disease, PAH associated with
congenital systemic-to-pulmonary shunts, PAH associated with portal
hypertension, PAH associated with HIV infection. PAH associated
with drugs or toxins, or PAH associated with Other; and PAH
associated with significant venous or capillary involvement.
[0298] Idiopathic PAH refers to PAH of undetermined cause.
[0299] Familial PAH refers to PAH for which hereditary transmission
is suspected or documented.
[0300] PAH associated with collagen vascular disease shall be
understood to encompass PAH associated with scleroderma, PAH
associated with CREST (calcinosis cutis, Raynaud's phenomenon,
esophageal dysfunction, sclerodactyly, and telangiectasias)
syndrome, PAH associated with systemic lupus erythematosus (SLE),
PAH associated with rheumatoid arthritis, PAH associated with
Takayasu's arteritis, PAH associated with polymyositis, and PAH
associated with dermatomyositis.
[0301] PAH associated with congenital systemic-to-pulmonary shunts
shall be understood to encompass PAH associated with atrial septic
defect (ASD), PAH associated with ventricular septic defect (VSD)
and PAH associated with patent ductus arteriosus.
[0302] PAH associated with drugs or toxins shall be understood to
encompass PAH associated with ingestion of aminorex, PAH associated
with ingestion of a fenfluramine compound (e.g., PAH associated
with ingestion of fenfluramine or PAH associated with ingestion of
dexfenfluramine), PAH associated with ingestion of certain toxic
oils (e.g., PAH associated with ingestion of rapeseed oil), PAH
associated with ingestion of pyrrolizidine alkaloids (e.g., PAH
associated with ingestion of bush tea) and PAH associated with
ingestion of monocrotaline.
[0303] PAH associated with Other shall be understood to encompass
PAH associated with a thyroid disorder, PAH associated with
glycogen storage disease, PAH associated with Gaucher disease, PAH
associated with hereditary hemorrhagic telangiectasia, PAH
associated with a hemoglobinopathy, PAH associated with a
myeloproliferative disorder, and PAH associated with
splenectomy.
[0304] PAH associated with significant venous or capillary
involvement shall be understood to encompass PAH associated with
pulmonary veno-occlusive disease (PVOD) and PAH associated with
pulmonary capillary hemangiomatosis (PCH).
[0305] (See, e.g., Simonneau et al., J. Am. Coll. Cardiol., 2004,
43:5S-12S; McGoon et al., Chest, 2004, 126:14S-34S; Rabinovitch,
Annu. Rev. Pathol. Mech. Dis., 2007, 2:369-399; McLaughlin et al.,
Circulation, 2006, 114:1417-1431; Strauss et al., Clin. Chest.
Med., 2007, 28:127-142; Taichman et al., Clin. Chest. Med., 2007,
28:1-22.)
[0306] Evidence for the association of PAH with scleroderma and the
beneficial effect of an agonist of the PGI2 receptor on PAH is
given by Badesch et al. (Badesch et al., Ann. Intern. Med., 2000,
132:425-434). Evidence for the association of PAH with the collagen
vascular diseases mixed connective tissue disease (MCTD), systemic
lupus erythematosus (SLE), Sjogren's syndrome and CREST syndrome
and the beneficial effect of an agonist of the PGI2 receptor on PAH
is given by Humbert et al. (Eur. Respir. J., 1999, 13:1351-1356).
Evidence for the association of PAH with CREST syndrome and the
beneficial effect of an agonist of the PGI2 receptor on PAH is
given by Miwa et al. (Int. Heart J., 2007, 48:417-422). Evidence
for the association of PAH with SLE and the beneficial effect of an
agonist of the PGI2 receptor on PAH is given by Robbins et al.
(Chest, 2000, 117:14-18). Evidence for the association of PAH with
HIV infection and the beneficial of an agonist of the PGI2 receptor
on PAH is given by Aguilar et al. (Am. J. Respir. Crit. Care Med.,
2000, 162:1846-1850). Evidence for the association of PAH with
congenital heart defects (including ASD, VSD and patent ductus
arteriosus) and the beneficial effect of an agonist of the PGI2
receptor on PAH is given by Rosenzweig et a. (Circulation, 1999,
99:1858-1865). Evidence for the association of PAH with
fenfluramine and with dexfenfluramine, anorexigens, is given by
Archer et al. (Am. J. Respir. Crit. Care Med., 1998,
158:1061-1067). Evidence for the association of PAH with hereditary
hemorrhagic telangiectasia is given by McGoon et al. (Chest, 2004,
126:14-34). Evidence for the association of PAH with splenectomy is
given by Hoeper et al. (Ann. Intern. Med., 1999, 130:506-509).
Evidence for the association of PAH with portal hypertension and
the beneficial effect of an agonist of the PGI2 receptor on PAH is
given by Hoeper et al. (Eur. Respir. J., 2005, 25:502-508).
[0307] Symptoms of PAH include dyspnea, angina, syncope and edema
(McLaughlin et a., Circulation, 2006, 114:1417-1431). The compounds
of the present invention disclosed herein are useful in the
treatment of symptoms of PAH.
[0308] Tawara et al. have demonstrated that long-term inhibition of
Rho-kinase, an effector of the small GTPase Rho, ameliorates
monocrotaline-induced PAH in rats and hypoxia-induced PAH in mice.
The same group also reported that prostacyclin and its oral analog,
beraprost sodium (BPS), may lack direct inhibitory effect on
Rho-kinase in vitro, suggesting that combination therapy with a
Rho-kinase inhibitor and BPS is effective for the treatment of PAH.
Thus, male Sprague-Dawley rats were given a s.c. injection of
monocrotaline (60 mg/kg) and maintained with or without the
treatment with a Rho-kinase inhibitor, fasudil (30 mg/kg/day), BPS
(200 .mu.g/kg/day), or a combination of both drugs for three weeks.
The combination therapy, when compared with each monotherapy,
showed significantly more improvement in PAH, right ventricular
hypertrophy, and pulmonary medial thickness without any adverse
effects. (See, Tawara et al., Journal of Cardiovascular
Pharmacology (2007), 50(2), 195-200.)
[0309] The PGI2 receptor agonists disclosed herein, alone or in
combination with a Rho-kinase inhibitor, are useful in the
treatment of pulmonary arterial hypertension (PAR) and symptoms
thereof.
[0310] The enzyme tryptophan hydroxylase (TPH), has two known
isoforms: TPH1, which is expressed in the periphery, and TPH2,
which is expressed primarily in the brain. Mice genetically
deficient for the TPH1 gene ("knockout mice") have been reported.
In one case, the mice reportedly expressed normal amounts of
serotonin in classical serotonergic brain regions, but largely
lacked serotonin in the periphery. Walther, D. J., et al., Science
299:76 (2003). In another, the knockout mice exhibited abnormal
cardiac activity, which was attributed to a lack of peripheral
serotonin. Cote, F., et al., PNAS 100(23):13525-13530 (2003).
[0311] Recently. TPH knockout mice were studied in a
hypoxia-induced pulmonary arterial hypertension model. Morecroft,
I., et al., Hypertension 49:232-236 (2007). The results of those
studies suggest that TPH1 and peripheral serotonin play an
essential role in the development of hypoxia-induced elevations in
pulmonary pressures and hypoxia-induced pulmonary vascular
remodeling.
[0312] The PGI2 receptor agonists disclosed herein, alone or in
combination with a tryptophan hydroxylase inhibitor, are useful in
the treatment of pulmonary arterial hypertension (PAH) and symptoms
thereof.
[0313] 2. Antiplatelet Therapies (Conditions Related to Platelet
Aggregation)
[0314] Antiplatelet agents (antiplatelets) are prescribed for a
variety of conditions. For example, in coronary artery disease they
are used to help prevent myocardial infarction or stroke in
patients who are at risk of developing obstructive blood clots
(e.g., coronary thrombosis).
[0315] In a myocardial infarction ("TIA" or "heart attack"), the
heart muscle does not receive enough oxygen-rich blood as a result
of a blockage in the coronary blood vessels. If taken while an
attack is in progress or immediately afterward (preferably within
30 min), antiplatelets can reduce the damage to the heart.
[0316] A transient ischemic attack ("TIA" or "mini-stroke") is a
brief interruption of oxygen flow to the brain due to decreased
blood flow through arteries, usually due to an obstructing blood
clot. Antiplatelet drugs have been found to be effective in
preventing TIAs.
[0317] Angina is a temporary and often recurring chest pain,
pressure or discomfort caused by inadequate oxygen-rich blood flow
(ischemia) to some parts of the heart. In patients with angina,
antiplatelet therapy can reduce the effects of angina and the risk
of myocardial infarction.
[0318] Stroke is an event in which the brain does not receive
enough oxygen-rich blood, usually due to blockage of a cerebral
blood vessel by a blood clot. In high-risk patients, taking
antiplatelets regularly has been found to prevent the formation of
blood clots that cause first or second strokes.
[0319] Angioplasty is a catheter based technique used to open
arteries obstructed by a blood clot. Whether or not stenting is
performed immediately after this procedure to keep the artery open,
antiplatelets can reduce the risk of forming additional blood clots
following the procedure(s).
[0320] Coronary bypass surgery is a surgical procedure in which an
artery or vein is taken from elsewhere in the body and grafted to a
blocked coronary artery, rerouting blood around the blockage and
through the newly attached vessel. After the procedure,
antiplatelets can reduce the risk of secondary blood clots.
[0321] Atrial fibrillation is the most common type of sustained
irregular heart rhythm (arrhythmia). Atrial fibrillation affects
about two million Americans every year. In atrial fibrillation, the
atria (the heart's upper chambers) rapidly fire electrical signals
that cause them to quiver rather than contract normally. The result
is an abnormally fast and highly irregular heartbeat. When given
after an episode of atrial fibrillation, antiplatelets can reduce
the risk of blood clots forming in the heart and traveling to the
brain (embolism).
[0322] There is evidence that a PGI2 receptor agonist will inhibit
platelet aggregation and thus be a potential treatment as an
antiplatelet therapy (see, e.g., Moncada et al., Lancet, 1977,
1:18-20). It has been shown that genetic deficiency of the PGI2
receptor in mice leads to an increased propensity towards
thrombosis (Murata et al., Nature, 1997, 388:678-682).
[0323] PGI2 receptor agonists can be used to treat, for example,
claudication or peripheral artery disease as well as cardiovascular
complications, arterial thrombosis, atherosclerosis,
vasoconstriction caused by serotonin, ischemia-reperfusion injury,
and restenosis of arteries following angioplasty or stent
placement. (See. e.g., Fetalvero et al., Prostaglandins Other Lipid
Mediat., 2007, 82:109-118; Arehart et al., Curr. Med. Chem., 2007,
14:2161-2169; Davi et al., N. Engl. J. Med., 2007, 357:2482-2494;
Fetalvero et al., Am. J. Physiol. Heart. Circ. Physiol., 2006,
290:H1337-H1346; Murata et al., Nature, 1997, 388:678-682; Wang et
al., Proc. Natl. Acad. Sci. USA, 2006, 103:14507-14512; Xiao et
al., Circulation, 2001, 104:2210-2215; McCormick et al., Biochem.
Soc. Trans., 2007, 35:910-911; Arehart et al., Circ. Res., 2008,
102(8), 986-93.)
[0324] PGI2 receptor agonists can also be used alone or in
combination with thrombolytic therapy, for example, tissue-type
plasminogen activator (t-PA), to provide cardioprotection following
MI or postischemic myocardial dysfunction or protection from
ischemic injury during percutaneous coronary intervention, and the
like, including complications resulting therefrom. PGI2 receptor
agonists can also be used in antiplatelet therapies in combination
with, for example, alpha-tocopherol (vitamin E), echistatin (a
disintegrin) or, in states of hypercoagulability, heparin. (See,
e.g., Chan., J. Nutr., 1998, 128:1593-1596; Mardla et al.,
Platelets, 2004, 15:319-324; Bernabei et al., Ann. Thorac. Surg.,
1995, 59:149-153; Gainza et al., J. Nephrol., 2006,
19:648-655.)
[0325] The PGI2 receptor agonists disclosed herein provide
beneficial improvement in microcirculation to patients in need of
antiplatelet therapy by antagonizing the vasoconstrictive products
of the aggregating platelets in, for example and not limited to the
indications described above. Accordingly, in some embodiments, the
present invention provides methods for reducing platelet
aggregation in a patient in need thereof, comprising administering
to the patient a composition comprising a PGI2 receptor agonist
disclosed herein. In further embodiments, the present invention
provides methods for treating coronary artery disease, myocardial
infarction, transient ischemic attack, angina, stroke, atrial
fibrillation, or a symptom of any of the foregoing in a patient in
need of the treatment, comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed
herein.
[0326] In further embodiments, the present invention provides
methods for reducing risk of blood clot formation in an angioplasty
or coronary bypass surgery patient, or a patient suffering from
atrial fibrillation, comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein at
a time where such risk exists.
[0327] 3. Atherosclerosis
[0328] Atherosclerosis is a complex disease characterized by
inflammation, lipid accumulation, cell death and fibrosis. It is
the leading cause of mortality in many countries, including the
United States. Atherosclerosis, as the term is used herein, shall
be understood to encompass disorders of large and medium-sized
arteries that result in the progressive accumulation within the
intima of smooth muscle cells and lipids.
[0329] It has been shown that an agonist of the PGI2 receptor can
confer protection from atherosclerosis, such as from
atherothrombosis (Arehart et al., Cur. Med. Chem., 2007,
14:2161-2169; Stitham et al., Prostaglandins Other Lipid Mediat.,
2007, 82:95-108; Fries et al., Hematology Am. Soc. Hematol. Educ.
Program, 2005, 445-451; Egan et al., Science, 2004, 306:1954-1957;
Kobayashi et al., J. Clin. Invest., 2004, 114:784-794; Arehart et
al., Circ. Res., 2008, 102(8), 986-93).
[0330] It has been shown that defective PGI2 receptor signaling
appears to accelerate atherothrombosis in humans, i.e. that an
agonist of the PGI2 receptor can confer protection from
atherothrombosis in humans (Arehart et al., Circ. Res., 2008,
102(8), 986-93).
[0331] The compounds of the present invention disclosed herein are
useful in the treatment of atherosclerosis, and the treatment of
the symptoms thereof. Accordingly, in some embodiments, the present
invention provides methods for treating atherosclerosis in a
patient in need of the treatment, comprising administering to the
patient a composition comprising a PGI2 receptor agonist disclosed
herein. In further embodiments, methods are provided for treating a
symptom of atherosclerosis in a patient in need of the treatment,
comprising administering to the patient a composition comprising a
PGI2 receptor agonist disclosed herein.
[0332] 4. Asthma
[0333] Asthma is a lymphocyte-mediated inflammatory airway disorder
characterized by airway cosinophilia, increased mucus production by
goblet cells, and structural remodeling of the airway wall. The
prevalence of asthma has dramatically increased worldwide in recent
decades. It has been shown that genetic deficiency of the PGI2
receptor in mice augments allergic airway inflammation (Takahashi
et al., Br J Pharmacol, 2002, 137:315-322). It has been shown that
an agonist of the PGI2 receptor can suppress not only the
development of asthma when given during the sensitization phase,
but also the cardinal features of experimental asthma when given
during the challenge phase (Idzko et al., J. Clin. Invest., 2007,
117:464-472; Nagao et al., Am. J. Respir. Cell Mol. Biol., 2003,
29:314-320), at least in part through markedly interfering with the
function of antigen-presenting dendritic cells within the airways
(Idzko et al., J. Clin. Invest., 2007, 117:464-472; Zhou et al., J.
Immunol., 2007, 178:702-710; Jaffar et al., J. Immunol., 2007,
179:6193-6203; Jozefowski et al., Int. Immunopharmacol., 2003,
3:865-878). These cells are crucial for both the initiation and the
maintenance phases of allergic asthma, as depletion of airway
dendritic cells during secondary challenge in sensitized mice
abolished all characteristic features of asthma, an effect that
could be completely restored by adoptive transfer of wild-type
dendritic cells (van Rijt et al., J. Exp. Med., 2005, 201:981-991).
It has also been shown that an agonist of the PGI2 receptor can
inhibit proinflammatory cytokine secretion by human alveolar
macrophages (Raychaudhuri et al., J. Biol. Chem., 2002,
277:33344-33348). The compounds of the present invention disclosed
herein are useful in the treatment of asthma, and the treatment of
the symptoms thereof. Accordingly, in some embodiments, the present
invention provides methods for treating asthma in a patient in need
of the treatment, comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein. In
further embodiments, methods are provided for treating a symptom of
asthma in a patient in need of the treatment, comprising
administering to the patient a composition comprising a PGI2
receptor agonist disclosed herein.
[0334] 5. Diabetic-Related Pathologies
[0335] Although hyperglycemia is the major cause for the
pathogenesis of diabetic complications such as diabetic peripheral
neuropathy (DPN), diabetic nephropathy (DN) and diabetic
retinopathy (DR), enhanced vasoconstriction and platelet
aggregation in diabetic patients has also been implicated to play a
role in disease progression (Cameron et al., Naunyn Schmiedebergs
Arch. Pharmacol., 2003, 367:607-614). Agonists of the PGI2 receptor
promote vasodilation and inhibit platelet aggregation. Improving
microvascular blood flow is able to benefit diabetic complications
(Cameron, Diabetologia, 2001, 44:1973-1988).
[0336] It has been shown that an agonist of the PGI2 receptor can
prevent and reverse motor and sensory peripheral nerve conduction
abnormalities in streptozotocin-diabetic rats (Cotter et al.,
Naunyn Schmiedebergs Arch. Pharmacol., 1993, 347:534-540). Further
evidence for the beneficial effect of an agonist of the PGI2
receptor in the treatment of diabetic peripheral neuropathy is
given by Hotta et al. (Diabetes, 1996, 45:361-366), Ueno et al.
(Jpn. J. Pharmacol., 1996, 70:177-182), Ueno et al. (Life Sci.,
1996, 59:PL105-PL110). Hotta et al. (Prostaglandins, 1995,
49:339-349), Shindo et al. (Prostaglandins, 1991, 41:85-96), Okuda
et al. (Prostaglandins, 1996, 52:375-384), and Koike et al. (FASEB
J., 2003, 17:779-781). Evidence for the beneficial effect of an
agonist of the PGI2 receptor in the treatment of diabetic
nephropathy is given by Owada et al. (Nephron, 2002, 92:788-796)
and Yamashita et al. (Diabetes Res. Clin. Pract., 2002,
57:149-161). Evidence for the beneficial effect of an agonist of
the PGI2 receptor in the treatment of diabetic retinopathy is given
by Yamagishi et al. (Mol. Med., 2002, 8:546-550), Burnette et al.
(Exp. Eye Res., 2006, 83:1359-1365), and Hotta et al. (Diabetes,
1996, 45:361-366). It has been shown that an agonist of the PGI2
receptor can reduce increased tumor necrosis factor-.alpha.
(TNF-.alpha.) levels in diabetic patients, implying that an agonist
of the PGI2 receptor may contribute to the prevention of
progression in diabetic complications (Fujiwara et al., Exp. Clin.
Endocrinol. Diabetes, 2004, 112:390-394).
[0337] 6. Glaucoma
[0338] Evidence that topical administration of an agonist of the
PGI2 receptor can result in a decrease in intraocular pressure
(IOP) in rabbits and dogs and thereby have beneficial effect in the
treatment of glaucoma is given by Hoyng et al. (Hoyng et al.,
Invest. Ophthalmol. Vis. Sci., 1987, 28:470-476).
[0339] 7. Hypertension
[0340] Agonists of the PGI2 receptor have been shown to have
activity for regulation of vascular tone, for vasodilation, and for
amelioration of pulmonary hypertension (see, e.g., Strauss et al.,
Clin Chest Med, 2007, 28:127-142; Driscoll et al., Expert Opin.
Pharmacother., 2008, 9:65-81). Evidence for a beneficial effect of
an agonist of the PGI2 receptor in the treatment of hypertension is
given by Yamada et al. (Peptides, 2008, 29:412-418). Evidence that
an agonist of the PGI2 receptor can protect against cerebral
ischemia is given by Dogan et al. (Gen. Pharmacol., 1996,
27:1163-1166) and Fang et al. (J. Cereb. Blood Flow Metab., 2006,
26:491-501).
[0341] 8. Anti-Inflammation Therapies
[0342] Anti-inflammation agents are prescribed for a variety of
conditions. For example, in an inflammatory disease they are used
to interfere with and thereby reduce an underlying deleterious
There is evidence that a PGI2 receptor agonist can inhibit
inflammation and thus be a potential treatment as an
anti-inflammation therapy. It has been shown that an agonist of the
PGI2 receptor can inhibit pro-inflammatory cytokine and chemokine
(interleukin-12 (IL-12), tumor necrosis factor-.alpha.
(TNF-.alpha.). IL-1.alpha., IL-6, macrophage inflammatory
protein-1alpha (MIP-1.alpha.), monocyte chemoattractant protein-1
(MCP-1)) production and T cell stimulatory function of dendritic
cells (Jozefowski et al., Int. Immunopharmacol., 2003, 865-878;
Zhou et al., J. Immunol., 2007, 178:702-710; Nagao et al., Am. J.
Respir. Cell Mol. Biol., 2003, 29:314-320; Idzko et al., J. Clin.
Invest., 2007, 117:464-472). It has been shown that an agonist of
the PGI2 receptor can inhibit pro-inflammatory cytokine
(TNF-.alpha., IL-1.beta., IL-6, granulocyte macrophage stimulating
factor (GM-CSF)) production by macrophages (Raychaudhuri et al., J.
Biol. Chem., 2002, 277:33344-33348; Czeslick et al., Eur. J. Clin.
Invest., 2003, 33:1013-1017; Di Renzo et al., Prostaglandin Leukot.
Essent. Fatty Acids, 2005, 73:405-410; Shinomiya et al., Biochem.
Pharmacol., 2001, 61:1153-1160). It has been shown that an agonist
of the PGI2 receptor can stimulate anti-inflammatory cytokine
(IL-10) production by dendritic cells (Jozefowski et al., Int.
Immunopharmacol., 2003, 865-878; Zhou et al., J. Immunol., 2007,
178:702-710). It has been shown that an agonist of the PGI2
receptor can stimulate anti-inflammatory cytokine (IL-10)
production by macrophages (Shinomiya et a., Biochem. Pharmacol.,
2001, 61:1153-1160). It has been shown that an agonist of the PGI2
receptor can inhibit a chemokine (CCL17)-induced chemotaxis of
leukocytes (CD4.sup.+ Th2 T cells) (Jaffar et al., J. Immunol.,
2007, 179:6193-6203). It has been shown that an agonist of the PGI2
receptor can confer protection from atherosclerosis, such as from
atherothrombosis (Arehart et al., Curr. Med. Chem., 2007,
14:2161-2169; Stitham et al., Prostaglandins Other Lipid Mediat.,
2007, 82:95-108; Fries et al., Hematology Am. Soc. Hematol. Educ.
Program, 2005, :445-451; Egan et al. Science, 2004, 306:1954-1957;
Kobayashi et al., J. Clin. Invest., 2004, 114:784-794; Arehart et
al., Circ. Res., 2008, 102(8), 986-93). It has been shown that an
agonist of the PGI2 receptor can attenuate asthma (Idzko et al., J.
Clin. Invest., 2007, 117:464-472; Jaffar et al., J. Immunol., 2007,
179:6193-6203; Nagao et al., Am. J. Respir. Cell. Mol. Biol., 2003,
29:314-320). It has been shown that an agonist of the PGI2 receptor
can decrease TNF-.alpha. production in type 2 diabetes patients
(Fujiwara et al., Exp. Clin. Endocrinol. Diabetes, 2004,
112:390-394; Goya et al., Metabolism, 2003, 52:192-198). It has
been shown that an agonist of the PGI2 receptor can inhibit
ischemia-reperfusion injury (Xiao et al., Circulation, 2001,
104:2210-2215). It has been shown that an agonist of the PGI2
receptor can inhibit restenosis (Cheng et al., Science, 2002,
296:539-541). It has been shown that an agonist of the PGI2
receptor can attenuate pulmonary vascular injury and shock in a rat
model of septic shock (Harada et al., Shock, 2008, Feb. 21 Epub
ahead of print). It has been shown that an agonist of the PGI2
receptor can reduce the serum levels of TNF-.alpha. in vivo in
patients with rheumatoid arthritis, and this is associated with
improvement in the clinical course of the disease (Gao et al.,
Rheumatol. Int., 2002, 22:45-51; Boehme et al., Rheumatol. Int.,
2006, 26:340-347).
[0343] The compounds of the present invention disclosed herein
provide beneficial reduction of inflammation. The compounds of the
present invention disclosed herein provide beneficial reduction of
a deleterious inflammatory response associated with an inflammatory
disease. Accordingly, in some embodiments, the present invention
provides methods for reducing inflammation in a patient in need
thereof, comprising administering to the patient a composition
comprising a PGI2 receptor agonist disclosed herein. In some
embodiments, the present invention provides methods for decreasing
IL-12, TNF-.alpha., IL-1.alpha., IL-1.beta., IL-6, MIP-1.alpha. or
MCP-1 production in a patient in need thereof, comprising
administering to the patient a composition comprising a PGI2
receptor agonist disclosed herein. In some embodiments, the present
invention provides methods for decreasing TNF-.alpha. production in
a patient in need thereof, comprising administering to the patient
a composition comprising a PGI2 receptor agonist disclosed herein.
In some embodiments, the present invention provides methods for
increasing IL-10 production in a patient in need thereof,
comprising administering to the patient a composition comprising a
PGI2 receptor agonist disclosed herein. In some embodiments, the
present invention provides methods for reducing a deleterious
inflammatory response associated with an inflammatory disease in a
patient in need thereof, comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein. In
some embodiments, the present invention provides methods for
treating an inflammatory disease or a symptom thereof in a patient
in need of the treatment comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein. In
some embodiments, the present invention provides methods for
treating an inflammatory disease or a symptom thereof in a patient
in need of the treatment comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein. In
some embodiments, the present invention provides methods for
treating an inflammatory disease or a symptom thereof in a patient
in need of the treatment comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein,
wherein the inflammatory disease is selected from the group
consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis,
Crohn's disease, transplant rejection, multiple sclerosis, systemic
lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, diabetes (including type
1 diabetes and type 2 diabetes), sepsis, chronic obstructive
pulmonary disease (COPD), and asthma.
[0344] 9. Traumatic Brain Injury
[0345] Prostacyclin production is known to increase after brain
trauma, and in a recent study, the importance of prostacyclin for
posttraumatic hemodynamic alterations and neuron survival was
investigated. Prostacyclin receptor-deficient (IP.sup.-/-) mice
were compared to mice with functional prostacyclin receptors
(IP.sup.+/+) after a controlled cortical injury. Contusion volume
was increased in IP.sup.-/- mice compared with IP.sup.+/+ mice.
Three hours after trauma, cortical blood flow was decreased in the
injured cortex of both groups and the reduction in blood flow in
the cortex of the IP.sup.-/- mice persisted from 3 to 24 h, whereas
blood flow approached normal values in the IP.sup.+/+ mice after 24
h. (See, e.g., Lundblad et al. Journal of Cerebral Blood Flow &
Metabolism (2008) 28, 367-376).
[0346] The PGI2 receptor agonists disclosed herein provide
beneficial improvement in neuron survival after brain trauma.
Accordingly, in some embodiments, the present invention provides
methods for treating a traumatic brain injury in a patient in need
thereof, comprising administering to the patient a composition
comprising a PGI2 receptor agonist disclosed herein.
Pharmaceutical Compositions
[0347] A further aspect of the present invention pertains to
pharmaceutical compositions comprising one or more compounds as
described herein and one or more pharmaceutically acceptable
carriers. Some embodiments pertain to pharmaceutical compositions
comprising a compound of the present invention and a
pharmaceutically acceptable carrier.
[0348] Some embodiments of the present invention include a method
of producing a pharmaceutical composition comprising admixing at
least one compound according to any of the compound embodiments
disclosed herein and a pharmaceutically acceptable carrier.
[0349] Formulations may be prepared by any suitable method,
typically by uniformly mixing the active compound(s) with liquids
or finely divided solid carriers, or both, in the required
proportions and then, if necessary, forming the resulting mixture
into a desired shape.
[0350] Conventional excipients, such as binding agents, fillers,
acceptable wetting agents, tabletting lubricants and disintegrants
may be used in tablets and capsules for oral administration. Liquid
preparations for oral administration may be in the form of
solutions, emulsions, aqueous or oily suspensions and syrups.
Alternatively, the oral preparations may be in the form of dry
powder that can be reconstituted with water or another suitable
liquid vehicle before use. Additional additives such as suspending
or emulsifying agents, non-aqueous vehicles (including edible
oils), preservatives and flavorings and colorants may be added to
the liquid preparations. Parenteral dosage forms may be prepared by
dissolving the compound of the invention in a suitable liquid
vehicle and filter sterilizing the solution before filling and
sealing an appropriate vial or ampule. These are just a few
examples of the many appropriate methods well known in the art for
preparing dosage forms.
[0351] A compound of the present invention can be formulated into
pharmaceutical compositions using techniques well known to those in
the art. Suitable pharmaceutically-acceptable carriers, outside
those mentioned herein, are known in the art; for example, see
Remington, The Science and Practice of Pharmacy, 20.sup.th Edition,
2000, Lippincott Williams & Wilkins, (Editors: Gennaro et
al.)
[0352] While it is possible that, for use in the prophylaxis or
treatment, a compound of the invention may, in an alternative use,
be administered as a raw or pure chemical, it is preferable however
to present the compound or active ingredient as a pharmaceutical
formulation or composition further comprising a pharmaceutically
acceptable carrier.
[0353] Pharmaceutical formulations include those suitable for oral,
rectal, nasal, topical (including buccal and sub-lingual), vaginal
or parenteral (including intramuscular, sub-cutaneous and
intravenous) administration or in a form suitable for
administration by inhalation, insufflation or by a transdermal
patch. Transdermal patches dispense a drug at a controlled rate by
presenting the drug for absorption in an efficient manner with
minimal degradation of the drug. Typically, transdermal patches
comprise an impermeable backing layer, a single pressure sensitive
adhesive and a removable protective layer with a release liner. One
of ordinary skill in the art will understand and appreciate the
techniques appropriate for manufacturing a desired efficacious
transdermal patch based upon the needs of the artisan.
[0354] The compounds of the invention, together with a conventional
adjuvant, carrier, or diluent, may thus be placed into the form of
pharmaceutical formulations and unit dosages thereof and in such
form may be employed as solids, such as tablets or filled capsules,
or liquids such as solutions, suspensions, emulsions, elixirs, gels
or capsules filled with the same, all for oral use, in the form of
suppositories for rectal administration; or in the form of sterile
injectable solutions for parenteral (including subcutaneous) use.
Such pharmaceutical compositions and unit dosage forms thereof may
comprise conventional ingredients in conventional proportions, with
or without additional active compounds or principles and such unit
dosage forms may contain any suitable effective amount of the
active ingredient commensurate with the intended daily dosage range
to be employed.
[0355] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are capsules, tablets,
powders, granules or a suspension, with conventional additives such
as lactose, mannitol, corn starch or potato starch; with binders
such as crystalline cellulose, cellulose derivatives, acacia, corn
starch or gelatins; with disintegrators such as corn starch, potato
starch or sodium carboxymethyl-cellulose; and with lubricants such
as talc or magnesium stearate. The active ingredient may also be
administered by injection as a composition wherein, for example,
saline, dextrose or water may be used as a suitable
pharmaceutically acceptable carrier.
[0356] Compounds of the present invention or a solvate, hydrate or
physiologically functional derivative thereof can be used as active
ingredients in pharmaceutical compositions, specifically as PGI2
receptor modulators. By the term "active ingredient" is defined in
the context of a "pharmaceutical composition" and is intended to
mean a component of a pharmaceutical composition that provides the
primary pharmacological effect, as opposed to an "inactive
ingredient" which would generally be recognized as providing no
pharmaceutical benefit.
[0357] The dose when using the compounds of the present invention
can vary within wide limits and as is customary and is known to the
physician, it is to be tailored to the individual conditions in
each individual case. It depends, for example, on the nature and
severity of the illness to be treated, on the condition of the
patient, on the compound employed or on whether an acute or chronic
disease state is treated or prophylaxis is conducted or on whether
further active compounds are administered in addition to the
compounds of the present invention. Representative doses of the
present invention include, but not limited to, about 0.001 mg to
about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to
about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg,
about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about
0.001 mg to about 25 mg. Multiple doses may be administered during
the day, especially when relatively large amounts are deemed to be
needed, for example 2, 3 or 4 doses. Depending on the individual
and as deemed appropriate from the patient's physician or caregiver
it may be necessary to deviate upward or downward from the doses
described herein.
[0358] The amount of active ingredient, or an active salt or
derivative thereof, required for use in treatment will vary not
only with the particular salt selected but also with the route of
administration, the nature of the condition being treated and the
age and condition of the patient and will ultimately be at the
discretion of the attendant physician or clinician. In general, one
skilled in the art understands how to extrapolate in vivo data
obtained in a model system, typically an animal model, to another,
such as a human. In some circumstances, these extrapolations may
merely be based on the weight of the animal model in comparison to
another, such as a mammal, preferably a human, however, more often,
these extrapolations are not simply based on weights, but rather
incorporate a variety of factors. Representative factors include
the type, age, weight, sex, diet and medical condition of the
patient, the severity of the disease, the route of administration,
pharmacological considerations such as the activity, efficacy,
pharmacokinetic and toxicology profiles of the particular compound
employed, whether a drug delivery system is utilized, on whether an
acute or chronic disease state is being treated or prophylaxis is
conducted or on whether further active compounds are administered
in addition to the compounds of the present invention and as part
of a drug combination. The dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
is selected in accordance with a variety factors as cited above.
Thus, the actual dosage regimen employed may vary widely and
therefore may deviate from a preferred dosage regimen and one
skilled in the art will recognize that dosage and dosage regimen
outside these typical ranges can be tested and, where appropriate,
may be used in the methods of this invention.
[0359] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations. The daily dose can be
divided, especially when relatively large amounts are administered
as deemed appropriate, into several, for example 2, 3 or 4 part
administrations. If appropriate, depending on individual behavior,
it may be necessary to deviate upward or downward from the daily
dose indicated.
[0360] The compounds of the present invention can be administrated
in a wide variety of oral and parenteral dosage forms. It will be
obvious to those skilled in the art that the following dosage forms
may comprise, as the active component, either a compound of the
invention or a pharmaceutically acceptable salt, solvate or hydrate
of a compound of the invention.
[0361] For preparing pharmaceutical compositions from the compounds
of the present invention, the selection of a suitable
pharmaceutically acceptable carrier can be either solid, liquid or
a mixture of both. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0362] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component.
[0363] In tablets, the active component is mixed with the carrier
having the necessary binding capacity in suitable proportions and
compacted to the desire shape and size.
[0364] The powders and tablets may contain varying percentage
amounts of the active compound. A representative amount in a powder
or tablet may contain from 0.5 to about 90 percent of the active
compound; however, an artisan would know when amounts outside of
this range are necessary. Suitable carriers for powders and tablets
are magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter and
the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as
carrier providing a capsule in which the active component, with or
without carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets and lozenges can be used
as solid forms suitable for oral administration.
[0365] For preparing suppositories, a low melting wax, such as an
admixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool and thereby to
solidify.
[0366] Formulations suitable for vaginal administration may be
presented as pessaries tampons, creams, gels, pastes, foams or
sprays containing in addition to the active ingredient such
carriers as are known in the art to be appropriate.
[0367] Liquid form preparations include solutions, suspensions and
emulsions, for example, water or water-propylene glycol solutions.
For example, parenteral injection liquid preparations can be
formulated as solutions in aqueous polyethylene glycol solution.
Injectable preparations, for example sterile injectable aqueous or
oleaginous suspensions may be formulated according to the known an
using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable
solution or suspension in a nontoxic parenterally acceptable
diluent or solvent, for example, as a solution in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0368] The compounds according to the present invention may thus be
formulated for parenteral administration (e.g. by injection, for
example bolus injection or continuous infusion) and may be
presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with an added
preservative. The pharmaceutical compositions may take such forms
as suspensions, solutions, or emulsions in oily or aqueous vehicles
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents. Alternatively, the active ingredient may
be in powder form, obtained by aseptic isolation of sterile solid
or by lyophilization from solution, for constitution with a
suitable vehicle, e.g. sterile, pyrogen-free water, before use.
[0369] Aqueous formulations suitable for oral use can be prepared
by dissolving or suspending the active component in water and
adding suitable colorants, flavors, stabilizing and thickening
agents, as desired.
[0370] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, or other well-known
suspending agents.
[0371] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions and emulsions. These preparations may contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents and the like.
[0372] For topical administration to the epidermis the compounds
according to the invention may be formulated as ointments, creams
or lotions, or as a transdermal patch.
[0373] Ointments and creams may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening
and/or gelling agents. Lotions may be formulated with an aqueous or
oily base and will in general also contain one or more emulsifying
agents, stabilizing agents, dispersing agents, suspending agents,
thickening agents, or coloring agents.
[0374] Formulations suitable for topical administration in the
mouth include lozenges comprising active agent in a flavored base,
usually sucrose and acacia or tragacanth pastilles comprising the
active ingredient in an inert base such as gelatin and glycerin or
sucrose and acacia; and mouthwashes comprising the active
ingredient in a suitable liquid carrier.
[0375] Solutions or suspensions are applied directly to the nasal
cavity by conventional means, for example with a dropper, pipette
or spray. The formulations may be provided in single or multi-dose
form. In the latter case of a dropper or pipette, this may be
achieved by the patient administering an appropriate, predetermined
volume of the solution or suspension. In the case of a spray, this
may be achieved for example by means of a metering atomizing spray
pump.
[0376] Administration to the respiratory tract may also be achieved
by means of an aerosol formulation in which the active ingredient
is provided in a pressurized pack with a suitable propellant. If
the compounds of the present invention or pharmaceutical
compositions comprising them are administered as aerosols, for
example as nasal aerosols or by inhalation, this can be carried
out, for example, using a spray, a nebulizer, a pump nebulizer, an
inhalation apparatus, a metered inhaler or a dry powder inhaler.
Pharmaceutical forms for administration of the compounds of the
present invention as an aerosol can be prepared by processes well
known to the person skilled in the art. For their preparation, for
example, solutions or dispersions of the compounds of the present
invention in water, water/alcohol mixtures or suitable saline
solutions can be employed using customary additives, for example
benzyl alcohol or other suitable preservatives, absorption
enhancers for increasing the bioavailability, solubilizers,
dispersants and others and, if appropriate, customary propellants,
for example include carbon dioxide, CFCs, such as,
dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane; and the like. The aerosol may
conveniently also contain a surfactant such as lecithin. The dose
of drug may be controlled by provision of a metered valve.
[0377] In formulations intended for administration to the
respiratory tract, including intranasal formulations, the compound
will generally have a small particle size for example of the order
of 10 microns or less. Such a particle size may be obtained by
means known in the art, for example by micronization. When desired,
formulations adapted to give sustained release of the active
ingredient may be employed.
[0378] Alternatively the active ingredients may be provided in the
form of a dry powder, for example, a powder mix of the compound in
a suitable powder base such as lactose, starch, starch derivatives
such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone
(PVP). Conveniently the powder carrier will form a gel in the nasal
cavity. The powder composition may be presented in unit dose form
for example in capsules or cartridges of, e.g., gelatin, or blister
packs from which the powder may be administered by means of an
inhaler.
[0379] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0380] Tablets or capsules for oral administration and liquids for
intravenous administration are preferred compositions.
[0381] The compounds according to the invention may optionally
exist as pharmaceutically acceptable salts including
pharmaceutically acceptable acid addition salts prepared from
pharmaceutically acceptable non-toxic acids including inorganic and
organic acids. Representative acids include, but are not limited
to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethenesulfonic, dichloroacetic, formic, fumaric, gluconic,
glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic,
pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric,
oxalic, p-toluenesulfonic and the like. Certain compounds of the
present invention which contain a carboxylic acid functional group
may optionally exist as pharmaceutically acceptable salts
containing non-toxic, pharmaceutically acceptable metal cations and
cations derived from organic bases. Representative metals include,
but are not limited to, aluminium, calcium, lithium, magnesium,
potassium, sodium, zinc and the like. In some embodiments the
pharmaceutically acceptable metal is sodium. Representative organic
bases include, but are not limited to, benzathine
(N.sup.1,N.sup.2-dibenzylethane-1,2-diamine), chloroprocaine
(2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline,
diethanolamine, ethylenediamine, meglumine
((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine
(2-(diethylamino)ethyl 4-aminobenzoate), and the like. Certain
pharmaceutically acceptable salts are listed in Berge, et al.,
Journal of Pharmaceutical Sciences, 66:1-19 (1977), incorporated
herein by reference in its entirety.
[0382] The acid addition salts may be obtained as the direct
products of compound synthesis. In the alternative, the free base
may be dissolved in a suitable solvent containing the appropriate
acid and the salt isolated by evaporating the solvent or otherwise
separating the salt and solvent. The compounds of this invention
may form solvates with standard low molecular weight solvents using
methods known to the skilled artisan.
[0383] Compounds of the present invention can be converted to
"pro-drugs." The term "pro-drugs" refers to compounds that have
been modified with specific chemical groups known in the art and
when administered into an individual these groups undergo
biotransformation to give the parent compound. Pro-drugs can thus
be viewed as compounds of the invention containing one or more
specialized non-toxic protective groups used in a transient manner
to alter or to eliminate a property of the compound. In one general
aspect, the "pro-drug" approach is utilized to facilitate oral
absorption. A thorough discussion is provided in T. Higuchi and V.
Stella. Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.
Symposium Series; and in Bioreversble Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon
Press, 1987, both of which are hereby incorporated by reference in
their entirety.
[0384] Some embodiments of the present invention include a method
of producing a pharmaceutical composition for "combination-therapy"
comprising admixing at least one compound according to any of the
compound embodiments disclosed herein, together with at least one
known pharmaceutical agent as described herein and a
pharmaceutically acceptable carrier.
[0385] It is noted that when the PGI2 receptor modulators are
utilized as active ingredients in a pharmaceutical composition,
these are not intended for use only in humans, but in other
non-human mammals as well. Indeed, recent advances in the area of
animal health-care mandate that consideration be given for the use
of active agents, such as PGI2 receptor modulators, for the
treatment of an PGI2-associated disease or disorder in
companionship animals (e.g., cats, dogs, etc.) and in livestock
animals (e.g., cows, chickens, fish, etc.) Those of ordinary skill
in the art are readily credited with understanding the utility of
such compounds in such settings.
Hydrates and Solvates
[0386] It is understood that when the phrase pharmaceutically
acceptable salts, solvates and hydrates is used in referring to a
particular formula herein, it is intended to embrace solvates
and/or hydrates of compounds of the particular formula,
pharmaceutically acceptable salts of compounds of the particular
formula as well as solvates and/or hydrates of pharmaceutically
acceptable salts of compounds of the particular formula.
[0387] The compounds of the present invention can be administrated
in a wide variety of oral and parenteral dosage forms. It will be
apparent to those skilled in the art that the following dosage
forms may comprise, as the active component, either a compound of
the invention or a pharmaceutically acceptable salt or as a solvate
or hydrate thereof. Moreover, various hydrates and solvates of the
compounds of the invention and their salts will find use as
intermediates in the manufacture of pharmaceutical compositions.
Typical procedures for making and identifying suitable hydrates and
solvates, outside those mentioned herein, are well known to those
in the art; see for example, pages 202-209 of K. J. Guillory,
"Generation of Polymorphs, Hydrates, Solvates, and Amorphous
Solids." in: Polymorphism in Pharmaceutical Solids, ed. Harry G.
Brittan, Vol. 95, Marcel Dekker, Inc., New York, 1999, incorporated
herein by reference in its entirety. Accordingly, one aspect of the
present invention pertains to hydrates and solvates of compounds of
Formula Ia and/or their pharmaceutical acceptable salts, as
described herein, that can be isolated and characterized by methods
known in the art, such as, thermogravimetric analysis (TGA),
TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray
diffraction (XRPD), Karl Fisher titration, high resolution X-ray
diffraction, and the like. There are several commercial entities
that provide quick and efficient services for identifying solvates
and hydrates on a routine basis. Example companies offering these
services include Wilmington PharmaTech (Wilmington, Del.), Avantium
Technologies (Amsterdam) and Aptuit (Greenwich, Conn.).
Pro-Drugs of the Present Invention
[0388] The compounds of Formula Ia may be administered in the form
of a pro-drug which is broken down in the human or animal body to
give a compound of the Formula Ia. Pro-drugs of the present
invention may employ any pro-drug strategy known in the art. A
pro-drug may be used to alter or improve the physical and/or
pharmacokinetic profile of the parent compound and can be formed
when the parent compound contains a suitable group or substituent
which can be derivatized to form a pro-drug. Examples of pro-drugs
include in-vivo hydrolyzable amides of a compound of the Formula Ia
or pharmaceutically-acceptable salts thereof.
[0389] One aspect of the present invention pertains to compounds of
Formula II useful as pro-drugs for the delivery of compounds of
Formula Ia:
##STR00100##
[0390] wherein:
[0391] R.sup.2 and R.sup.3 are each independently selected from: H,
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen;
[0392] X is selected from: N and CH; and
[0393] R.sup.4 is a radical derived from any natural or unnatural
amino acid, upon the loss of a hydrogen atom from the .alpha.-amino
group of said natural or unnatural amino acid; or
[0394] R.sup.4 is --NHCH.sub.2CH.sub.2SO.sub.3H.
[0395] One aspect of the present invention pertains to compounds of
Formula Ha useful as pro-drugs for the delivery of compounds of
Formula Ia:
##STR00101##
[0396] wherein:
[0397] R.sup.2 and R.sup.3 are each independently selected from: H,
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen;
[0398] R.sup.5 is selected from: H and carboxyl; and
[0399] R.sup.6 is selected from: H and C.sub.1-C.sub.6 alkyl;
wherein C.sub.1-C.sub.6 alkyl is optionally substituted with
4-hydroxyphenyl, amino, carboxamide, carboxyl, guanidino, hydroxyl,
imidazolyl, indolyl, methylthio, phenyl, pyrrolidinyl, sulfo and
thiol.
[0400] In some embodiments, R.sup.2 is selected from:
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 alkylthio, aryl, C.sub.1-C.sub.8 haloalkyl and
halogen.
[0401] In some embodiments, R.sup.2 is aryl optionally substituted
with one or more C.sub.1-C.sub.8 alkyl substituents.
[0402] In some embodiments, R.sup.2 is p-tolyl.
[0403] In some embodiments, R.sup.3 is selected from: H,
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl; wherein said
C.sub.1-C.sub.8 alkyl, aryl and heteroaryl are each optionally
substituted with one or more substituents each independently
selected from: C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy and
halogen.
[0404] In some embodiments, R.sup.3 is phenyl.
[0405] In some embodiments, R.sup.5 is H; and R.sup.6 is
--CH.sub.2SO.sub.3H.
[0406] In some embodiments, R.sup.5 is carboxyl; and R.sup.6 is
H.
[0407] In some embodiments: R.sup.2 is p-tolyl; R.sup.3 is phenyl;
R is H; and R.sup.6 is --CH.sub.2SO.sub.3H.
[0408] In some embodiments: R.sup.2 is p-tolyl; R.sup.3 is phenyl;
R.sup.5 is carboxyl; and R.sup.5 is H.
[0409] Certain pro-drugs of compounds of the present invention are
described in Examples 1.88 and 1.89.
Other Utilities
[0410] Another object of the present invention relates to
radio-labeled compounds of the present invention that would be
useful not only in radio-imaging but also in assays, both in vitro
and in vivo, for localizing and quantitating the PGI2 receptor in
tissue samples, including human and for identifying PGI2 receptor
ligands by inhibition binding of a radio-labeled compound. It is a
further object of this invention to develop novel PGI2 receptor
assays of which comprise such radio-labeled compounds.
[0411] The present invention embraces isotopically-labeled
compounds of the present invention. Isotopicaly or radio-labeled
compounds are those which are identical to compounds disclosed
herein, but for the fact that one or more atoms are replaced or
substituted by an atom having an atomic mass or mass number
different from the atomic mass or mass number most commonly found
in nature. Suitable radionuclides that may be incorporated in
compounds of the present invention include but are not limited to
.sup.2H (also written as D for deuterium), .sup.3H (also written as
T for tritium), .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.18F, .sup.35S, .sup.36Cl,
.sup.75Br, .sup.76Br, .sup.77Br, .sup.82Br, .sup.123I, .sup.124I,
.sup.125I and .sup.131I. The radionuclide that is incorporated in
the instant radio-labeled compounds will depend on the specific
application of that radio-labeled compound. For example, for in
vitro PGI2 receptor labeling and competition assays, compounds that
incorporate .sup.3H, .sup.14C, .sup.82Br, .sup.125I, .sup.131I or
.sup.35S will generally be most useful. For radio-imaging
applications .sup.11C, .sup.18F, .sup.125I, .sup.123I, .sup.124I,
.sup.131I, .sup.75Br, .sup.76Br or .sup.77Br will generally be most
useful.
[0412] It is understood that a "radio-labeled" or "labeled
compound" is a compound of Formula Ia, Ic, Ie, Ig, or Ii that has
incorporated at least one radionuclide; in some embodiments the
radionuclide is selected from the group consisting of .sup.3H,
.sup.14C, .sup.25I, .sup.35S and .sup.82Br.
[0413] Certain isotopically-labeled compounds of the present
invention are useful in compound and/or substrate tissue
distribution assays. In some embodiments the radionuclide .sup.3H
and/or .sup.14C isotopes are useful in these studies. Further,
substitution with heavier isotopes such as deuterium (i.e.,
.sup.2H) may afford certain therapeutic advantages resulting from
greater metabolic stability (e.g., increased in vivo half-life or
reduced dosage requirements) and hence may be preferred in some
circumstances. Isotopically labeled compounds of the present
invention can generally be prepared by following procedures
analogous to those disclosed in the Drawings and Examples infra, by
substituting an isotopically labeled reagent for a non-isotopically
labeled reagent. Other synthetic methods that are useful are
discussed infra. Moreover, it should be understood that all of the
atoms represented in the compounds of the invention can be either
the most commonly occurring isotope of such atoms or the scarcer
radio-isotope or nonradioactive isotope.
[0414] Synthetic methods for incorporating radio-isotopes into
organic compounds are applicable to compounds of the invention and
are well known in the art. These synthetic methods, for example,
incorporating activity levels of tritium into target molecules, are
as follows:
[0415] A. Catalytic Reduction with Tritium Gas: This procedure
normally yields high specific activity products and requires
halogenated or unsaturated precursors.
[0416] B. Reduction with Sodium Borohydride [.sup.3H]: This
procedure is rather inexpensive and requires precursors containing
reducible functional groups such as aldehydes, ketones, lactones,
esters and the like.
[0417] C. Reduction with Lithium Aluminum Hydride [.sup.3H]: This
procedure offers products at almost theoretical specific
activities. It also requires precursors containing reducible
functional groups such as aldehydes, ketones, lactones, esters and
the like.
[0418] D. Tritium Gas Exposure Labeling: This procedure involves
exposing precursors containing exchangeable protons to tritium gas
in the presence of a suitable catalyst.
[0419] E. N-Methylation using Methyl Iodide [.sup.3H]: This
procedure is usually employed to prepare O-methyl or N-methyl (3H)
products by treating appropriate precursors with high specific
activity methyl iodide (3H). This method in general allows for
higher specific activity, such as for example, about 70-90
Ci/mmol.
[0420] Synthetic methods for incorporating activity levels of
.sup.125I into target molecules include:
[0421] A. Sandmeyer and like reactions: This procedure transforms
an aryl amine or a heteroaryl amine into a diazonium salt, such as
a diazonium tetrafluoroborate salt and subsequently to .sup.125I
labeled compound using Na.sup.125I. A represented procedure was
reported by Zhu, G-D. and co-workers in J. Org. Chem., 2002, 67,
943-948.
[0422] B. Ortho .sup.125Iodination of phenols: This procedure
allows for the incorporation of .sup.125I at the ortho position of
a phenol as reported by Collier. T. L. and co-workers in J.
Labelled Compd Radiopharm., 1999, 42, S264-S266.
[0423] C. Aryl and heteroaryl bromide exchange with .sup.125I: This
method is generally a two step process. The first step is the
conversion of the aryl or heteroaryl bromide to the corresponding
tri-alkyltin intermediate using for example, a Pd catalyzed
reaction [i.e. Pd(Ph.sub.3P).sub.4] or through an aryl or
heteroaryl lithium, in the presence of a tri-alkyltinhalide or
hexaalkylditin [e.g., (CH.sub.3).sub.3SnSn(CH.sub.3).sub.3]. A
representative procedure was reported by Le Bas, M.-D. and
co-workers in J. Labelled Compd Radiopharm. 2001, 44,
S280-S282.
[0424] A radiolabeled PGI2 receptor compound of Formula Ia can be
used in a screening assay to identify/evaluate compounds. In
general terms, a newly synthesized or identified compound (i.e.,
test compound) can be evaluated for its ability to reduce binding
of the "radio-labeled compound of Formula Ia" to the PGI2 receptor.
Accordingly, the ability of a test compound to compete with the
"radio-labeled compound of Formula Ia" for the binding to the PGI2
receptor directly correlates to its binding affinity.
[0425] The labeled compounds of the present invention bind to the
PGI2 receptor. In one embodiment the labeled compound has an
IC.sub.50 less than about 500 .mu.M, in another embodiment the
labeled compound has an IC.sub.50 less than about 100 .mu.M, in yet
another embodiment the labeled compound has an IC.sub.50 less than
about 10 .mu.M, in yet another embodiment the labeled compound has
an IC.sub.50 less than about 1 .mu.M and in still yet another
embodiment the labeled inhibitor has an IC.sub.50 less than about
0.1 .mu.M.
[0426] Other uses of the disclosed receptors and methods will
become apparent to those skilled in the art based upon, inter alia,
a review of this disclosure.
[0427] As will be recognized, the steps of the methods of the
present invention need not be performed any particular number of
times or in any particular sequence. Additional objects, advantages
and novel features of this invention will become apparent to those
skilled in the art upon examination of the following examples
thereof, which are intended to be illustrative and not intended to
be limiting.
EXAMPLES
Example 1: Syntheses of Compounds of the Present Invention
[0428] Illustrated syntheses for compounds of the present invention
are shown in FIGS. 2 through 6 where the symbols have the same
definitions as used throughout this disclosure.
[0429] The compounds of the invention and their syntheses are
further illustrated by the following examples. The following
examples are provided to further define the invention without,
however, limiting the invention to the particulars of these
examples. The compounds described herein, supra and info, are named
according to the CS ChemDraw Ultra Version 7.0.1, AutoNom version
2.2, or CS ChemDraw Ultra Version 9.0.7. In certain instances
common names are used and it is understood that these common names
would be recognized by those skilled in the art.
[0430] Chemistry:
[0431] Proton nuclear magnetic resonance (.sup.1H NMR) spectra were
recorded on a Bruker Avance-400 equipped with a QNP (Quad Nucleus
Probe) or a BBI (Broad Band Inverse) and z-gradient. Chemical
shifts are given in parts per million (ppm) with the residual
solvent signal used as reference. NMR abbreviations are used as
follows: s=singlet, d=doublet, dd=doublet of doublets, ddd=doublet
of doublet of doublets, dt=doublet of triplets, t=triplet,
td=triplet of doublets, tt=triplet of triplets, q=quartet,
m=multiplet, bs=broad singlet, bt=broad triplet. Microwave
irradiations were carried out using a Smith Synthesizer.TM. or an
Emrys Optimizer.TM. (Biotage). Thin-layer chromatography (TLC) was
performed on silica gel 60 F.sub.254 (Merck), preparatory
thin-layer chromatography (prep TLC) was preformed on PK6F silica
gel 60 A 1 mm plates (Whatman) and column chromatography was
carried out on a silica gel column using Kieselgel 60, 0.063-0.200
mm (Merck). Evaporation was done under reduced pressure on a Buchi
rotary evaporator.
[0432] LCMS spec: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC
system controller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A
VP, Shimadzu Inc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass
spectrometer: API 150EX with Turbo Ion Spray source. AB/MDS Sciex;
Software: Analyst 1.2.
Example 1.1: Preparation of
2-(((1s,4s)-4-((3-Oxo-1-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic Acid (Compound 68) and Sodium Salt
Thereof
Step A: Preparation of
2-(Hydroxyimino)-2-phenyl-1-p-tolylethanone
[0433] To a solution of 2-phenyl-1-p-tolylethanone (5.0 g, 23.78
mmol) in EtOH (475.0 mL) at room temperature was added dropwise
tert-butyl nitrite (5.5 mL, 46.2 mmol) followed by sodium ethoxide
(4.07 g, 59.8 mmol). The reaction was stirred at room temperature
overnight and concentrated under reduced pressure. The residue was
dissolved in EtOAc, washed with H.sub.2O, brine, dried over
MgSO.sub.4 and concentrated. The residue was purified by silica gel
column chromatography to give the title compound as an orange oil
(5.31 g). LCMS m/z=239.9 [M+H].sup.+.
Step B: Preparation of
3-(Methythio)-5-phenyl-6-p-tolyl-1,2,4-triazine
[0434] To a suspension of
2-(hydroxyimino)-2-phenyl-1-p-tolylethanone (1.99 g, 8.32 mmol) in
a 1:1 mixture of MeOH/H.sub.2O (40.0 mL) was added
hydrazinecarbothioamide (1.134 g, 12.44 mmol) followed by
concentrated HCl (0.75 mL, 24.68 mmol). The reaction was stirred at
room temperature for 1 h then at 60.degree. C. overnight.
Additional hydrazinecarbothioamide (.about.3.times.100 mg) was
added portionwise and the reaction was stirred at 60.degree. C.
until the starting material was consumed. The reaction was
neutralized with saturated NaHCO.sub.3. The solid was removed by
filtration and rinsed with H.sub.2O. To the solid was added a
solution of potassium carbonate (5.78 g, 41.8 mmol) in H.sub.2O (85
mL) and the mixture was heated at 90.degree. C. overnight. The
reaction mixture was cooled to room temperature then placed in an
ice bath. Iodomethane (0.52 mL, 8.35 mmol) was added and the
reaction was stirred at 0.degree. C. and then slowly warmed to room
temperature. After stirring overnight, the solution was decanted.
The solid was dissolved in CH.sub.2Cl.sub.2, and the solution was
washed with H.sub.2O and brine, dried over MgSO.sub.4, and
concentrated. The residue was purified by silica gel column
chromatography to give the title compound as a yellow solid (1.302
g). LCMS m/z=294.2 [M+H].sup.+.
Step C: Preparation of
3-(Methylsulfonyl)-5-phenyl-6-p-tolyl-1,2,4-triazine
[0435] To a solution of
3-(methylthio)-5-phenyl-6-p-tolyl-1,2,4-triazine (1.302 g, 4.44
mmol) in CH.sub.2Cl.sub.2 (25.0 mL) at 0.degree. C. was added MCPBA
(2.06 g, 9.19 mmol). The reaction mixture was stirred at 0.degree.
C. and then warmed to room temperature. After 18 h, the reaction
was quenched with saturated NaHCO.sub.3 solution and extracted with
CH.sub.2Cl.sub.2. The combined organic phases were washed with
H.sub.2O and brine, dried over MgSO.sub.4, and concentrated. The
residue was purified by silica gel column chromatography to give
the title compound as an off-white solid (1.69 g). LCMS m/z=326.2
[M+H].sup.+.
Step D: Preparation of
5-Phenyl-6-p-tolyl-1,2,4-triazin-3(2H)-one
[0436] To a solution of
3-(methylsulfonyl)-5-phenyl-6-p-tolyl-1,2,4-triazine (98.9 mg,
0.304 mmol) in a 1:1 mixture of H.sub.2O/THF (6.0 mL) was added
potassium hydroxide (109.1 mg, 1.945 mmol). The mixture was heated
at reflux for 1 h. The reaction mixture was cooled to room
temperature and neutralized with 1 M HCl, then extracted with
CH.sub.2Cl.sub.2. The combined organic phases were washed with
H.sub.2O and brine, dried over MgSO.sub.4, and concentrated to give
the title compound as a yellow solid (73.7 mg). LCMS m/z=264.1
[M+H].sup.+.
Step E: Preparation of
2-(((1s,4s)-4-((3-Oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic Acid and Sodium Salt Thereof
[0437] In a reaction vial was placed a mixture of
5-phenyl-6-p-tolyl-1,2,4-triazin-3(2H)-one (352.7 mg, 1.340 mmol)
and sodium hydride (58.3 mg, 1.458 mmol) in DMF (3.0 mL). The
reaction was stirred at room temperature for 15 min then added a
solution of tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (549.0 mg,
1.331 mmol) in DMF (6.0 mL). The mixture was heated at 45.degree.
C. Upon completion of the reaction, the mixture was quenched with
H.sub.2O and extracted with EtOAc. The combined organics were
washed with brine, dried over MgSO.sub.4, and concentrated. The
residue was purified by silica gel column chromatography. To the
above purified material was added 4 M HCl (1.0 mL) in 1,4-dioxane
and the mixture was stirred at room temperature overnight. Five
drops of 10% NaOH solution was added and the mixture was extracted
with MTBE. The combined organic phases were washed with brine,
dried over MgSO.sub.4, and concentrated. The residue was purified
by HPLC to give the title compound free acid as a yellowish solid
(289.1 mg). The free acid was dissolved in acetonitrile, 1 N
aqueous sodium hydroxide (0.646 mL, 0.646 mmol) was added and the
mixture was lyophilized to afford the sodium salt of the title
compound as an off-white solid (304.8 mg). LCMS m/z=448.5
[M+H].sup.+; .sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm
1.34-1.54 (m, 7H), 1.67-1.79 (m, 2H), 2.12-2.22 (m, 1H), 2.29 (s,
3H), 3.36 (d, J=7.0 Hz, 2H), 3.74 (s, 2H), 4.09 (d, J=7.5 Hz, 2H),
7.14 (s, 4H), 7.25-7.34 (m, 4H), 7.36-7.42 (m, 1H).
Example 1.2: Preparation of
2-(((1s,4s)-4-((3-Oxo-5,6-di-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cycloh-
exyl)methoxy)acetic Acid (Compound 43)
[0438] In a reaction vial was placed a mixture of
5,6-di-p-tolyl-1,2,4-triazin-3(2H)-one (73.3 mg, 0.264 mmol) and
sodium hydride (13.8 mg, 0.345 mmol) in THF (1.0 mL). The reaction
was stirred at room temperature for 30 min then added a solution of
tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate
(101.3 mg, 0.246 mmol) in THF (1.5 mL). DMF (1.0 mL) was added to
the reaction mixture and it was heated at 50.degree. C. for 45 h.
Upon completion, the reaction was quenched with H.sub.2O and
extracted with EtOAc. The combined organic layers were washed with
brine, dried over MgSO.sub.4, and concentrated. The residue was
purified by silica gel column chromatography to give a yellow oil.
To this oil was added 4 M HCl (0.50 mL, 2.0 mmol) in 1,4-dioxane
and the mixture was stirred at room temperature overnight. Upon
completion of the reaction, 10% NaOH solution (6 drops) was added
and the reaction mixture was diluted with acetonitrile. The
reaction mixture was filtered and purified by HPLC to give the
title compound as a yellow solid (35.0 mg). LCMS m/z=462.3
[M+H].sup.+; .sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm
1.36-1.54 (m, 7H), 1.68-1.79 (m, 2H), 2.12-2.21 (m, 1H), 2.29-2.32
(m, 6H), 3.39 (d, J=6.9 Hz, 2H), 3.98 (s, 2H), 4.08 (d, J=7.5 Hz,
2H), 7.14-7.18 (m, 6H), 7.28-7.31 (m, 2H).
Example 1.3: Preparation of
2-(((1s,4s)-4-((3-Oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 48)
[0439] From 5,6-diphenyl-1,2,4-triazin-3(2H)-one, the title
compound was prepared using a similar method to the one described
in Example 1.1, Step E. LCMS m/z=434.4 [M+H].sup.+; .sup.1H NMR
(400 M Hz, DMSO-d.sub.6) .delta. ppm 1.39-1.54 (m, 7H), 1.69-1.80
(m, 2H), 2.14-2.23 (m, 1H), 3.40 (d, J=6.9 Hz, 2H), 3.99 (s, 2H),
4.10 (d, J=7.5 Hz, 2H), 7.24-7.49 (m, 10H).
Example 1.4: Preparation of
2-(((1s,4s)-4-((5,6-Bis(4-fluorophenyl)-3-oxo-1,2,4-triazin-2(3H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 49)
[0440] From 5,6-bis(4-fluorophenyl)-1,2,4-triazin-3(2H)-one, the
title compound was prepared using a similar method to the one
described Example 1.1, Step E to give a yellow solid. .sup.1H NMR
(400 M Hz, DMSO-d.sub.6) .delta. ppm 1.39-1.55 (m, 7H), 1.69-1.80
(m, 2H), 2.13-2.21 (m, 1H), 3.38 (d, J=6.8 Hz, 2H), 3.95 (s, 2H),
4.09 (d, J=7.5 Hz, 2H), 7.17-7.25 (m, 4H), 7.29-7.35 (m, 2H),
7.41-7.47 (m, 2H).
Example 1.5: Preparation of
2-(((1s,4s)-4-((6-(4-Fluorophenyl)-3-oxo-1-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetic Acid (Compound 64)
[0441] From 1-(4-fluorophenyl)-2-phenylethanone, the title compound
was prepared using a similar method to the one described in Example
1.1 to give a yellow solid. LCMS m/z=452.3 [M+H].sup.+. LCMS
m/z=452.3 [M+H].sup.+; .sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta.
ppm 1.38-1.55 (m, 7H), 1.70-1.80 (m, 2H), 2.14-2.22 (m, 1H), 3.40
(d, J=6.9 Hz, 2H), 3.99 (s, 2H), 4.10 (d, J=7.5 Hz, 2H), 7.15-7.50
(m, 9H).
Example 1.6: Preparation of
2-(((1s,4s)-4-((5-(3-Chlorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetic Acid (Compound 67)
[0442] From 2-(3-chlorophenyl)-1-phenylethanone, the title compound
was prepared using a similar method to the one described in Example
1.1 to give a yellow solid. LCMS m/z=468.4 [M+H].sup.+; .sup.1H NMR
(400 M Hz, DMSO-d.sub.6) .delta. ppm 1.38-1.55 (m, 7H), 1.70-1.80
(m, 2H), 2.14-2.22 (m, 1H), 3.40 (d, J=6.9 Hz, 2H), 3.99 (s, 2H),
4.11 (d, J=7.5 Hz, 2H), 7.25-7.54 (m, 9H).
Example 1.7: Preparation of
2-(((1s,4s)-4-((6-(4-Methoxyphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 69)
[0443] From 1-(4-methoxyphenyl)-2-phenylethanone, the title
compound was prepared using a similar method to the one described
in Example 1.1 to give a yellow solid. LCMS m/z=464.5 [M+H].sup.+;
.sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 1.40-1.54 (m, 7H),
1.68-1.80 (m, 2H), 2.14-2.22 (m, 1H), 3.39 (d, J=6.9 Hz, 2H), 3.75
(s, 3H), 3.99 (s, 2H), 4.09 (d, J=7.5 Hz, 2H), 6.86-7.81 (m,
9H).
Example 1.8: Preparation of
2-(((1s,4s)-4-((5-(3-Methoxyphenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 70)
[0444] From 2-(3-methoxyphenyl)-1-phenylethanone, the title
compound was prepared using a similar method to the one described
in Example 1.1 to give a yellow solid. LCMS m/z=464.3 [M+H].sup.+;
.sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 1.39-1.54 (m, 7H),
1.70-1.80 (m, 2H), 2.15-2.22 (m, 1H), 3.39 (d, J=6.9 Hz, 2H), 3.60
(s, 3H), 3.99 (s, 2H), 4.10 (d, J=7.5 Hz, 2H), 6.91-7.03 (m, 3H),
7.22-7.41 (m, 6H).
Example 1.9: Preparation of
2-(((1s,4s)-4-((6-(2-Fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin--
2(3H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 71)
[0445] From 1-(2-fluoro-4-methylphenyl)-2-phenylethanone, the title
compound was prepared using a similar method to the one described
in Example 1.1 to give a yellow solid. LCMS m/z=466.3 [M+H].sup.+;
.sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 1.36-1.54 (m, 7H),
1.69-1.80 (m, 2H), 2.12-2.21 (m, 1H), 2.33 (s, 3H), 3.39 (d, J=6.9
Hz, 2H), 3.98 (s, 2H), 4.10 (d, J=7.5 Hz, 2H), 6.94-6.98 (m, 1H),
7.11-7.15 (m, 1H), 7.32-7.49 (m, 6H).
Example 1.10: Preparation of
2-(((1s,4s)-4-((6-(4-Chlorophenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetic Acid (Compound 72)
[0446] From 1-(4-chlorophenyl)-2-phenylethanone, the title compound
was prepared using a similar method to the one described in Example
1.1 to give a yellow solid. LCMS m/z=468.5 [M+H].sup.+; .sup.1H NMR
(400 M Hz, DMSO-d.sub.6) .delta. ppm 1.38-1.54 (m, 7H), 1.70-1.80
(m, 2H), 2.13-2.22 (m, 1H), 3.40 (d, J=6.9 Hz, 2H), 3.99 (s, 2H),
4.10 (d, J=7.5 Hz, 2H), 7.25-7.30 (m, 2H), 7.35-7.50 (m, 7H).
Example 1.11: Preparation of
2-(((1r,4r)-4-((6-(2-Fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin--
2(3H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 75)
[0447] A reaction vial was charged with
6-(2-fluoro-4-methylphenyl)-5-phenyl-1,2,4-triazin-3(2H)-one (from
Example 1.9) (102.9 mg, 0.366 mmol), cesium carbonate (133.8 mg,
0.411 mmol) and tert-butyl
2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (152.3 mg,
0.369 mmol) in DMF (5.0 mL). The reaction mixture was stirred at
60.degree. C. overnight. Upon completion, the reaction was quenched
with H.sub.2O and extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO.sub.4, and concentrated.
The residue was purified by silica gel column chromatography to
give tert-butyl
2-(((1r,4r)-4-((6-(2-fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin--
2(3H)-yl)methyl)cyclohexyl)methoxy)acetate as a colorless oil
(108.5 mg). To this was added 4 M HCl (2.0 mL, 8.0 mmol) in
1,4-dioxane at room temperature. The reaction was stirred overnight
and concentrated under reduced pressure. The residue was dissolved
in acetonitrile, filtered and purified by HPLC to give the title
compound as a yellow solid (66.7 mg). LCMS m/z=466.5 [M+H].sup.+;
.sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 0.86-0.99 (m, 2H),
1.01-1.13 (m, 2H), 1.45-1.58 (m, 1H), 1.69-1.80 (m, 4H), 1.84-1.96
(m, 1H), 2.33 (s, 3H), 3.26 (d, J=6.4 Hz, 2H), 3.95 (s, 2H), 3.99
(d, J=7.1 Hz, 2H), 6.96 (d, J=11.1 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H),
7.32-7.49 (m, 6H).
Example 1.12: Preparation of
2-(((1r,4r)-4-((3-Oxo-5-phenyl-6-p-tolyl-1,24-triazin-2(3H)-yl)methyl)cyc-
lohexyl)methoxy)acetic Acid (Compound 76)
[0448] From 5-phenyl-6-p-tolyl-1,2,4-triazin-3(2H)-one, the title
compound was prepared using a similar method to the one described
in Example 1.11 to give a yellow solid. LCMS m/z=448.3 [M+H].sup.+;
.sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 0.86-0.99 (m, 2H),
1.02-1.14 (m, 2H), 1.46-1.58 (m, 1H), 1.70-1.80 (m, 4H), 1.85-1.98
(m, 1H), 2.30 (s, 3H), 3.255 (d, J=6.4 Hz, 2H), 3.95 (s, 2H), 3.99
(d, J=7.1 Hz, 2H), 7.15 (s, 4H), 7.26-7.49 (m, 5H).
Example 1.13: Preparation of
2-(((1s,4s)-4-((5-(3-Fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetic Acid (Compound 74)
Step A: Preparation of
2-(3-Fluorophenyl)-2-(hydroxyimino)-1-phenylethanone
[0449] From 2-(3-fluorophenyl)-1-phenylethanone, the title compound
was prepared using a similar method to the one described in Example
1.1, Step A to give a yellow solid. LCMS m/z=244.2 [M+H].sup.+.
Step B: Preparation of
5-(3-Fluorophenyl)-3-(methylthio)-6-phenyl-1,2,4-triazine
[0450] From 2-(3-fluorophenyl)-2-(hydroxyimino)-1-phenylethanone,
the title compound was prepared using a similar method to the one
described in Example 1.1, Step B to give a yellow solid. .sup.1H
NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 2.72 (s, 3H), 7.45-7.50
(m, 3H), 7.38-7.45 (m, 3H), 7.24-7.36 (m, 3H).
Step C: Preparation of
5-(3-Fluorophenyl)-3-(methylsulfonyl)-6-phenyl-1,2,4-triazine
[0451] From
5-(3-fluorophenyl)-3-(methylthio)-6-phenyl-1,2,4-triazine, the
title compound was prepared using a similar method to the one
described in Example 1.1, Step C to give a yellow solid. .sup.1H
NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 3.61 (s, 3H), 7.55-7.60
(m, 2H), 7.52-7.55 (m, 1H), 7.44-7.51 (m, 3H), 7.33-7.43 (m,
3H).
Step D: Preparation of
5-(3-Fluorophenyl)-6-phenyl-1,2,4-triazin-3(2H)-one
[0452] From
5-(3-fluorophenyl)-3-(methylsulfonyl)-6-phenyl-1,2,4-triazine, the
title compound was prepared using a similar method to the one
described in Example 1.1, Step D to give a white solid. .sup.1H NMR
(400 M Hz, DMSO-d.sub.6) .delta. ppm 7.11-7.24 (m, 3H), 7.31-7.43
(m, 4H), 7.25-7.31 (m, 2H), 13.60 (s, 1H).
Step E: Preparation of tert-Butyl
2-(((1s,4s)-4-((5-(3-Fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetate
[0453] To a solution of
5-(3-fluorophenyl)-6-phenyl-1,2,4-triazin-3(2H)-one (0.267 g, 1
mmol) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (0.342 g, 1.05
mmol). The reaction was stirred for 15 min. A solution of
tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate
(0.413 g, 1.000 mmol) in DMF (5 mL) was added. The reaction was
heated to 60.degree. C. for 18 h. The reaction was cooled to room
temperature and then diluted with water and extracted with EtOAc
three times. The combined organic extracts were washed with brine,
dried (MgSO.sub.4) and concentrated. The residue was purified by
silica gel column chromatography to give the title compound as a
white solid (0.365 g). .sup.1H NMR (400 M Hz, CDCl.sub.3) .delta.
ppm 1.48 (s, 9H), 1.52 (dd, J=6.32, 4.80 Hz, 1H), 1.55-1.66 (m,
6H), 1.83-1.93 (m, 2H), 2.35 (bs, 1H), 3.45 (d, J=7.07 Hz, 2H),
3.96 (s, 2H), 4.23 (d, J=7.58 Hz, 2H), 7.09-7.17 (m, 1H), 7.19-7.25
(m, 2H), 7.26-7.31 (m, 3H), 7.32-7.45 (m, 3H).
Step F: Preparation of
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-m-fluoro-1,2,4-triazin-2(3H)-yl)methyl)c-
yclohexyl)methoxy)acetic Acid
[0454] To a solution of tert-butyl
2-(((1s,4s)-4-((5-(3-fluorophenyl)-3-oxo-1-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetate (0.365 g, 0.719 mmol) in dioxane
(3.60 mL) was added 4 N HCl (2.88 mL, 11.51 mmol). The reaction was
stirred overnight and concentrated under reduced pressure to give
the title compound (0.299 g) as a yellow oil. LCMS m/z=453.2
[M+H].sup.+; .sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm
1.34-1.55 (m, 6H), 1.69-1.80 (m, 2H), 2.18 (bs, 1H), 3.23-3.28 (m,
1H), 3.40 (d, J=6.82 Hz, 2H), 3.98 (s, 2H), 4.11 (d, J=7.33 Hz,
22H), 7.13-7.22 (m, 2H), 7.25-7.32 (m, 3H), 7.32-7.35 (m, 1H),
7.35-7.44 (m, 3H), 12.52 (s, 1H).
Example 1.14: Preparation of
2-(((1s,4s)-4-((3-Oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)c-
yclohexyl)methoxy)acetic Acid (Compound 80)
Step A: Preparation of Ethyl
3-Oxo-2-m-tolyl-3-p-tolylpropanoate
[0455] To a cooled (-78.degree. C.) solution of ethyl
2-m-tolylacetate (1.697 g, 9.52 mmol) in THF (10.58 mL) was added
LiHMDS (9.52 mL, 9.52 mmol). The reaction was stirred for 15
minutes and 4-methylbenzoyl chloride (1.546 g, 10 mmol) in THF
(21.16 mL) was slowly added. The reaction was allowed to warm to
room temperature over 2 h. The reaction was quenched with AcOH,
diluted with water and extracted with EtOAc three times. The
combined extracts were washed with brine, dried (MgSO.sub.4) and
concentrated. The residue was purified by silica gel column
chromatography to give the title compound as a yellow oil (2.213
g). .sup.1H NMR (400 M Hz, CDCl.sub.3) .delta. ppm 1.24 (t, J=7.07
Hz, 3H), 2.33 (s, 3H), 2.37 (s, 3H), 4.15-4.28 (m, 2H), 5.54 (s,
1H), 7.10 (d, J=7.07 Hz, 1H), 7.16-7.25 (m, 5H), 7.85 (d, J=8.08
Hz, 2H).
Step B: Preparation of 2-m-Tolyl-1-p-tolylethanone
[0456] To ethyl 3-oxo-2-m-tolyl-3-p-tolylpropanoate (2.213 g, 7.47
mmol) was added aqueous HCl solution (8.96 mL, 112 mmol). The
reaction was heated to reflux overnight. The reaction was cooled to
room temperature, the mixture was diluted with water and extracted
with EtOAc three times. The combined extracts were washed with
brine, dried (MgSO.sub.4) and concentrated. The residue was
purified by silica gel column chromatography to give the title
compound as a white solid (1.174 g). .sup.1H NMR (400 M Hz,
CDCl.sub.3) .delta. ppm 2.31-2.32 (m, 3H), 2.40 (s, 3H), 4.21 (s,
2H), 7.00-7.09 (m, 3H), 7.20 (t, J=7.45 Hz, 1H), 7.22-7.27 (m, 2H),
7.91 (d, J=8.34 Hz, 2H).
Step C: Preparation of
2-(Hydroxyimino)-2-m-tolyl-1-p-tolylethanone
[0457] From 2-m-tolyl-1-p-tolylethanone, the title compound was
prepared using a similar method to the one described in Example
1.1, Step A to give a yellow oil. .sup.1H NMR (400 M Hz,
DMSO-d.sub.6) .delta. ppm 2.32 (s, 3H), 2.39 (s, 3H), 7.20-7.26 (m,
1H), 7.26-7.31 (m, 3H), 7.33-7.37 (m, 2H), 7.84 (d, J=8.08 Hz, 2H),
12.28 (s, 1H).
Step D: Preparation of
3-(Methylthio)-5-m-tolyl-6-p-tolyl-1,2,4-triazine
[0458] From 2-(hydroxyimino)-2-m-tolyl-1-p-tolylethanone, the title
compound was prepared using a similar method to the one described
in Example 1.1, Step B to give a yellow solid. .sup.1H NMR (400 M
Hz, DMSO-d.sub.6) .delta. ppm 2.27 (s, 3H), 2.33 (s, 3H), 2.71 (s,
3H), 7.15-7.23 (m, 4H), 7.23-7.31 (m, 1H), 7.33-7.37 (m, 2H),
7.38-7.44 (m, 1H).
Step E: Preparation of
3-(Methylsulfonyl)-5-m-tolyl-6-p-tolyl-1,2,4-triazine
[0459] From 3-(methylthio)-5-m-tolyl-6-p-tolyl-1,2,4-triazine, the
title compound was prepared using a similar method to the one
described in Example 1.1, Step C to give a yellow solid. .sup.1H
NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 2.30 (s, 3H), 2.36 (s,
3H), 3.58 (s, 3H), 7.22-7.31 (m, 4H), 7.34 (t, J=7.45 Hz, 1H), 7.47
(d, J=8.08 Hz, 2H), 7.48-7.53 (m, 1H).
Step F: Preparation of
5-m-Tolyl-6-p-tolyl-1,2,4-triazin-3(2H)-one
[0460] From 3-(methylsulfonyl)-5-m-tolyl-6-p-tolyl-1,2,4-triazine,
the title compound was prepared using a similar method to the one
described in Example 1.1, Step D to give a yellow solid. .sup.1H
NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 2.26 (s, 3H), 2.30 (s,
3H), 7.04 (d, J=7.83 Hz, 1H), 7.14 (s, 3H), 7.15-7.22 (m, 2H),
7.25-7.31 (m, 2H), 13.45 (s, 1H).
Step G: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-Oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)c-
yclohexyl)methoxy)acetate
[0461] From 5-m-tolyl-6-p-tolyl-1,2,4-triazin-3(2H)-one and
tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the title
compound was prepared using a similar method to the one described
in Example 1.13, Step E to give a yellow solid. .sup.1H NMR (400 M
Hz, CDCl.sub.3) .delta. ppm 1.44-1.52 (m, 2H), 1.48 (s, 9H),
1.52-1.65 (m, 6H), 1.76-1.92 (m, J=3.28 Hz, 2H), 2.30 (s, 3H), 2.36
(s, 3H), 3.45 (d, J=7.07 Hz, 2H), 3.95 (s, 2H), 4.21 (d, J=7.58 Hz,
2H), 7.04-7.20 (m, 6H), 7.23 (dd, J=6.82, 2.53 Hz, 1H), 7.47 (s,
1H).
Step H: Preparation of
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-m-fluoro-1,2,4-triazin-2(3H)-yl)methyl)c-
yclohexyl)methoxy)acetic Acid
[0462] From tert-butyl
2-(((1s,4s)-4-((3-oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)c-
yclohexyl)methoxy)acetate, the title compound was prepared using a
similar method to the one described in Example 1.13, Step F to give
a yellow solid. LCMS m/z=462.5 [M+H].sup.+; .sup.1H NMR (400 M Hz,
DMSO-d.sub.6) .delta. ppm 1.31-1.54 (m, 8H), 1.74 (bs, 1H), 2.17
(bs, 1H), 2.26 (s, 3H), 2.30 (s, 3H), 3.39 (d, J=6.82 Hz, 2H), 3.98
(s, 2H), 4.09 (d, J=7.58 Hz, 2H), 7.06 (d, J=7.58 Hz, 1H),
7.13-7.16 (m, 3H), 7.16-7.21 (m, 2H), 7.27 (d, J=7.33 Hz, 1H),
7.29-7.35 (m, 1H).
Example 1.15: Preparation of
2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic Acid (Compound 81)
Step A: Preparation of tert-Butyl
2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetate
[0463] From 6-phenyl-5-m-tolyl-1,2,4-triazin-3(2H)-one and
tert-butyl
2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the title
compound was prepared using a similar method to the one described
in Example 1.13, Step E to give a yellow oil. .sup.1H NMR (400 M
Hz, DMSO-d.sub.6) .delta. ppm 0.86-1.01 (m, 2H), 1.01-1.13 (m, 2H),
1.41 (s, 9H), 1.46-1.59 (m, 1H), 1.75 (d, J=10.48 Hz, 4H),
1.87-1.96 (m, J=3.54 Hz, 1H), 2.24 (s, 3H), 3.25 (d, J=6.32 Hz,
2H), 3.91 (s, 2H), 3.99 (d, J=7.20 Hz, 2H), 7.08 (d, J=7.58 Hz,
1H), 7.19 (t, J=7.96 Hz, 1H), 7.24-7.30 (m, 4H), 7.31-7.42 (m,
3H).
Step B: Preparation of
2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic Acid
[0464] From tert-butyl
2-(((1r,4r)-4-((3-oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetate, the title compound was prepared using a
similar method to the one described in Example 1.13, Step F to give
a yellow solid. LCMS m/z=448.5 [M+H].sup.+; .sup.1H NMR (400 M Hz,
DMSO-d.sub.b) .delta. ppm 0.84-0.99 (m, 2H), 1.01-1.15 (m, 2H),
1.45-1.59 (m, J=8.34, 3.28 Hz, 1H), 1.71-1.80 (m, 4H), 1.85-2.00
(m, J=8.08, 4.55 Hz, 1H), 2.24 (s, 3H), 3.26 (d, J=6.32 Hz, 2H),
3.95 (s, 2H), 3.99 (d, J=7.07 Hz, 2H), 7.09 (d, J=7.83 Hz, 1H),
7.16-7.22 (m, 1H), 7.24-7.30 (m, 4H), 7.31-7.43 (m, 3H), 12.48 (bs,
1H).
Example 1.16: Preparation of
2-(((1r,4r)-4-((5-(3-Fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetic Acid (Compound 82)
Step A: Preparation of tert-Butyl
2-(((1r,4r)-4-((5-(3-Fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetate
[0465] From 5-(3-fluorophenyl)-6-phenyl-1,2,4-triazin-3(2H)-one and
tert-butyl
2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the title
compound was prepared using a similar method to the one described
in Example 1.13, Step E to give an white solid. .sup.1H NMR (400 M
Hz, DMSO-d.sub.6) .delta. ppm 0.93 (q, J=12.00 Hz, 2H), 1.02-1.14
(m, 2H), 1.41 (s, 9H), 1.46-1.59 (m, 1H), 1.76 (d, J=10.99 Hz, 4H),
1.86-1.98 (m, 1H), 3.25 (d, J=6.19 Hz, 2H), 3.91 (s, 2H), 4.00 (d,
J=7.07 Hz, 2H), 7.14-7.22 (m, 2H), 7.27-7.30 (m, 2H), 7.30-7.35 (m,
1H), 7.34-7.43 (m, 4H).
Step B: Preparation of
2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic acid
[0466] From tert-butyl
2-(((1r,4r)-4-((5-(3-fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)-
methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.13, Step F
to give a yellow solid. LCMS m/z=452.4 [M+H].sup.+; .sup.1H NMR
(400 M Hz, DMSO-d.sub.6) .delta. ppm 0.84-1.00 (m, 2H), 1.02-1.15
(m, 2H), 1.41-1.59 (m, 1H), 1.71-1.82 (m, 4H), 1.86-2.00 (m, J=6.32
Hz, 1H), 3.26 (d, J=6.32 Hz, 2H), 3.95 (s, 2H), 4.00 (d, J=7.07 Hz,
2H), 7.14-7.23 (m, 2H), 7.25-7.31 (m, 3H), 7.32-7.44 (m, 4H), 12.50
(bs, 1H).
Example 1.17: Preparation of
2-(((1r,4r)-4-((3-Oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)c-
yclohexyl)methoxy)acetic Acid (Compound 83)
Step A: Preparation of tert-Butyl
2-(((1r,4r)-4-((3-Oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)c-
yclohexyl)methoxy)acetate
[0467] From 5-m-tolyl-6-p-tolyl-1,2,4-triazin-3(2H)-one and
tert-butyl
2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the title
compound was prepared using a similar method to the one described
in Example 1.13, Step E to give a yellow solid. .sup.1H NMR (400 M
Hz, CDCl.sub.3) .delta. ppm 0.93-1.06 (m, 2H), 1.09-1.22 (m, 2H),
1.47 (s, 9H), 1.56-1.69 (m, 1H), 1.74-1.92 (m, J=28.04, 10.61 Hz,
4H), 2.03-2.12 (m, 1H), 2.30 (s, 3H), 2.36 (s, 3H), 3.32 (d, J=6.32
Hz, 2H), 3.92 (s, 2H), 4.10 (d, J=7.07 Hz, 2H), 7.06-7.12 (m, 1H),
7.11-7.17 (m, 3H), 7.17-7.24 (m, 2H), 7.40 (d, J=8.34 Hz, 1H), 7.48
(s, 1H).
Step B: Preparation of
2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic Acid
[0468] From tert-butyl
2-(((1r,4r)-4-((3-oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)c-
yclohexyl)methoxy)acetate, the title compound was prepared using a
similar method to the one described in Example 1.13, Step F to give
a yellow solid. LCMS m/z=462.4 [M+H].sup.+; .sup.1H NMR (400 M Hz,
DMSO-4) .delta. ppm 0.84-1.00 (m, 2H), 1.01-1.14 (m, 2H), 1.46-1.58
(m, 1H), 1.70-1.80 (m, 4H), 1.85-1.98 (m, 1H), 2.26 (s, 3H), 2.30
(s, 3H), 3.25 (d, J=6.32 Hz, 2H), 3.95 (s, 2H), 3.98 (d, J=7.07 Hz,
2H), 7.07 (d, J=7.83 Hz, 1H), 7.12-7.18 (m, 4H), 7.18-7.22 (m, 1H),
7.24-7.29 (m, 1H), 7.30-7.33 (m, 1H).
Example 1.18: Preparation of
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)-yl)m-
ethyl)cyclohexyl)methoxy)acetic Acid (Compound 84)
Step A: Preparation of Ethyl
3-Oxo-3-phenyl-2-(thiophen-2-yl)propanoate
[0469] From benzoyl chloride and ethyl 2-(thiophene-2-yl)acetate,
the title compound was prepared using a similar method to the one
described in Example 1.14, Step A to give a clear oil. .sup.1H NMR
(400 M Hz, CDCl.sub.3) .delta. ppm 1.22 (t, J=7.07 Hz, 3H),
4.16-4.26 (m, 2H), 5.88 (s, 1H), 6.96-7.02 (m, 1H), 7.07 (d, J=3.03
Hz, 1H), 7.31 (dd, J=5.18, 1.14 Hz, 1H), 7.46 (t, J=7.71 Hz, 2H),
7.57 (t, J=7.33 Hz, 1H), 7.98-8.02 (m, 2H).
Step B: Preparation of 1-Phenyl-2-(thiophen-2-yl)ethanone
[0470] From ethyl 3-oxo-3-phenyl-2-(thiophen-2-yl)propanoate, the
title compound was prepared using a similar method to the one
described in Example 1.14, Step B to give a yellow solid. .sup.1H
NMR (400 M Hz, CDCl.sub.3) .delta. ppm 4.48 (s, 2H), 6.91-6.95 (m,
1H), 6.95-6.99 (m, 1H), 7.22 (d, J=5.05 Hz, 1H), 7.47 (t, J=7.71
Hz, 2H), 7.52-7.60 (m, 1H), 8.02 (d, J=8.34 Hz, 2H).
Step C: Preparation of
2-(Hydroxyimino)-1-phenyl-2-(thiophen-2-yl)ethanone
[0471] From 1-phenyl-2-(thiophen-2-yl)ethanone, the title compound
was prepared using a similar method to the one described in Example
1.1, Step A to give a yellow solid. .sup.1H NMR (400 M Hz,
DMSO-d.sub.6) .delta. ppm 7.17 (dd, J=5.18, 3.92 Hz, 1H), 7.51-7.58
(m, 3H), 7.64-7.71 (m, 1H), 7.86 (dd, J=5.18, 1.14 Hz, 1H),
7.88-7.92 (m, 2H), 13.00 (s, 1H).
Step D: Preparation of
2-(Hydroxyimino)-1-phenyl-2-(thiophen-2-yl)ethanone
[0472] From 2-(hydroxyimino)-1-phenyl-2-(thiophen-2-yl)ethanone,
the title compound was prepared using a similar method to the one
described in Example 1.1, Step B to give a yellow solid. .sup.1H
NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 2.70 (s, 3H), 6.91 (dd,
J=3.92, 1.14 Hz, 1H), 7.04 (dd, J=5.05, 3.79 Hz, 1H), 7.52-7.64 (m,
5H), 7.90 (dd, J=4.93, 1.14 Hz, 1H).
Step E: Preparation of
3-(Methylsulfonyl)-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazine
[0473] From 2-(hydroxyimino)-1-phenyl-2-(thiophen-2-yl)ethanone,
the title compound was prepared using a similar method to the one
described in Example 1.1, Step C to give a yellow solid. .sup.1H
NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 3.58 (s, 3H), 7.07-7.15
(m, 2H), 7.56-7.77 (m, 5H), 8.02 (dd, J=4.74, 1.33 Hz, 1H).
Step F: Preparation of
6-Phenyl-5-(thiophen-2-yl)-1,2,4-triazin-3(2H)-one
[0474] From
3-(methylsulfonyl)-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazine, the
title compound was prepared using a similar method to the one
described in Example 1.1, Step D to give a yellow solid. .sup.1H
NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 6.67 (dd, J=4.04, 1.01 Hz,
1H), 7.00 (dd, J=5.05, 4.04 Hz, 1H), 7.47-7.59 (m, 5H), 7.91 (dd,
J=5.05, 1.01 Hz, 1H), 13.32 (s, 1H).
Step G: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)-yl)m-
ethyl)cyclohexyl)methoxy)acetate
[0475] From 6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-3(2H)-one and
tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the title
compound was prepared using a similar method to the one described
in Example 1.13, Step E to give a yellow solid. .sup.1H NMR (400 M
Hz, CDCl.sub.3) .delta. ppm 1.41-1.46 (m, 4H), 1.48 (s, 9H),
1.49-1.54 (m, 2H), 1.56-1.62 (m, 2H), 1.81-1.93 (m, J=6.57, 3.79
Hz, 1H), 2.25-2.33 (m, J=6.44, 3.41 Hz, 1H), 3.43 (d, J=6.82 Hz,
2H), 3.94 (s, 2H), 4.17 (d, J=7.58 Hz, 2H), 6.87-6.90 (m, 1H),
6.91-6.94 (m, 1H), 7.41-7.49 (m, 4H), 7.50-7.54 (m, 1H), 7.56 (dd,
J=5.05, 1.01 Hz, 1H).
Step H: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)-yl)m-
ethyl)cyclohexyl)methoxy)acetic Acid
[0476] From tert-butyl
2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)-yl)m-
ethyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.13, Step F
to give a yellow solid. LCMS m/z=440.5 [M+H].sup.+; .sup.1H NMR
(400 M Hz, DMSO-d.sub.6) .delta. ppm 1.33-1.52 (m, 8H), 1.67-1.78
(m, J=10.11, 10.11 Hz, 1H), 2.07-2.18 (m, J=3.03 Hz, 1H), 3.37 (d,
J=7.07 Hz, 2H), 3.97 (s, 2H), 4.04 (d, J=7.58 Hz, 2H), 6.69 (dd,
J=3.79, 1.01 Hz, 1H), 7.00 (dd, J=5.05, 3.79 Hz, 1H), 7.50-7.60 (m,
5H), 7.91 (dd, J=5.05, 1.01 Hz, 1H).
Example 1.19: Preparation of
2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-
-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 31)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-Bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate
[0477] To a solution of 5-bromo-6-phenylpyridazin-3(2H)-one (1.522
g, 6.06 mmol) in DMF (90 mL) was added tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (2.50 g,
6.06 mmol), potassium 2-methylpropan-2-olate (1.360 g, 12.12 mmol)
and 18-crown-6 (0.320 g, 1.212 mmol). The reaction was stirred at
40.degree. C. for 16 h, quenched with water (40 mL), extracted with
EtOAc (4.times.50 mL), and washed with brine. The combined organic
phases were dried over MgSO.sub.4, filtered, and concentrated to
give a brown oil. The brown oil was purified by silica gel column
chromatography to give the title compound as a yellow oil (1.346
g). LCMS m/z=491.3 [M+H].sup.+; .sup.1H NMR (400 M Hz, CDCl.sub.3)
.delta. ppm, 1.37-1.64 (m, 17H), 1.80-1.90 (m, 1H), 2.23 (bs, 1H),
3.42 (d, J=7.07 Hz, 2H), 3.94 (s, 2H), 4.17 (d, J=7.71 Hz, 2H),
7.44-7.49 (m, 4H), 7.50-7.55 (m, 2H).
Step B: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-
-yl)methyl)cyclohexyl)methoxy)acetate
[0478] A vial was charged with 3-chloro-2-fluorophenylboronic acid
(10.64 mg, 0.061 mmol), tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate (30.0 mg, 0.061 mmol), aqueous Na.sub.2CO.sub.4
(2 M, 0.061 mL, 0.122 mmol), and Pd(PPh.sub.3).sub.4 (2.12 mg,
0.002 mmol) in a mixture of EtOH (1 mL) and benzene (3 mL). The
reaction was heated under microwave irradiation at 130.degree. C.
for 1 h. The reaction mixture was diluted with water and the
organic phase was removed. The aqueous layer was extracted with
EtOAc three times. The combined organic phases were dried over
MgSO.sub.4, filtered and concentrated to give a white solid. This
white solid was purified by silica gel column chromatography to
give the title compound as a clear oil (0.033 g). LCMS m/z=541.3
[M+H].sup.+.
Step C: Preparation of
2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-
-yl)methyl)cyclohexyl)methoxy)acetic Acid
[0479] To a solution of tert-butyl
2-(((1s,4s)-4-((4-(3-chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-
-yl)methyl)cyclohexyl)methoxy)acetate (0.033 g, 0.061 mmol) in DCM
(2 mL) was added 4 M HC in dioxane (0.152 mL, 0.610 mmol). The
reaction was stirred at 25.degree. C. for 16 h and concentrated to
give a yellow oil. The yellow oil was purified by HPLC to give the
title compound as a clear oil (0.012 g). LCMS m/z=485.5
[M+H].sup.+; .sup.1H NMR (400 M Hz, CDCl.sub.3) .delta. ppm
1.43-1.65 (m, 8H), 1.78-1.94 (m, 1H), 2.34 (bs, 1H), 3.52 (d,
J=7.07 Hz, 2H), 4.11 (s, 2H), 4.28 (d, J=7.71 Hz, 2H), 7.03-7.12
(m, 3H), 7.14-7.19 (m, 2H), 7.23-7.29 (m, 2H), 7.29-7.35 (m, 1H),
7.37-7.45 (m, 1H).
Example 1.20: Preparation of
2-(((1s,4s)-4-((4-(5-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-y-
l)methyl)cyclohexyl)methoxy)acetic Acid (Compound 45)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(5-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-y-
l)methyl)cyclohexyl)methoxy)acetate
[0480] From 5-methylthiophen-2-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=509.5 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(5-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-y-
l)methyl)cyclohexyl)methoxy)acetic Acid
[0481] From tert-butyl
2-(((1s,4s)-4-((4-(5-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-y-
l)methyl)cyclohexyl)methoxy)acetate, the title compound was
prepared using a similar method to the one described in Example
1.19, Step C, to give a white solid. LCMS m/z=453.3 [M+H].sup.+;
.sup.1H NMR (400 M Hz, CDCl.sub.3) .delta. ppm 1.39-1.62 (m, 8H),
1.73-1.91 (m, 1H), 2.28 (bs, 1H), 2.43 (s, 3H), 3.50 (d, J=6.95 Hz,
2H), 4.11 (s, 2H), 4.22 (d, J=7.71 Hz, 2H), 6.54-6.59 (m, 2H),
7.16-7.21 (m, 1H), 7.29-7.48 (m, 5H).
Example 1.21: Preparation of
2-(((1s,4s)-4-((4-(4-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-y-
l)methyl)cyclohexyl)methoxy)acetic Acid (Compound 50)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(4-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-y-
l)methyl)cyclohexyl)methoxy)acetate
[0482] From 4-methylthiophen-2-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=509.4 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(4-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-y-
l)methyl)cyclohexyl)methoxy)acetic Acid
[0483] From tert-butyl
2-(((1s,4s)-4-((4-(4-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.19, Step
C, to give a white solid. LCMS m/z=453.2 [M+H].sup.+.
Example 1.22: Preparation of
2-(((1s,4s)-4-((4-(2-Methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 51)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(2-Methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0484] From 2-methylpyridin-4-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=504.4 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(2-Methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0485] From tert-butyl
2-(((1s,4s)-4-((4-(2-methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.19, Step
C, to give a white solid. LCMS m/z=448.4 [M+H].sup.+.
Example 1.23: Preparation of
2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-6-oxo-3-phenylpyridazin-(6H)-yl)me-
thyl)cyclohexyl)methoxy)acetic Acid (Compound 8)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)m-
ethyl)cyclohexyl)methoxy)acetate
[0486] From 2,3-difluorophenylboronic acid and ter-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=525.7 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)m-
ethyl)cyclohexyl)methoxy)acetic Acid
[0487] From tert-butyl
2-(((1s,4s)-4-((4-(2,3-difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)m-
ethyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.19, Step
C, to give a white solid. LCMS m/z=469.5 [M+H].sup.+; .sup.1H NMR
(400 M Hz, CDCl.sub.3) .delta. ppm 1.42-1.67 (m, 8H), 1.77-1.93 (m,
1H), 2.34 (bs, 1H), 3.52 (d, J=6.95 Hz, 2H), 4.13 (s, 2H), 4.31 (d,
J=7.58 Hz, 2H), 6.92-7.01 (m, 1H), 7.07-7.14 (m, 1H), 7.14-7.30 (m,
6H), 7.30-7.37 (m, 1H).
Example 1.24: Preparation of
2-(((1s,4s)-4-((4-(2-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 54)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(2-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0488] From 2-fluoropyridin-3-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=508.3 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(2-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0489] From tert-butyl
2-(((1s,4s)-4-((4-(2-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.19, Step
C, to give a white solid. LCMS m/z=452.3 [M+H].sup.+.
Example 1.25: Preparation of
2-(((1s,4s)-4-((4-(6-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 55)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(6-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0490] From 6-fluoropyridin-3-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=508.2 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(6-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0491] From tert-butyl
2-(((1s,4s)-4-((4-(6-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-(6H)-yl)-
methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.19, Step
C, to give a white solid. LCMS m/z=452.3 [M+H].sup.+; .sup.1H NMR
(400 M Hz, CDCl.sub.3) .delta. ppm 1.42-1.67 (m, 8H), 1.77-1.93 (m,
1H), 2.33 (bs, 1H), 3.52 (d, J=6.95 Hz, 2H), 4.13 (s, 2H), 4.30 (d,
J=7.58 Hz, 2H), 6.88 (dd, J=8.46, 2.78 Hz, 1H), 7.12-7.23 (m, 3H),
7.28-7.41 (m, 3H), 7.46-7.54 (m, 1H), 8.08 (d, J=2.40 Hz, 1H).
Example 1.26: Preparation of
2-(((1s,4s)-4-((4-(2-Chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 56)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(2-Chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0492] From 2-chloropyridin-4-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=524.7, 526.6 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(2-Chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0493] From tert-butyl
2-(((1s,4s)-4-((4-(2-chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.19, Step
C, to give a white solid. LCMS m/z=468.4, 470.5 [M+H].sup.+.
Example 1.27: Preparation of
2-(((1s,4s)-4-((4-(2-Fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 59)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(2-Fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0494] From 2-fluoropyridin-4-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=508.4 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(2-Fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0495] From tert-butyl
2-(((1s,4s)-4-((4-(2-fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.19, Step
C, to give a white solid. LCMS m/z=452.3 [M+H].sup.+; .sup.1H NMR
(400 M Hz. CDCl.sub.3) .delta. ppm 1.42-1.65 (m, 8H), 1.76-1.94 (m,
1H), 2.32 (bs, 1H), 3.51 (d, J=6.95 Hz, 2H), 4.11 (s, 2H), 4.26 (d,
J=7.58 Hz, 2H), 6.73 (s, 1H), 6.89-6.93 (m, 1H), 7.04 (s, 1H),
7.13-7.18 (m, 2H), 7.25-7.40 (m, 3H), 8.16 (d, J=5.05 Hz, 1H).
Example 1.28: Preparation of
2-(((1s,4s)-4-((4-(5-Methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 60)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(5-Methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0496] From 5-methylpyridin-3-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=504.5 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(5-Methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0497] From tert-butyl
2-(((1s,4s)-4-((4-(5-methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.19, Step
C, to give a white solid. LCMS m/z=448.3 [M+H].sup.+; .sup.1H NMR
(400 M Hz, CDCl.sub.3) .delta. ppm 1.42-1.65 (m, 8H), 1.78-1.94 (m,
1H), 2.29 (bs, 1H), 2.44 (bs, 3H), 3.51 (d, J=7.07 Hz, 2H), 4.10
(s, 2H), 4.30 (d, J=7.07 Hz, 2H), 7.10-7.17 (m, 3H), 7.29-7.42 (m,
3H), 7.73 (s, 1H), 8.43 (s, 1H), 8.60 (s, 1H).
Example 1.29: Preparation of
2-(((1s,4s)-4-((4-(5-Chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 66)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-(5-Chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0498] From 5-chloropyridin-3-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.19, Step B, to give a
white solid. LCMS m/z=524.7 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((4-(5-Chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0499] From tert-butyl
2-(((1s,4s)-4-((4-(5-chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.19, Step
C, to give a white solid. LCMS m/z=468.4 [M+H].sup.+.
Example 1.30: Preparation of
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic Acid (Compound 73)
Step A: Preparation of
2-(Hydroxyimino)-1-phenyl-2-m-tolylethanone
[0500] From 1-phenyl-2-m-tolylethanone, the title compound was
prepared using a similar method to the one described in Example
1.1, Step A to give a yellow oil. .sup.1H NMR (400 M Hz,
CDCl.sub.3) .delta. ppm 2.28-2.40 (m, 3H), 3.49 (d, J=5.05 Hz, 1H),
7.19-7.27 (m, 1H), 7.30-7.36 (m, 1H), 7.37-7.42 (m, 1H), 7.44-7.53
(m, 2), 7.55-7.65 (m, 1H), 7.94-7.99 (m, 1H), 8.00-8.03 (m, 1H),
8.06 (s, 1H).
Step B: Preparation of
3-(Methythio)-6-phenyl-5-m-tolyl-1,2,4-triazine
[0501] From 2-(hydroxyimino)-1-phenyl-2-m-tolylethanone, the title
compound was prepared using a similar method to the one described
in Example 1.1, Step B to give a yellow solid. .sup.1H NMR (400 M
Hz, DMSO-d.sub.6) .delta. ppm 2.25 (s, 3H), 2.72 (s, 3H), 7.15-7.31
(m, 3), 7.35-7.52 (m, 6H).
Step C: Preparation of
3-(Methylsulfonyl)-6-phenyl-5-m-tolyl-1,2,4-triazine
[0502] From 3-(methylthio)-6-phenyl-5-m-tolyl-1,2,4-triazine, the
title compound was prepared using a similar method to the one
described in Example 1.1, Step C as a yellow solid. .sup.1H NMR
(400 M Hz, DMSO-d.sub.6) .delta. ppm 2.28 (s, 3H), 3.60 (s, 3H),
7.24-7.28 (m, 2H), 7.32-7.38 (m, 1H), 7.44-7.49 (m, 2H), 7.50-7.61
(m, 3H), 7.86-7.91 (m, 1H).
Step D: Preparation of
6-Phenyl-5-m-tolyl-1,2,4-triazin-3(2H)-one
[0503] From 3-(methylsulfonyl)-6-phenyl-5-m-tolyl-1,2,4-triazine,
the title compound was prepared using a similar method to the one
described in Example 1.1, Step D as a yellow solid. .sup.1H NMR
(400 M Hz, DMSO-d.sub.6) .delta. ppm 2.24 (s, 3H), 7.06 (d, J=7.83
Hz, 1H), 7.18 (t, J=7.83 Hz, 1H), 7.23-7.30 (m, 4H), 7.30-7.41 (m,
3H), 13.52 (s, 1H).
Step E: Preparation of
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic Acid
[0504] From tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate and
6-phenyl-5-m-tolyl-1,2,4-triazin-3(2H)-one, the title compound was
prepared using a similar method to the one described in Example
1.1, Step E to give a yellow oil. LCMS m/z=448.5 [M+H].sup.+;
.sup.1H NMR (400 M Hz, DMSO-d.sub.6) .delta. ppm 1.37-1.53 (m, 6H),
1.68-1.80 (m, 2H), 2.13-2.21 (m, J=3.79 Hz, 1H), 2.24 (s, 3H),
3.23-3.27 (m, 1H), 3.40 (d, J=7.07 Hz, 2H), 3.99 (s, 2H), 4.10 (d,
J=7.58 Hz, 2H), 7.08 (d, J=7.58 Hz, 1H), 7.19 (t, J=7.83 Hz, 1H),
7.23-7.30 (m, 4H), 7.31-7.41 (m, 3H), 12.50 (s, 1H).
Example 1.31: Preparation of t-Butyl
2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate
Step A: Preparation of (1s,4s)-Diethyl
Cyclohexane-1,4-dicarboxylate
[0505] To a solution of (1s,4s)-cyclohexane-1,4-dicarboxylic acid
(25 g, 145 mmol) in ethanol (150 mL) was added concentrated
H.sub.2SO.sub.4 (1 mL). The reaction was refluxed for 16 h. cooled
to room temperature and concentrated. The residue was extracted
with EtOAc and saturated NaHCO.sub.3, washed with brine, dried over
MgSO.sub.4, and filtered. The filtrate was concentrated to provide
the title compound as a colorless oil (30.5 g). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.25 (t, J=7.14 Hz, 6H), 1.64-1.70 (m,
4H), 1.87-1.92 (m, 4H), 2.44-2.46 (m, 2H), 4.11-1.46 (quartet.
J=7.12 Hz, 4H).
Step B: Preparation of (1s,4s)-Cyclohexane-1,4-diyldimethanol
[0506] To a solution of (1s,4s)-diethyl
cyclohexane-1,4-dicarboxylate (13.0 g, 56.9 mmol) in THF (500 mL)
was added lithium aluminum hydride (4.54 g, 120 mmol) in portions
at 0.degree. C. The mixture was stirred at that temperature for 2 h
and quenched with cold water, filtered and concentrated to give the
title compound as a colorless oil (8.2 g). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.27-1.42 (m, 8H), 1.46-1.54 (m, 2H),
3.26-3.31 (m, 4H), 4.27-4.30 (t, J=5.31 Hz, 2H).
Step C: Preparation of tert-Butyl
2-(((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methoxy) acetate
[0507] To a solution of (1s,4s)-cyclohexane-1,4-diyldimethanol
(18.2 g, 126 mmol) in toluene (200 mL) was added NaOH (50% aqueous,
60 mL) and tetrabutylammonium iodide (2.331 g, 6.31 mmol), followed
by tert-butyl-2-bromoacetate (20.50 mL, 139 mmol) at room
temperature. The reaction mixture was stirred vigorously at room
temperature for 2 h and diluted with ethyl acetate and water. After
separation, the aqueous layer was extracted with EtOAc (3.times.30
mL). The combined organic layers were dried over MgSO.sub.4,
concentrated, and purified by silica gel column chromatography to
give the title compound as a colorless oil (13.5 g). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 1.35-1.47 (m, 4H), 1.48 (s, 9H),
1.50-1.60 (m, 4H), 1.63-1.74 (m, 1H), 1.79-1.92 (m, 1H), 3.42 (d,
J=6.95 Hz, 2H), 3.55 (d, J=6.82 Hz, 2H), 3.93 (s, 1H), 3.94 (s,
2H).
Step D: Preparation of tert-Butyl
2-(((1s,4s)-4-(Toyloxymethyl)cyclohexyl)methoxy)acetate
[0508] To a solution of tert-butyl
2-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (12.0 g,
46.4 mmol) in dichloromethane (150 mL) were added triethylamine
(4.70 g, 46.4 mmol) and 4-(dimethylamino)pyridine (0.567 g, 4.64
mmol), followed by 4-methylbenzene-1-sulfonyl chloride (8.86 g,
46.4 mmol). The reaction was stirred at room temperature for 16 h.
The solvent was removed and the residue was extracted with
EtOAc/H.sub.2O. The organic extracts were dried over MgSO.sub.4,
and concentrated. The residue was purified by silica gel column
chromatography to give the title compound as a pale liquid (9.5 g).
LCMS m/z=413.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.28-1.43 (m, 4H), 1.46-1.48 (m, 9H), 1.49-1.56 (m,
4H), 1.76-1.91 (m, 2H), 2.45 (s, 3H), 3.36 (d, J=6.95 Hz, 2H), 3.92
(d, J=7.05 Hz, 2H), 3.92 (s, 2H), 7.35 (d, J=8.46 Hz, 2H), 7.78 (d,
J=8.34 Hz, 2H).
Example 1.32: Preparation of tert-Butyl
2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate
Step A: Preparation of (1s,4s)-Cyclohexane-1,4-diyldimethanol
[0509] To a solution of (1s,4s)-cyclohexane-1,4-dicarboxylic acid
(8.617 g, 50.0 mmol) in THF (50.0 mL) at 0.degree. C. was added LAH
(100 mL, 200 mmol) via cannula. The reaction mixture was stirred at
0.degree. C. and allowed to warm to room temperature overnight.
After 24 h, the reaction was quenched with H.sub.2O (7.6 mL), 10%
NaOH (15.2 mL), and followed by additional H.sub.2O (22.8 mL). The
precipitate formed was filtered and rinsed with EtOAc. The filtrate
was washed with brine, dried over MgSO.sub.4, and concentrated to
give the title compound as a colorless oil (5.91 g).
Step B: Preparation of ((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methyl
4-methylbenzenesulfonate
[0510] To a solution of (1s,4s)-cyclohexane-1,4-diyldimethanol
(5.91 g, 41.0 mmol) in CH.sub.2Cl.sub.2 (300 mL) was added
4-methylbenzene-1-sulfonyl chloride (7.80 g, 40.9 mmol) and
triethylamine (7.75 mL, 55.6 mmol) followed by DMAP (0.246 g, 2.014
mmol). The resulting reaction mixture was stirred at room
temperature overnight. Upon completion, the solvent was removed
under reduced pressure and the residue was washed with H.sub.2O and
brine, dried over MgSO.sub.4 and concentrated. The residue was
purified by silica gel column chromatography to give the title
compound as a colorless oil (5.30 g). LCMS m/z=299.4.
Step C: Preparation of tert-Butyl
2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate
[0511] To a solution of ((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl
4-methylbenzenesulfonate (5.30 g, 17.76 mmol) in CH.sub.2Cl.sub.2
(100 mL) was added diacetoxyrhodium (472.4 mg, 1.069 mmol). The
resulting reaction mixture was stirred at room temperature for 30
min then placed in an ice bath. To the reaction mixture at
0.degree. C. was added dropwise a solution of tert-butyl
2-diazoacetate (4.0 g, 28.1 mmol) in CH.sub.2Cl.sub.2 (10.0 mL)
over 1 h. The reaction mixture was stirred at 0.degree. C. and
slowly warmed to room temperature.
[0512] After 48 h, the reaction mixture was filtered through
Celite.RTM. which was rinsed with CH.sub.2Cl.sub.2 and the combined
filtrate and rinsings were concentrated. The residue was purified
by silica gel column chromatography to give the title compound as a
colorless oil (5.659 g).
Example 1.33: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)-yl)methyl-
)cyclohexyl)methoxy)acetic Acid (Compound 61)
[0513] Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-Chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate.
[0514] To a solution of 6-chloro-5-phenylpyridazin-3(2H)-one (0.480
g, 2.323 mmol), in DMF (34 mL) was added tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.958 g,
2.323 mmol), potassium 2-methylpropan-2-olate (0.521 g, 4.650 mmol)
and 18-crown-6 (0.123 g, 0.465 mmol). The resulting mixture was
stirred at 40.degree. C. for 16 h. The reaction mixture was
quenched with water (20 mL), extracted with EtOAc (4.times.20 mL)
and washed with brine. The combined organics were dried over
MgSO.sub.4, filtered, and concentrated to give a brown oil. This
brown oil was purified by silica gel column chromatography to give
the title compound as a yellow oil (1.346 g). LCMS m/z=447.5
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
1.38-1.66 (m, 17H), 1.82-1.93 (m, 1H), 2.24 (bs, 1H), 3.45 (d,
J=7.07 Hz, 2H), 3.96 (s, 2H), 4.13 (d, J=7.71 Hz, 2H), 6.89 (s,
1H), 7.40-7.53 (m, 5H).
Step B: Preparation of tert-Butyl
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)-yl)methyl-
)cyclohexyl)methoxy)acetate
[0515] A vial was charged with thiophen-3-ylboronic acid (31.0 mg,
0.246 mmol), tert-butyl
2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate (100 mg, 0.224 mmol), aqueous Na.sub.2CO.sub.3
(2 M solution, 0.224 mL, 0.447 mmol), and Pd(PPh.sub.3).sub.4 (7.76
mg, 0.007 mmol) in a mixture of EtOH (1 mL) and benzene (3 mL). The
reaction was heated in the under microwave irradiation at
130.degree. C. for 1 h. The reaction mixture was diluted with water
and the organic layer was removed. The aqueous layer was extracted
three times with EtOAc. The combined organics were dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
HPLC to give the title compound as a clear oil (0.037 g). LCMS
m/z=495.4 [M+H].sup.+.
Step C: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)-yl)methyl-
)cyclohexyl)methoxy)acetic Acid
[0516] To a solution of tert-butyl
2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)-yl)methyl-
)cyclohexyl)methoxy)acetate (0.037 g, 0.074 mmol) in DCM (2 mL) was
added 4 M HCl in dioxane (0.186 mL, 0.744 mmol). The reaction
mixture was stirred at 25.degree. C. for 6Hand evaporated down to
give a yellow oil. This yellow oil was purified by HPLC to give the
title compound as a white solid (0.025 g). LCMS m/z=439.2
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
1.42-1.67 (m, 8H), 1.76-1.93 (m, 1H), 2.32 (bs, 1H), 3.52 (d,
J=6.95 Hz, 2H), 4.12 (s, 2H), 4.25 (d, J=7.58 Hz, 2H), 6.91-7.01
(m, 3H), 7.14-7.23 (m, 3H), 7.31-7.46 (m, 3H).
Example 1.34: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)-yl)methyl)-
cyclohexyl)methoxy)acetic Acid (Compound 57)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)-yl)methyl)-
cyclohexyl)methoxy)acetate
[0517] From pyridin-4-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.33, Step B, to give a
white solid. LCMS m/z=490.5 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)-yl)methyl)-
cyclohexyl)methoxy)acetic Acid
[0518] From tert-butyl
2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)-yl)methyl)-
cyclohexyl)methoxy)acetate, the title compound was prepared using a
similar method to the one described in Example 1.33, Step C, to
give a white solid. LCMS m/z=434.4 [M+H].sup.+.
Example 1.35: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)-
cyclohexyl)methoxy)acetic Acid (Compound 42)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)-
cyclohexyl)methoxy)acetate
[0519] From pyridin-3-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.33, Step B, to give a
white solid. LCMS m/z=490.5 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)-
cyclohexyl)methoxy)acetic Acid
[0520] From tert-butyl
2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)-
cyclohexyl)methoxy)acetate, the title compound was prepared using a
similar method to the one described in Example 1.33, Step C, to
give a white solid. LCMS m/z=434.3 [M+H].sup.+.
Example 1.36: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)methyl-
)cyclohexyl)methoxy)acetic Acid (Compound 58)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)methyl-
)cyclohexyl)methoxy)acetate
[0521] From thiophen-2-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.33, Step B, to give a
white solid. LCMS m/z=495.5 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)methyl-
)cyclohexyl)methoxy)acetic Acid
[0522] From tert-butyl
2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)methyl-
)cyclohexyl)methoxy)acetate, the title compound was prepared using
a similar method to the one described in Example 1.33, Step B, to
give a white solid. LCMS m=439.3 [M+H]J.
Example 1.37: Preparation of
2-(((1s,4s)-4-((3-(5-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 62)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-(5-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0523] From 5-methylpyridin-3-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.33, Step B, to give a
white solid. LCMS m/z=504.4 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((3-(5-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0524] From tert-butyl
2-(((1s,4s)-4-((3-(5-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.33, Step
C, to give a white solid. LCMS m/z=448.5 [M+H].sup.+.
Example 1.38: Preparation of
2-(((1s,4s)-4-((3-(6-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 63)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-(6-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0525] From 6-methylpyridin-3-ylboronic acid hydrate and tert-butyl
2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.33, Step B, to give a
white solid. LCMS m/z=504.4 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((3-(6-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0526] From tert-butyl
2-(((1s,4s)-4-((3-(6-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.33, Step
C, to give a white solid. LCMS m/z=448.5 [M+H].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 1.40-1.70 (m, 8H), 1.80-1.93 (m,
1H), 2.32 (bs, 1H), 2.82 (s, 3H), 3.51 (d, J=6.95 Hz, 2H), 4.10 (s,
2H), 4.29 (d, J=7.71 Hz, 2H), 7.07 (s, 1H), 7.16 (d, 2H), 7.35 (d,
J=8.46 Hz, 1H), 7.37-7.50 (m, 3H), 7.63 (dd, J=8.40, 1.71 Hz, 1H),
8.94 (s, 1H).
Example 1.39: Preparation of
2-(((1s,4s)-4-((3-(6-Chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 65)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-(6-Chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0527] From 6-chloropyridin-3-ylboronic acid and tert-butyl
2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate, the title compound was prepared using a similar
method to the one described in Example 1.33, Step B, to give a
white solid. LCMS m/z=524.7 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((3-(6-Chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid
[0528] From tert-butyl
2-(((1s,4s)-4-((3-(6-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetate, the title compound was prepared
using a similar method to the one described in Example 1.33, Step
C, to give a white solid. LCMS m/z=468.5 [M+H].sup.+.
Example 1.40: Preparation of
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)me-
thyl)cyclohexyl)methoxy)acetic Acid (Compound 77)
Step A: Preparation of Ethyl
3-Oxo-3-phenyl-2-(pyridin-3-yl)propanoate
[0529] To a cooled solution (-78.degree. C.) of ethyl
2-(pyridin-3-yl)acetate (1.842 mL, 12.11 mmol) in THF (12.2 mL) was
added LiHMDS (12.11 mL, 12.11 mmol) and the mixture was stirred 15
min. A solution of benzoyl chloride (1.474 mL, 12.71 mmol) in THF
(24.4 mL) was added slowly and the mixture was warmed to room
temperature and stirred for 12 h. The reaction was quenched with
AcOH (1.386 mL, 24.21 mmol), diluted with H.sub.2O (50 mL), and
extracted with EtOAc (3.times.75 mL). The combined extracts were
washed with brine, dried over MgSO.sub.4 and concentrated. The
residue was purified by silica gel column chromatography to give
the title compound as a clear oil (1.82 g). LCMS m/z=270.2
[M+H].sup.+.
Step B: Preparation of 1-Phenyl-2-(pyridine-3-yl)ethanone
[0530] Ethyl 3-oxo-3-phenyl-2-(pyridin-3-yl)propanoate (1.82 g,
6.76 mmol) was dissolved in hydrogen chloride (8.11 mL, 101.0 mmol)
and heated to 100.degree. C. overnight. The reaction was then
diluted with H.sub.2O (25 mL), extracted with EtOAc (3.times.50
mL), dried over MgSO.sub.4, filtered and concentrated. The residue
was purified by silica gel column chromatography to give the title
compound as a clear oil (0.894 g). LCMS m/Z=198.3 [M+H].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 4.29 (s, 2H), 7.27
(dd, J=7.07, 5.56 Hz, 1H), 7.49 (t, J=7.58 Hz, 2H), 7.55-7.64 (m,
2H), 7.99-8.05 (m, 2H), 8.49-8.56 (m, 2H).
Step C: Preparation of
2-(Hydroxyimino)-1-phenyl-2-(pyridin-3-yl)ethanone
[0531] To a solution of 1-phenyl-2-(pyridine-3-yl)ethanone (0.494
g, 2.505 mmol) in EtOH (36.8 mL) at room temperature was added
tert-butyl nitrite (0.586 mL, 4.93 mmol) dropwise followed by
sodium ethoxide (0.435 g, 2.55 mmol). The reaction was stirred at
room temperature overnight. Upon completion, the solvent was
evaporated to give a yellow oil. This oil was then diluted with
H.sub.2O (25 mL), extracted with EtOAc (3.times.50 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
silica gel column chromatography to give the title compound as a
yellow solid (0.214 g). LCMS m/z=227.4 [M+H].sup.+.
Step D: Preparation of
3-(Methylthio)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine
[0532] To a suspension of
2-(hydroxyimino)-1-phenyl-2-(pyridin-3-yl)ethanone (0.434 g, 1.918
mmol) in a 1:1 mixture of EtOH/H.sub.2O (8.0 mL) was added
hydrazinecarbothioamide (0.262 g, 2.88 mmol) followed by
concentrated HC (0.307 mL, 3.84 mmol). The reaction was stirred at
room temperature for 1 h then heated to 90.degree. C. overnight.
Upon completion, the reaction mixture was neutralized with
saturated NaHCO.sub.3. The solid formed was filtered and rinsed
with H.sub.2O. The solid was added to a solution of potassium
carbonate (1.326 g, 9.59 mmol) in H.sub.2O (50 mL) and heated to
90.degree. C. overnight. Upon completion, the reaction mixture was
cooled to room temperature then placed in an ice bath. To the ice
cooled mixture was added iodomethane (0.119 mL, 1.918 mmol). The
reaction was stirred at 0.degree. C. and slowly warmed to room
temperature. After stirring overnight, the solution was extracted
with CH.sub.2Cl.sub.2 (3.times.75 mL), washed with H.sub.2O, brine,
dried over MgSO.sub.4 and concentrated. The residue was purified by
silica gel column chromatography to give the title compound as a
yellow solid (0.152 g). LCMS m/z=281.1 [M+H].sup.+.
Step E: Preparation of
3-(Methylsulfonyl)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine
[0533] To a solution of
3-(methylthio)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine (0.152 g,
0.542 mmol) in CH.sub.2Cl.sub.2 (3.0 mL) at 0.degree. C. was added
MCPBA (0.255 g, 1.139 mmol). The reaction mixture was stirred at
0.degree. C. and then allowed to warm to room temperature
overnight. The reaction was quenched with saturated NaHCO.sub.3
solution and extracted with CH.sub.2Cl.sub.2. The organic extracts
were washed with H.sub.2O, brine, dried over MgSO.sub.4 and
concentrated. The residue was purified by silica gel column
chromatography to give the title compound as a yellow solid (0.169
g). LCMS m/z=313.3 [M+H].sup.+.
Step F: Preparation of
6-Phenyl-5-(pyridine-3-yl)-1,2,4-triazin-3(2)-one
[0534] To a solution of
3-(methylsulfonyl)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine (0.035
g, 0.112 mmol) in a 1:1 mixture of H.sub.2O/THF (1.5 mL) was added
potassium hydroxide (0.037 g, 0.560 mmol). The reaction was heated
at reflux for 2 h. Upon completion, the reaction mixture was cooled
to room temperature and neutralized with 1 M HCl, then extracted
with EtOAc. The combined organic layers were washed with H.sub.2O,
brine, dried over MgSO.sub.4 and concentrated to give the title
compound as a yellow solid (0.026 g) without further purification.
LCMS m/z=251.1 [M+H].sup.+.
Step G: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)me-
thyl)cyclohexyl)methoxy)acetate
[0535] To a solution
6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-3(2H)-one (0.034 g, 0.136
mmol) in dry DMF (1.5 mL) was added cesium carbonate (0.044 g,
0.136 mmol) and tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.056 g,
0.136 mmol). The reaction mixture was heated to 80.degree. C. and
stirred for 1 h. Upon completion, the reaction mixture was quenched
with H.sub.2O and extracted with EtOAc (twice). The combined
organics layers were washed with brine, dried over MgSO.sub.4,
filtered and concentrated down to give the title compound as a
yellow solid (0.067 g) without further purification. LCMS m/z=491.4
[M+H].sup.+.
Step H: Preparation of
2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)me-
thyl)cyclohexyl)methoxy)acetic Acid
[0536] To tert-butyl
2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)me-
thyl)cyclohexyl)methoxy)acetate obtained above was added 4 M HCl
(0.512 mL, 2.049 mmol) in 1,4-dioxane. The reaction was stirred at
25.degree. C. for 16 h. The reaction was evaporated down to give a
yellow oil. This yellow oil was purified by HPLC to give the TFA
salt of the title compound (0.042 g) as a white solid. LCMS
m/z=435.4 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 1.43-1.68 (m, 8H), 1.83-1.96 (m, 1H), 2.32 (bs, 1H), 3.52 (d,
J=7.07 Hz, 2H), 4.11 (s, 2H), 4.30 (d, J=7.07 Hz, 2H), 7.28 (s,
2H), 7.41 (t, J=7.45 Hz, 2H), 7.46 (d, J=7.33 Hz, 1H), 7.63 (d,
1H), 8.26 (d, J=8.08 Hz, 1H), 8.79 (s, 2H).
Example 1.41: Preparation of
2-(((1s,4s)-4-((3-Oxo-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-2(3H)-yl)m-
ethyl)cyclohexyl)methoxy)acetic Acid (Compound 78)
Step A: Preparation of
2-(Hydroxyimino)-1-(pyridin-3-yl)-2-p-tolylethanone
[0537] From 1-(pyridin-3-yl)-2-p-tolylethanone, the title compound
was prepared using a similar method to the one described in Example
1.40, Step C, to give a yellow oil. LCMS m/z=241.1 [M+H].sup.+.
Step B: Preparation of
3-(Methylthio)-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazine
[0538] From 2-(hydroxyimino)-1-(pyridin-3-yl)-2-p-tolylethanone,
the title compound was prepared using a similar method to the one
described in Example 1.40, Step D, to give a yellow solid. LCMS
m/z=295.2 [M+H].sup.+.
Step C: Preparation of
3-(Methylsulfonyl)-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazine
[0539] From
3-(methylthio)-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazine, the title
compound was prepared using a similar method to the one described
in Example 1.40, Step E, to give a yellow solid. LCMS m/z=327.2
[M+H].sup.+.
Step D: Preparation of
6-(Pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-3(2H)-one
[0540] From
3-(methylsulfonyl)-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazine, the
title compound was prepared using a similar method to the one
described in Example 1.40, Step F, to give a yellow solid. LCMS
m/z=265.1 [M+H].sup.+.
Step E: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-oxo-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-2(3H)-yl)m-
ethyl)cyclohexyl)methoxy)acetate
[0541] From 6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-3(2H)-one, the
title compound was prepared using a similar method to the one
described in Example 1.40, Step G, to give a yellow solid. LCMS
m/z=505.4 [M+H].sup.+.
Step F: Preparation of
2-(((1s,4s)-4-((3-Oxo-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-2(3H)-yl)m-
ethyl)cyclohexyl)methoxy)acetic Acid
[0542] From tert-butyl
2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)me-
thyl)cyclohexyl)methoxy)acetate, the TFA salt of the title compound
was prepared using a similar method to the one described in Example
1.40, Step H, to give a white solid. LCMS m/z=449.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.43-1.75 (m, 8H),
1.82-1.94 (m, 2H), 2.41 (s, 3H), 3.54 (d, J=7.07 Hz, 2H), 4.14 (s,
2H), 4.32 (d, J=8.34 Hz, 2H), 7.17-7.24 (m, 2H), 7.39 (d, J=8.08
Hz, 2H), 7.66 (bs, 1H), 7.85 (d, J=8.08 Hz, 1H), 9.20 (bs, 1H),
9.45 (bs, 1H).
Example 1.42: Preparation of
2-(((1s,4s)-4-((3-Oxo-5-(pyridin-4-yl)-6-p-tolyl-1,2,4-triazin-2(3H)-yl)m-
ethyl)cyclohexyl)methoxy)acetic Acid (Compound 79)
[0543] From 2-(pyridin-4-yl)-1-p-tolylethanone, the TFA salt of the
title compound was prepared using a similar method to the one
described in Example 1.41 to give a white solid. LCMS m/z=449.3
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
1.43-1.69 (m, 8H), 1.78-1.94 (m, 2H), 2.40 (s, 3H), 3.52 (d, J=7.07
Hz, 2H), 4.11 (s, 2H), 4.26 (d, J=7.58 Hz, 2H), 7.12 (d, J=8.00 Hz,
2H), 7.20 (d, J=8.00 Hz, 2H), 7.69 (bs, 2H), 8.75 (bs, 2H).
Example 1.43: Preparation of
2-(((1r,4r)-4-((4-(3-Methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 1)
[0544] A mixture of tert-butyl
2-(((1r,4r)-4-((methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate
(30.0 mg, 0.089 mmol),
5-(3-methoxyphenyl)-6-phenylpyridazin-3(2H)-one (27.3 mg, 0.098
mmol), potassium tert-butoxide (25.01 mg, 0.223 mmol) and
18-crown-6 (4.71 mg, 0.018 mmol) in DMF (2 mL) was stirred
overnight at room temperature. The reaction was quenched with
water, extracted with EtOAc and dried over anhydrous MgSO.sub.4 and
concentrated. The residue was purified by preparative HPLC to give
the title compound as a pale yellow solid (4.90 mg). LCMS m/z=463.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
0.96-1.06 (m, 2H), 1.13-1.23 (m, 2H), 1.63-1.69 (m, 1H), 1.81-1.88
(m, 4H), 2.03-2.08 (m, 1H), 3.39 (d, J=6.5 Hz, 2H), 3.63 (s, 3H),
4.09 (s, 2H), 4.18 (d, J=7.3 Hz, 2H), 6.60 (t, J=2 Hz, 1H), 6.71
(d, J=7.6 Hz, 1H), 6.88 (dd, J=8.3 Hz, 2.5 Hz, 1H), 7.12 (s, 1H),
7.18-7.23 (m, 3H), 7.25-7.35 (m, 3H).
Example 1.44: Preparation of
2-(((1r,4r)-4-((3-Benzhydryl-6-oxopyridazin-1(6H)-yl)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 7)
[0545] To a solution of 6-benhydrylpyridazin-3(2H)-one (30 mg,
0.114 mmol) and K.sub.2CO.sub.3 (39.5 mg, 0.286 mmol) in DMF (1 mL)
at room temperature was added tert-butyl
2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (47.2 mg,
0.114 mmol). The reaction was stirred at 40.degree. C. overnight,
quenched with water and extracted with EtOAc. The EtOAc extracts
were dried over MgSO.sub.4 and concentrated. The residue was
treated with 4 M HCl in dioxane (0.029 mL, 0.114 mmol) and purified
by preparative LCMS to give the title compound as a white solid (20
mg). LCMS m/z=447.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.08-0.88 (m, 4H), 1.55-1.64 (m, 1H), 1.65 (d, J=12.8
Hz, 2H), 1.80 (d, J=11.6 Hz, 2H), 1.85-1.95 (m, 1H), 3.36 (d, J=6.3
Hz, 2H), 4.0 (d, J=7.08 Hz, 2H), 4.08 (s, 2H), 5.46 (s, 1H), 6.99
(d, J=9.3 Hz, 2H), 7.12-7.16 (m, 5H), 7.24-7.34 (m, 5H).
Example 1.45: Preparation of
2-(((1r,4r)-4-((6-Oxo-3,4-diphenylpyridazin-1(6H)-yl)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 19)
[0546] To a solution of 5,6-diphenylpyridazin-3(2H)-one (30 mg,
0.121 mmol) and potassium carbonate (50.1 mg, 0.362 mmol) in DMF (1
mL) at room temperature was added ter-butyl
2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (49.8 mg,
0.121 mmol). The reaction was stirred at 40.degree. C. overnight.
NaOH (0.201 mL, 0.604 mmol) was added and the reaction was again
stirred overnight before quenched with water and extracted with
EtOAc. The EtOAc extracts were concentrated and purified by
preparative LCMS to give a white solid (17.1 mg). LCMS m/z=433.2
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
0.96-1.06 (m, 2H), 1.13-1.23 (m, 2H), 1.61-1.71 (m, 1H), 1.80-1.88
(t, J=16 Hz, 4H), 2.03-2.07 (m, 1H), 3.38 (d, J=6.3 Hz, 2H), 4.09
(s, 2H), 4.18 (d, J=7.3 Hz, 2H), 7.10-7.13 (m, 3H), 7.16-7.19 (m,
2H), 7.36-7.24 (m, 5H).
Example 1.46: Preparation of
2-(((1s,4s)-4-((4-(3-Chlorophenyl)-6-oxo-3-p-tolylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 47)
Step A: Preparation of 3,4-Dibromo-5-p-tolylfuran-2(5H)-one
[0547] To a mixture of 3,4-dibromo-5-hydroxyfuran-2(5H)-one (0.5 g,
1.939 mmol) in toluene (5 mL, 1.939 mmol) was added AlCl.sub.3
(0.310 g, 2.327 mmol) at room temperature. The mixture was stirred
at room temperature overnight. The reaction was quenched with
water, extracted with EtOAc (3.times.20 mL), dried over anhydrous
MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure to give the title compound without further
purification. LCMS m/z=332.8 [M+H].sup.+.
Step B: Preparation of 5-Bromo-6-p-tolylpyridazin-3(2H)-one
[0548] To a mixture of 3,4-dibromo-5-p-tolylfuran-2(5H)-one (0.5 g,
1.506 mmol) in ethanol (5 mL) was added NH.sub.2NH.sub.2 (0.047 mL,
1.506 mmol) at 0.degree. C. The mixture was stirred at room
temperature overnight. The precipitate was filtered and dried under
reduced pressure to give the title compound as a beige solid (0.22
g). LCMS m/z=264.9 [M+H].sup.+.
Step C: Preparation of
5-(3-Chlorophenyl)-6-p-tolylpyridazin-3(2H)-one
[0549] In a 10 mL heavy-walled sealed tube, a mixture of
5-bromo-6-p-tolylpyridazin-3(2H)-one (0.05 g, 0.189 mmol),
3-chlorophenylboronic acid (0.029 g, 0.189 mmol),
Pd(Ph.sub.3P).sub.4 (10.90 mg, 9.43 .mu.mol) and K.sub.2CO.sub.3
(0.283 mL, 0.566 mmol) in dioxane (2 mL) was heated under microwave
irradiation at 130.degree. C. for 2 h. The reaction was purified by
preparative HPLC to give the title compound (0.032 g). LCMS
m/z=297.1 [M+H].sup.+.
Step D: Preparation of
2-(((1s,4s)-4-((4-(3-Chlorophenyl)-6-oxo-3-p-tolylpyridazin-(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid
[0550] A mixture of 5-(3-chlorophenyl)-6-p-tolylpyridazin-3(2H)-one
(30 mg, 0.101 mmol), tert-butyl
2-(((1s,4s)-4-((methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate
(34.0 mg, 0.101 mmol), potassium tert-butoxide (22.69 mg, 0.202
mmol) and 18-crown-6 (5.34 mg, 0.020 mmol) in DMF (2 mL) was
stirred at room temperature overnight. The reaction was purified by
preparative LCMS to give the title compound as white solid (1 mg).
LCMS m/z=481.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.63-1.44 (m, 8H), 2.04-1.78 (m, 2H), 2.33 (s, 3H),
3.52 (d, J=6.8 Hz, 2H), 4.10 (s, 2H), 4.23 (d, J=7.6 Hz, 2H), 6.92
(s, 1H), 6.95 (d, J=8 Hz, 1H), 7.03-7.09 (m, 4H), 7.16 (t, J=1.8
Hz, 1H), 7.32 (d, 1H, J=8 Hz), 7.20 (t, J=8 Hz, 1H).
Example 1.47: Preparation of
2-(((1s,4s)-4-((6-Oxo-3,4-diphenylpyridazin-1(6H)-yl)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 3)
[0551] The title compound was prepared using a similar method to
the one described in Example 1.43 to give a white solid. LCMS
m/z=433.2 [M+H].sup.+.
Example 1.48: Preparation of
2-(((1s,4s)-4-((3-Benzhydryl-6-oxopyridazin-1(6H)-yl)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 4)
[0552] The title compound was prepared using a similar method to
the one described in Example 1.43 to give a white solid. LCMS
m/z=446.9 [M+H].sup.+.
Example 1.49: Preparation of
2-(((1s,4s)-4-((3-(4-Methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 5)
[0553] The title compound was prepared using a similar method to
the one described in Example 1.43 to give a white solid. LCMS
m/z=463.1 [M+H].sup.+.
Example 1.50: Preparation of
2-(((1s,4s)-4-((3-(3-Fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 21)
Step A: Preparation of
2-Benzyl-6-hydroxy-5-phenylpyridazin-3(2H)-one
[0554] 3-Phenylfuran-2,5-dione (2.00 g, 11.5 mmol), benzylhydrazine
(3.36 g, 17.2 mmol) and acetic acid (2 mL) were heated to
140.degree. C. for 3 h in a 20 mL heavy-walled sealed tube under
microwave irradiation. Upon cooling, a white precipitate formed
which was filtered and washed three times with hexane and DCM. The
white solid was dried under reduced pressure to give the title
compound (11.01 g). LCMS m/z=279.2 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 5.13 (s, 2H), 7.00 (s, 1H),
7.42-7.26 (m, 5H), 7.49-7.43 (m, 3H), 7.66-7.60 (m, 2H).
Step B: Preparation of
2-Benzyl-6-hydroxy-5-phenylpyridazin-3(2H)-one
[0555] 2-Benzyl-6-hydroxy-5-phenylpyridazin-3(2H)-one (3.33 g, 12.0
mmol) and phosphorus oxychloride (11.2 mL, 119.6 mmol) were heated
to 120.degree. C. for 0.5 h in a 20 mL heavy-walled sealed tube
under microwave irradiation. The mixture was concentrated under
reduced pressure and purified by column chromatography to give the
title compound as an orange solid (1.466 g). LCMS m/z=297.2
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 5.32 (s,
2H), 6.91 (s, 1H), 7.43-7.31 (m, 5H), 7.55-7.44 (m, 5H).
Step C: Preparation of 6-Chloro-5-phenylpyridazin-3(2H)-one
[0556] To a solution of
2-benzyl-6-chloro-5-phenylpyridazin-3(2H)-one (1.45 g, 4.89 mmol)
in toluene (15 mL) under argon at 90.degree. C. was added aluminum
chloride (1.629 g, 12.22 mmol) and the reaction was stirred for 20
min. It was then allowed to cool to room temperature and quenched
with water, extracted with EtOAc, dried over MgSO.sub.4 and
concentrated. The residue was purified by preparative HPLC to give
the title compound as a white solid (847.6 mg). LCMS m/z=207
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 6.97 (s,
1H), 7.41-7.54 (m, 5H).
Step D: Preparation of tert-Butyl
2-(((1s,4s)-4-((3-Chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate
[0557] To a solution of 6-chloro-5-phenylpyridazin-3(2H)-one (407
mg, 1.970 mmol) and potassium carbonate (544 mg, 3.94 mmol) in DMF
(2 mL) at room temperature was added tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (813 mg,
1.970 mmol). The reaction was stirred at 40.degree. C. overnight,
quenched with water and extracted with EtOAc. The organic extracts
were concentrated and purified by silica gel column chromatography
to give the title compound as a clear oil (678 mg). LCMS m/z=447.3
[M+H]; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.49 (s, 9H),
1.58-1.51 (m, 4H), 1.62 (bs, 4H), 1.84-1.90 (m, 1H), 2.20-2.27 (m,
1H), 3.45 (d, J=7.07 Hz, 2H), 3.96 (s, 2H), 4.13 (d, J=7.58 Hz,
2H), 6.89 (s, 1H), 7.42-7.44 (m, 2H), 7.45-7.50 (m, 3H).
Step E: Preparation of
2-(((1s,4s)-4-((3-(3-Fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid
[0558] To a solution of tert-butyl
2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetate (30.0 mg, 0.067 mmol) in dioxane (1 mL) was
added the 3-fluorophenylboronic acid (10.3 mg, 0.074 mmol), 2 M
K.sub.2CO.sub.3 (0.084 mL, 0.168 mmol) and Pd(PPh.sub.3).sub.4
(7.76 mg, 0.007 mmol). The reaction was heated under microwave
irradiation at 130.degree. C. for 2 h. The reaction was filtered
through a celite column with EtOAc and concentrated. The residue
was added 4 M HCl in dioxane (0.168 mL, 0.671 mmol) and the
reaction was stirred overnight. The reaction was concentrated and
purified by preparative LCMS to give the title compound as a white
solid (11.6 mg). LCMS m/z=451.1 [M+H].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.65-1.42 (m, 8H), 1.83-1.93 (m, 1H),
2.27-2.36 (m, 1H), 3.53 (d, J=6.82 Hz, 2H), 4.14-4.09 (m, 2H), 4.29
(d, J=7.83 Hz, 2H), 6.87-6.97 (m, 2H), 7.02 (td, J=8.34 Hz, 2.53
Hz, 1H), 7.16-7.09 (m, 3H), 7.21 (td, J=8.02, 5.94 Hz, 1H),
7.40-7.29 (m, 3H).
Example 1.51: Preparation of
2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-
-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 40)
[0559] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=465.1 [M+H]; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
1.36-1.51 (m, 8H), 1.72-1.84 (m, 1H), 2.17-2.24 (m, 1H), 2.28 (s,
3H), 3.39-3.46 (m, 2H), 3.94 (s, 2H), 4.12-4.19 (m, 2H), 6.65 (d,
J=10 Hz, 1H), 6.91 (s, 1H), 6.92 (d, J=7 Hz, 1H), 7.06 (d, J=7.6
Hz, 2H), 7.28-7.14 (m, 4H).
Example 1.52: Preparation of
2-(((1s,4s)-4-((3-(4-Chloro-2-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-
-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 52)
[0560] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=484.9 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 1.61-1.47 (m, 8H), 1.81-1.90 (m, 1H), 2.31 (s, 1H), 3.52 (d,
J=6.5 Hz, 2H), 4.10 (s, 2H), 4.25 (d, J=7.6 Hz, 2H), 6.94 (dd, J=8
Hz, 2 Hz, 1H), 7.04 (s, 1H), 7.09 (d, J=7.3 Hz, 2H), 7.16 (dd, J=8
Hz, 2 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.29 (d J=8 Hz, 2H), 7.34 (d,
J=8 Hz, 1H).
Example 1.53: Preparation of
2-(((1s,4s)-4-((3-(4-Chloro-3-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-
-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 53)
[0561] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=485.4 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 1.62-1.48 (m, 8H), 1.82-1.91 (m, 1H), 2.28-2.35 (m, 1H), 3.53
(d, J=7 Hz, 2H), 4.11 (s, 2H), 4.25 (d, J=7.5 Hz, 2H), 6.83 (dd,
J=8 Hz, 2 Hz, 1H), 6.99 (s, 1H), 7.03 (dd, J=8 Hz, 2 Hz, 1H), 7.12
(d, J=8 Hz, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.41-7.30 (m, 3H).
Example 1.54: Preparation of
2-(((1s,4s)-4-((3-(3-Fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(61)-
-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 38)
[0562] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=487.5 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 1.57-1.49 (m, 8H), 1.84-1.91 (m, 1H), 2.24 (s, 3H), 3.52 (d,
J=6 Hz, 2H), 2.28-2.34 (m, 1H), 4.23 (d, J=8 Hz, 2H), 4.09 (s, 2H),
6.76 (d, J=8 Hz, 1H), 6.87 (d, J=11 Hz, 1H), 6.93 (s, 1H), 7.01
(dd, J.sub.1=J.sub.2=8 Hz, 1H), 7.12 (d, J=8 Hz, 2H), 7.36-7.27 (m,
3H).
Example 1.55: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-p-tolylpyridazin-1(6H)-yl)methyl)cyclohe-
xyl)methoxy)acetic Acid (Compound 20)
[0563] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=469.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 1.52-1.44 (m, 8H), 1.83 (bs, 1H), 2.17 (bs, 1H), 2.30 (s, 3H),
3.48 (d, J=6 Hz, 2H), 4.02 (s, 2H), 4.20 (d, J=8 Hz, 2H), 6.91 (s,
1H), 7.03 (s, 4H), 7.09 (d, J=8 Hz, 2H), 7.31-7.24 (m, 3H).
Example 1.56: Preparation of
2-(((1s,4s)-4-((3-(4-Fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 22)
[0564] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=451.1 [M+H].sup.+.
Example 1.57: Preparation of
2-(((1s,4s)-4-((3-(2-Chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 23)
[0565] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=467.4 [M+H].sup.+.
Example 1.58: Preparation of
2-(((1s,4s)-4-((3-(4-Chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 24)
[0566] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=467.3 [M+H].sup.+.
Example 1.59: Preparation of
2-(((1s,4s)-4-((3-(2-Methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 25)
[0567] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=463.2 [M+H].sup.+.
Example 1.60: Preparation of
2-(((1s,4s)-4-((3-(3-Methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 26)
[0568] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=463.2 [M+H].sup.+.
Example 1.61: Preparation of
2-(((1s,4s)-4-((3-(3-Fluoro-5-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H-
)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 27)
[0569] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=481.3 [M+H].sup.+.
Example 1.62: Preparation of
2-(((1s,4s)-4-((3-(2,3-Fifluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)m-
ethyl)cyclohexyl)methoxy)acetic Acid (Compound 28)
[0570] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=469.4 [M+H].sup.+.
Example 1.63: Preparation of
2-(((1s,4s)-4-((3-(3-Chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 29)
[0571] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=467.6 [M+H].sup.+.
Example 1.64: Preparation of
2-(((1s,4s)-4-((3-(2-Fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 35)
[0572] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=451.1 [M+H].sup.+.
Example 1.65: Preparation of
2-(((1s,4s)-4-((3-(4-Ethylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl-
)cyclohexyl)methoxy)acetic Acid (Compound 36)
[0573] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=461.3 [M+H].sup.+.
Example 1.66: Preparation of
2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(4-(trifluoromethyl)phenyl)pyridazin-1(6-
H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 37)
[0574] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=501.2 [M+H].
Example 1.67: Preparation of
2-(((1s,4s)-4-((3-(4-Isopropylphenyl)-6-oxo-4-phenylpyridazin-(6H)-yl)met-
hyl)cyclohexyl)methoxy)acetic Acid (Compound 39)
[0575] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=475.1 [M+H].sup.+.
Example 1.68: Preparation of
2-(((1s,4s)-4-((3-(4-(Methylthio)phenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 41)
[0576] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=479.3 [M+H].sup.+.
Example 1.69: Preparation of
2-(((1s,4s)-4-((6-Oxo-3-phenyl-4-(1H-pyrazol-4-yl)pyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 46)
[0577] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=422.9 [M+H].sup.+.
Example 1.70: Preparation of
2-(((1s,4s)-4-((6-Oxo-3-phenyl-4-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)-
cyclohexyl)methoxy)acetic Acid (Compound 44)
[0578] The title compound was prepared using a similar method to
the one described in Example 1.50 to give a white solid. LCMS
m/z=434.2 [M+H].sup.+.
Example 1.71: Preparation of
2-(((1s,4s)-4-((4-(3-Fluoro-5-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H-
)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 18)
Step A: Preparation of 5-Bromo-6-phenylpyridazin-3(2H)-one
[0579] To a solution of 3,4-dibromo-5-phenylfuran-2(5H)-one (4.951
g, 15.57 mmol) in EtOH (5 mL) at 0.degree. C. was added hydrazine,
H.sub.2O (0.840 mL, 17.13 mmol). The reaction mixture was stirred
at room temperature for 10 min before heating to reflux for 2 h.
The reaction was cooled to room temperature. The precipitate formed
was collected by filtration and washed with cold ethanol to yield
the title compound as a pale yellow solid (2.530 g). LCMS m/z=351
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.47-7.49 (m, 3H), 7.51-7.54 (m, 3H).
Step B: Preparation of tert-Butyl
2-(((1s,4s)-4-((4-Bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate
[0580] To a solution of 5-bromo-6-phenylpyridazin-3(2H)-one (1.080
g, 4.30 mmol) and potassium carbonate (1.189 g, 8.60 mmol) in DMF
(10 mL) at room temperature was added tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (1.775 g,
4.30 mmol). The reaction was stirred overnight at 40.degree. C.,
quenched with water and extracted with EtOAc. The organic extracts
were concentrated and purified by silica gel column chromatography
to give the title compound as a clear oil (431 mg). LCMS m/z=491.4
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.48 (s,
9H), 1.60-1.49 (m, 4H), 1.80-1.88 (m, 1H), 2.26 (bs, 4H), 2.73 (t,
J=4.80 Hz, 1H), 3.42 (t, J=3.41 Hz, 2H), 3.94 (s, 2H), 4.15 (d,
J=7.58 Hz, 2H), 7.38 (s, 1H), 7.48-7.44 (m, 3H), 7.55-7.50 (m,
2H).
Step C: Preparation of
2-(((1s,4s)-4-((4-(3-Fluoro-5-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H-
)-yl)methyl)cyclohexyl)methoxy)acetic Acid
[0581] To a solution of tert-butyl
2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexy-
l)methoxy)acetate (30 mg, 0.061 mmol) in dioxane (0.5 mL) was added
3-fluoro-5-methoxyphenylboronic acid (12.5 mg, 0.073 mmol),
Pd(PPh.sub.3).sub.4 (7.05 mg, 0.0061 mmol) and 2 M potassium
carbonate (0.076 mL, 0.153 mmol). The reaction was heated under
microwave irradiation at 130.degree. C. for 1 h. It was filtered
through a celite column with EtOAc and concentrated. The residue
was added 4 M HCl in dioxane (10 eq.) and stirred overnight. The
mixture was extracted with EtOAc. The EtOAc extracts were
concentrated and the residue was purified by preparative LCMS to
give the title compound as a white solid (3.4 mg). LCMS m/z=481.2
[M+H].sup.+.
Example 1.72: Preparation of
2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 2)
[0582] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=463.3 [M+H].sup.+.
Example 1.73: Preparation of
2-(((1s,4s)-4-((6-Oxo-3-phenyl-4-m-tolylpyridazin-(6H)-yl)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 9)
[0583] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=447.0 [M+H].sup.+.
Example 1.74: Preparation of
2-(((1s,4s)-4-((6-Oxo-3-phenyl-4-p-tolypyridazin-1(6H)-yl)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 10)
[0584] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=446.9 [M+H].sup.+.
Example 1.75: Preparation of
2-(((1s,4s)-4-((4-(3-Fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 1H)
[0585] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=451.1 [M+H].sup.+.
Example 1.76: Preparation of
2-(((1s,4s)-4-((4-(4-Fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 12)
[0586] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=451.1 [M+H].sup.+.
Example 1.77: Preparation of
2-(((1s,4s)-4-((4-(2-Chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 13)
[0587] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=467.3 [M+H].sup.+.
Example 1.78: Preparation of
2-(((1s,4s)-4-((4-(4-Chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 14)
[0588] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=467.3 [M+H].sup.+.
Example 1.79: Preparation of
2-(((1s,4s)-4-((4-(2-Methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 15)
[0589] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=463.3 [M+H].sup.+.
Example 1.80: Preparation of
2-(((1s,4s)-4-((4-(4-Methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 16)
[0590] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=463.4 [M+H].sup.+.
Example 1.81: Preparation of
2-(((1s,4s)-4-((4-(2-Fluoro-3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H-
)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 17)
[0591] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=481.2 [M+H].sup.+.
Example 1.82: Preparation of
2-(((1s,4s)-4-((4-(5-Chloro-2-fluorphenyl)-6-oxo-3-phenylpyridazin-1(6H)--
yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 30)
[0592] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=485.3 [M+H].sup.+.
Example 1.83: Preparation of
2-(((1s,4s)-4-((4-(3-Chloro-4-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-
-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 32)
[0593] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=485.3 [M+H].sup.+.
Example 1.84: Preparation of
2-(((1s,4s)-4-((4-(3,5-Dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)m-
ethyl)cyclohexyl)methoxy)acetic Acid (Compound 33)
[0594] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=501.3 [M+H].sup.+.
Example 1.85: Preparation of
2-(((1s,4s)-4-((4-(3,4-Dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6)-yl)me-
thyl)cyclohexyl)methoxy)acetic Acid (Compound 34)
[0595] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. LCMS
m/z=501.4 [M+H].sup.+.
Example 1.86: Preparation of
2-(((1s,4s)-4-((4-(3-Chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methy-
l)cyclohexyl)methoxy)acetic Acid (Compound 6)
[0596] The title compound was prepared using a similar method to
the one described in Example 1.71 to give a white solid. The title
compound was converted to its sodium salt by treating it with one
equivalent of sodium methoxide. LCMS m/z=467.5 [M+H].sup.+.
Example 1.87: Preparation of
2-(((1s,4s)-4-((5-(3-Chlorophenyl)-3-oxo-6-p-tolyl-1,2,4-triazin-2(3)-yl)-
methyl)cyclohexyl)methoxy)acetic Acid (Compound 85)
Step A: Preparation of tert-Butyl
2-(((1s,4s)-4-((5-(3-chlorophenyl)-3-oxo-6-p-tolyl-1,2,4-triazin-2(3H)-yl-
)methyl)cyclohexyl)methoxy)acetate
[0597] From 5-(3-chlorophenyl)-6-p-tolyl-1,2,4-triazin-3(2H)-one
and tert-butyl
2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, using a
similar method to the one described in Example 1.13, step E, the
title compound was obtained as an yellow solid. .sup.1H NMR (400
MHz. CDCl.sub.3) .delta. ppm 1.43-1.48 (m, 2H), 1.48 (s, 9H),
1.49-1.53 (m, 2H), 1.56-1.65 (m, 4H), 1.84-1.92 (m, 1H), 2.29-2.35
(m, 1H), 2.38 (s, 3H), 3.45 (d, J=6.82 Hz, 2H), 3.95 (s, 2H), 4.22
(d, J=7.58 Hz, 2H), 7.12-7.17 (m, 4H), 7.19 (t, J=7.83 Hz, 1H),
7.23-7.28 (m, 1H), 7.37-7.43 (m, 1H), 7.61 (t, J=1.77 Hz, 1H).
Step B: Preparation of
2-(((1s,4s)-4-((5-(3-Chlorophenyl)-3-oxo-6-p-tolyl-1,2,4-triazin-2(3H)-yl-
)methyl)cyclohexyl)methoxy)acetic Acid (Compound 85)
[0598] From tert-butyl
2-(((1s,4s)-4-((5-(3-chlorophenyl)-3-oxo-6-p-tolyl-1,2,4-triazin-2(3H)-yl-
)methyl)cyclohexyl)methoxy)acetate, using a similar method to the
one described in Example 1.13, step F, the title compound was
obtained as a yellow solid. LCMS m/z=482.2 [M+H].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.36-1.54 (m, 6H), 1.68-1.80
(m, 2H), 2.12-2.21 (m, 1H), 2.30 (s, 3H), 3.22-3.27 (m, 1H), 3.39
(d, J=7.07 Hz, 2H), 3.98 (s, 2H), 4.10 (d, J=7.58 Hz, 2H),
7.13-7.19 (m, 4H), 7.24-7.30 (m, 1H), 7.36 (t, J=7.96 Hz, 1H), 7.47
(t, J=1.77 Hz, 1H), 7.51-7.54 (m, 1H), 12.49 (s, 1H).
Example 1.88: Preparation of Sodium
2-(2-(((1s,4s)-4-((3-Oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl-
)cyclohexyl)methoxy)acetamido)acetate (Compound 86 Sodium Salt)
Step A: Preparation of
2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl-
)cyclohexyl)methoxy)acetamido)acetic acid
[0599] A mixture of
2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic acid (0.2 g, 0.447 mmol), tert-butyl
2-aminoacetate (0.059 g, 0.447 mmol), HATU (0.170 g, 0.447 mmol)
and Et.sub.3N (0.187 mL, 1.341 mmol) in DMF (2 ml) was stirred at
room temperature overnight. The mixture was purified by preparative
HPLC. To the above product was added HCl (2 mL, 8.00 mmol) in 1,
4-dioxane. The mixture was stirred at room temperature for 4 h.
Then the solvent was removed under reduced pressure to give the
title compound. LCMS m/z=505.3 [M+H].sup.+.
Step B: Preparation of Sodium
2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl-
)cyclohexyl)methoxy)acetamido)acetate
[0600] To a mixture of
2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl-
)cyclohexyl)methoxy)acetamido)acetic acid (0.1 g, 0.198 mmol) in
DCM (5 ml) was added 0.5 M NaOH solution (0.3% ml, 0.198 mmol) at
room temperature. The mixture was stirred at 25.degree. C. for 2 h.
The solvent was removed under reduced pressure to give the title
compound as a yellow solid. .sup.1H NMR (400 MHz, CDCl3) .delta.
ppm 7.49 (d, J=7.6 Hz, 2H), 7.32 (d, J=7.2 Hz, 2H), 7.15 (m, 5H),
4.25 (d, J=7.7 Hz, 2H), 4.14 (d, J=5.4 Hz, 2H), 4.03 (s, 2H), 3.49
(d, J=6.4 Hz, 2H), 2.37 (s, 3H), 1.84 (m, 1H), 1.61-1.49 (m,
9H).
Example 1.89: Preparation of
2-(2-(((1s,4s)-4-((3-Oxo-1-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl-
)cyclohexyl)methoxy)acetamido)ethanesulfonic Acid (Compound 87)
[0601] In a 50 mL flask,
2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cy-
clohexyl)methoxy)acetic acid (1.0 g, 2.235 mmol) was dissolved in
thionyl chloride (7.6 g, 63.8 mmol) and heated at 80.degree. C. for
6 hours. The mixture was cooled and solvent was removed. The
residue was dissolved in 1,4-dioxane (5 mL) and cooled to
10.degree. C. Taurine (0.839 g, 6.70 mmol) dissolved in aqueous
sodium hydroxide solution (0.259 g in 5 mL H.sub.2O) was added. The
mixture was stirred at room temperature. The solvents were removed,
and the residue was dissolved in a mixture of ethyl acetate and 1 N
HCl (10 mL each). The aqueous layer was concentrated and the yellow
solid residue was suspended in ethanol and filtered. The filtrate
was concentrated and isopropanol was added. The brown solid was
filtered and dried to give the title compound (100 mg). LCMS
m/z=555.8 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.34-1.59 (m, 6H), 1.77 (s, 1H), 2.30 (s, 3H), 2.55 (t, J=6.44
Hz, 1H), 2.71 (s, 1H), 3.05 (s, 3H), 3.16-3.46 (m, 4H), 3.73-3.87
(m, 2H), 4.11 (d, 1H), 7.15 (s, 3H), 7.27-7.50 (m, 4H), 7.65 (s,
3H), 7.95 (t, J=5.18 Hz, 1H), 9.61 (s, 1H).
Example 2: Homogeneous Time-Resolved Fluorescence (HTRF.RTM.) Assay
for Direct cAMP Measurement
[0602] Compounds were screened for agonists of the human
prostacyclin (PGI2) receptor using the HTRF.RTM. assay for direct
cAMP measurement (Gabriel et al., ASSAY and Drug Development
Technologies, 1:291-303, 2003) and recombinant CHO-K1 cells stably
transfected with human prostacyclin receptor. CHO-K1 cells were
obtained from ATCC(@ (Manassas, Va.; Catalog #CCL-61). An agonist
of the prostacyclin receptor was detected in HTRF.RTM. assay for
direct cAMP measurement as a compound which increased cAMP
concentration. HTRF.RTM. assay also was used to determine EC.sub.50
values for prostacyclin receptor agonists.
[0603] Principle of the assay: The HTRF.RTM. assay kit was
purchased from Cisbio-US. Inc. (Bedford, Mass.; Catalog #62AM4PEC).
The HTRF.RTM. assay supported by the kit is a competitive
immunoassay between endogenous cAMP produced by the CHO-K1 cells
and tracer cAMP labeled with the dye d2. The tracer binding is
visualized by a monoclonal anti-cAMP antibody labeled with
Cryptate. The specific signal (i.e., fluorescence resonance energy
transfer. FRET) is inversely proportional to the concentration of
unlabeled cAMP in the standard or sample.
[0604] Standard curve: The fluorescence ratio (665 nm/620 nm) of
the standards (0.17 to 712 nM cAMP) included in the assay was
calculated and used to generate a cAMP standard curve according to
the kit manufacturer's instructions. The fluorescence ratio of the
samples (test compound or compound buffer) was calculated and used
to deduce respective cAMP concentrations by reference to the cAMP
standard curve.
[0605] Setup of the assay: The HTRF.RTM. assay was carried out
using a two-step protocol essentially according to the kit
manufacturer's instructions, in 20 .mu.L total volume per well in
384-well plate format (ProxiPlates; PerkinElmer, Fremont, Calif.;
catalog #6008280). To each of the experimental wells was
transferred 3000 recombinant CHO-K1 cells in 5 .mu.L assay buffer
(phosphate buffered saline containing calcium chloride and
magnesium chloride (Invitrogen, Carlsbad, Calif.; catalog #14040)
supplemented with IBMX (100 .mu.M) and rolipram (10 .mu.M)
(phosphodiesterase inhibitors; Sigma-Aldrich. St. Louis, Mo.;
catalog #15879 and catalog #R6520, respectively) and 0.1% bovine
serum albumin (BSA) fraction V (Sigma-Aldrich; catalog #A3059)),
followed by test compound in 5 .mu.L assay buffer or 5 .mu.L assay
buffer. The plate was then incubated at room temperature for 1 h.
To each well was then added 5 .mu.L cAMP-d2 conjugate in lysis
buffer and 5 .mu.L Cryptate conjugate in lysis buffer according to
the kit manufacturer's instructions. The plate was then further
incubated at room temperature for 1 h, after which the assay plate
was read.
[0606] Assay readout: The HTRF.RTM. readout was accomplished using
a PHERAstar (BMG LABTECH Inc., Durham, N.C.) or EnVision.TM.
(PerkinElmer. Fremont Calif.) microplate reader.
[0607] Certain compounds of the present invention and their
corresponding activity values are shown in TABLE B.
TABLE-US-00002 TABLE B human PGI2 receptor Compound No. EC.sub.50
(nM) (HTRF .RTM.) 69 8 nM 31 31 nM 43 36 nM 67 73 nM
[0608] Certain other compounds of the invention had activity values
ranging from about 2.1 nM to about 4 .mu.M in this assay.
Example 3: Human Platelet Aggregation Inhibition Test
[0609] Blood collected from healthy human volunteers in aqueous
trisodium citrate solution was centrifuged at 150 g for 15 min and
the upper layer was recovered to obtain platelet-rich plasma (PRP).
The residual blood was centrifuged at 3000 g for 10 min and the
supernatant was collected as platelet-poor plasma (PPP). Platelet
concentration in the PRP was determined using the Z series Beckman
Coulter particle counter (Beckman, Fullerton, Calif.) and adjusted
to 250,000 platelets/.mu.L using PPP. 480 .mu.L of PRP was
pre-incubated at 37.degree. C. and stirred at 1200 rpm with 10
.mu.L aqueous test compound solution for 1 min prior to induction
of aggregation by the addition of 10 .mu.L of aqueous adenosine
diphosphate (ADP) solution to adjust the final ADP concentration in
the PRP to 1.times.10 .sup.-5 M. The maximal amplitude of
aggregation response within 3 min was determined and measured in
triplicate using the Chronolog model 490 aggregometer (Chrono-log
Corp., Havertown, Pa.). Percent inhibition of aggregation was
calculated from the maximum decrease in optical density of the
control (addition of water in place of the test compound solution)
sample and of the samples containing test compound. The test
compound was added to adjust the final concentration to the range
10.sup.-9 to 10.sup.-4 M, and IC.sub.50 values were determined by
inhibition percentage of aggregation at each concentration. The
results are shown in Table C.
TABLE-US-00003 TABLE C Compound No. human PRP IC.sub.50 (nM) 69 22
nM 31 21 nM 43 130 nM 8 67 nM
[0610] Certain other compounds of the invention had activity values
ranging from about 12 nM to about 160 nM in this assay.
[0611] It is apparent that the compounds of the present invention
markedly inhibit platelet aggregation in human PRP.
Example 4: Rat Model of Pulmonary Arterial Hypertension
[0612] Animals: Male Wistar rats (100-150 g at start of study)
(Charles River Laboratories, Wilmington, Mass.) were housed two per
cage and maintained in a humidity--(40-60%) and
temperature--(68-72.degree. F.) controlled facility on a 12 hr:12
hr light/dark cycle (lights on at 6:30 am) with free access to food
(Harlan Teklad, Orange Calif., Rodent Diet 8604) and water. Rats
were allowed one week of habituation to the animal facility before
testing.
[0613] Rat monocrotaline model: The rat monocrotaline (MCT) model
is a standard and well-accepted model of pulmonary arterial
hypertension. MCT induces acute pulmonary endothelial damage
associated with pulmonary vascular inflammation. Subsequently,
pulmonary artery smooth muscle cells proliferate, occluding small
pulmonary vessels and leading to severe pulmonary arterial
hypertension including right ventricular hypertrophy. (See, e.g.,
Schermuly et al., Circ. Res., 2004, 94:1101-1108.)
[0614] Rats were randomly given a single subcutaneous injection of
either 60 mg/kg MCT (Sigma, St. Louis, Mo.) or 0.9% saline (sham)
and assigned to receive oral administration of 20% hydroxypropyl
beta-cyclodextrin (vehicle) or test compound (30 mg/kg; FIG. 1).
10-11 rats were used per treatment group. 24 h following MCT
administration, test compound or vehicle was administered by oral
gavage twice a day for 21 consecutive days. Heart chamber weights
were measured on Day 22. Rats were anesthetiaed with
intraperitoneal pentobarbital (50 mg/kg), the chest cavity was
opened and the heart was excised. The right ventricle was dissected
free from the septum and left ventricle and both parts were
weighed. The ratio of right ventricular (RV) weight to left
ventricle plus septum (LV+S) weight (this ratio is indicated as
"RV/(LV+S)" in FIG. 1) was calculated as an index of the
hypertrophic response to the induced pulmonary arterial
hypertension and, as such, as an index of a test compound's
therapeutic efficacy for pulmonary arterial hypertension.
[0615] It is apparent from inspection of FIG. 1 that oral
administration of Compound 68 inhibited the hypertrophic response
to the induced pulmonary arterial hypertension and, as such,
evidenced therapeutic efficacy for pulmonary arterial
hypertension.
[0616] Those skilled in the art will recognize that various
modifications, additions, substitutions and variations to the
illustrative examples set forth herein can be made without
departing from the spirit of the invention and are, therefore,
considered within the scope of the invention. All documents
referenced above, including, but not limited to, printed
publications and provisional and regular patent applications, are
incorporated herein by reference in their entirety.
* * * * *