Modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto

Patent metadata

Field	Value
Publication number	US-RE50267-E
Application number	US-202217747917-A
Country	US
Kind code	E1
Filing date	May 18, 2022
Priority date	Mar 18, 2008
Publication date	Jan 14, 2025
Grant date	Jan 14, 2025

Abstract

The present invention relates to amide derivatives of Formula (XIIIa) 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; 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).

First claim

What is claimed is:

1. A method for modulating a prostacyclin (PGI2) receptor in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a prostacyclin receptor modulator a compound selected from compounds of Formula (XIIIa) (Xa) and pharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:
R 1 and R 2 are each independently selected from: H, C 1 -C 6 alkyl, aryl and heteroaryl; wherein C 1 -C 6 alkyl, aryl and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloakoalkyl and halogen;
X is O or NR 3 ;
R 3 is selected from H and C 1 -C 6 alkyl; and
Q is selected from: OH, —NHCH 2 CH 2 SO 3 H, 1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino, carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino, 1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino, 5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino, 1-carboxy-2-(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4-hydroxyphenyl)ethylamino and 1-carboxy-2-methylpropylamino
R 10 is H; and
R 11 is selected from: H and C 1 -C 6 alkyl; and
performing radio-imaging to localize and quantitate the PGI2 receptor in tissues in the individual;
wherein the individual has a disorder that is diabetic neuropathy, diabetic peripheral neuropathy, diabetic retinopathy, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, acne, type 1 diabetes, or type 2 diabetes;
wherein the compound of Formula (Xa) is radio-labeled with 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br.

2. The method according to claim 1 , wherein R 1 and R 2 are each independently selected from: H, diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, methyl, phenyl, n-propyl, pyrazin-2-yl, pyridin-2-yl and pyridin-3-yl.

3. The method according to claim 1 , wherein R 1 is selected from: diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and pyridin-3-yl; and R 2 is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl.

4. The method according to claim 1 , wherein X is O; and Q is OH.

5. The method according to claim 1 , wherein the compound is selected from compounds of Formula (XIIIc) and pharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:
R 1 and R 2 are each independently selected from: H, C 1 -C 6 alkyl, aryl and heteroaryl; wherein C 1 -C 6 alkyl, aryl and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl and halogen;
X is O or NR 3 ;
R 3 is selected from H and C 1 -C 6 alkyl; and
Q is selected from: OH, —NHCH 2 CH 2 SO 3 H, 1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamine, 3-carboxy-1-carboxylatopropylamino, carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino, 1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino, 5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino, 1-carboxy-2(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4-hydroxyphenyl)ethylamino and 1-carboxy-2-methylpropylamino.

6. The method according to claim 1 , wherein the compound is selected from compounds of Formula (XIIIc) and pharmaceutically acceptable salts, solvate and hydrates thereof:

wherein:
R 1 is selected from: diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl, 4-trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and pyridin-3-yl;
R 2 is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl;
X is O or NR 3 ;
R 3 is selected from H and methyl; and
Q is selected from: OH, —NHCH 2 CH 2 SO 3 H and carboxymethylamino.

7. The method according to claim 1 , wherein the compound is selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:
R 1 and R 2 are each independently selected from: H, C 1 -C 6 alkyl, aryl and heteroaryl;

wherein C 1 -C 6 alkyl, aryl and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl and halogen;
X is O or NR 3 ; and
R 3 is selected from H and C 1 -C 6 alkyl.

8. The method according to claim 1 , wherein the compound is selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:
R 1 and R 2 are each independently selected

Assignees

• Arena Pharm Inc

Inventors

• Tran Thuy-Anh
• Chen Weichao
• Kramer Bryan A
• Sadeque Abu J M
• Shifrina Anna
• Shin Young-Jun
• Vallar Pureza
• Zou Ning

Classifications

• A61K31/4965

  Non-condensed pyrazines · CPC title

• A61K31/4406

  only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455) · CPC title

• A61K31/4402

  only substituted in position 2, e.g. pheniramine, bisacodyl · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/426

  1,3-Thiazoles · CPC title