Antagonists of CB1 Receptor

Patent metadata

Field	Value
Publication number	US-2016145294-A1
Application number	US-201615012471-A
Country	US
Kind code	A1
Filing date	Feb 1, 2016
Priority date	May 20, 2011
Publication date	May 26, 2016
Grant date	—

Abstract

The invention relates to an antagonist of CB1 receptor for use in the treatment of a pathologic condition or disorder selected from the group consisting of bladder and gastrointestinal disorders; inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma; spasticity; cancer; osteoporosis; metabolic disorders; obesity; addiction, dependence, abuse and relapse related disorders; psychiatric and neurological disorders; neurodegenerative disorders; autoimmune hepatitis and encephalitis; pain; reproductive disorders and skin inflammatory and fibrotic diseases.

First claim

1 . A compound of formula (A) or a pharmaceutical salt thereof:

wherein:
denotes that the bound is a single or a double bond,
R1 denotes that C3 is substituted with
—H, -halogen, —OH, C1-8 alkoxy, Bn-O— Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, ═O, —NR5R6 wherein R5 and R6 each independently is H, C1-8 alkyl, Bn or Ph, —O—CO—R7 wherein R7 is alkyl, O—CO—C 2 H 4 —COOH, or —N 3 ,
—R2 denotes that C17 is substituted with
—H,
—OH,
halogen,
C1-8 alkyl,
C1-8 alkoxy,
C2-6 alkenyl,
Bn optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen,
Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, carboxyl or halogen, or
Bn-O—,

R3 denotes that C20 is substituted with
—H, —OH, C1-8 alkyl, Bn, —NR8R9 wherein R8 and R9 each independently is H, C1-8 alkyl or Bn, ═CR10R11 wherein R10 and R11 each independently is H or C1-7 alkyl, or ═O,
R4 denotes that C16 is substituted with
—H, —OH, or =0,
with the proviso that
when the bond between C16 and C17 is double, R2 is absent and the bond between C17 and C20 is single, and
when the bond between C17 and C20 is double, C20 is substituted with —H or —OH and R2 is absent,
when the bond between C4 and C5 is double, the bond between C5 and C6 is single and inversely,

for use in the treatment of a pathologic condition or disorder selected from the group consisting of bladder and gastrointestinal disorders; inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma; spasticity; cancer; osteoporosis; metabolic disorders; obesity; addiction, dependence, abuse and relapse related disorders; psychiatric and neurological disorders; neurodegenerative disorders; autoimmune hepatitis and encephalitis; pain; reproductive disorders and skin inflammatory and fibrotic diseases.

2 . The compound according to claim 1 , the compound being of formula (I) or a pharmaceutical salt thereof:

wherein:
denotes that the bound is a single or a double bond,
R1 denotes that C3 is substituted with
—H,
-halogen,
—OH,
C1-8 alkoxy,
Bn-O—
Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen,
Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen,
═O,
—NR5R6 wherein R5 and R6 each independently is H, C1-8 alkyl, Bn or Ph,
—O—CO—R7 wherein R7 is alkyl, or
—O—CO—C 2 H 4 —COOH,
—R2 denotes that C17 is substituted with
—H,
—OH,
halogen,
C1-8 alkyl,
C1-8 alkoxy,
C2-6 alkenyl,
Bn optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen,
Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, carboxyl or halogen, or
Bn-O—,
R3 denotes that C20 is substituted with
—H,
—OH,
C1-8 alkyl,
Bn,
—NR8R9 wherein R8 and R9 each independently is H, C1-8 alkyl or Bn,
═CR10R11 wherein R10 and R11 each independently is H or C1-7 alkyl, or
═O,
R4 denotes that C16 is substituted with
—H,
—OH, or
═O,
with the proviso that
when the bond between C16 and C17 is double, R2 is absent and the bond between C17 and C20 is single, and
when the bond between C17 and C20 is double, C20 is substituted with —H or —OH and R2 is absent,
for use in the treatment of a pathologic condition or disorder selected from the group consisting of bladder and gastrointestinal disorders; inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma; spasticity; cancer; osteoporosis; metabolic disorders; obesity; addiction, dependence, abuse and relapse related disorders; psychiatric and neurological disorders; neurodegenerative disorders; autoimmune hepatitis and encephalitis; pain; and reproductive disorders.

3 . The compound according to claim 1 or 2 , wherein the compound is pregnenolone or a pharmaceutical salt thereof.

4 . The compound according to claim 1 or 2 , wherein
R1 denotes that C3 is substituted with
—H, -halogen, —OH, C2-8 alkoxy, Bn-O—,
Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen,
Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen,
═O,
—NR5R6 wherein R5 and R6 each independently is H, C1-8 alkyl, Bn or Ph,
—O—CO—R7 wherein R7 is alkyl, or
—O—CO—C 2 H 4 —COOH and wherein —R2, R3, R4 are as defined in claim 2 .

5 . The compound according to any one of claim 1 , 2 or 4 , wherein said compound is not substantially converted into active pregnenolone down stream derivatives after administration to a subject.

6 . The compound according to any one of claim 1 , 2 , 4 or 5 , wherein the bond between C16 and C17 and the bond between C17 and C20 are single bonds.

7 . The compound according to claim 6 wherein said compound has the formula (B)

wherein
R1 denotes that C3 is substituted with —OH or ═O,
—R2 denotes that C17 is substituted with —H, —OH, C1-8 alkyl, halogen or Bn,
R3 denotes that C20 is substituted with —OH or ═O,
R4 denotes that C16 is substituted with —H.

8 . The compound according to claim 6 wherein said compound has the formula (C):

wherein
R1 denotes that C3 is substituted with ═O or —OH
—R2 denotes that C17 is substituted with —H
R3 denotes that C20 is substituted with ═O, and
R4 denotes that C16 is substituted with —H.

9 . The compound according to claim 6 , wherein:
R1 denotes that C3 is substituted with
—H, -halogen, C1-8 alkoxy, Bn-O—, Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, ═O, —NR5R6 wherein R5 and R6 each independently is H, C1-8 alkyl, Bn or Ph, —O—CO—R7 wherein R7 is alkyl, or −0-CO—C 2 H 4 —COOH, —R2 denotes that C17 is substituted with —H R3 denotes that C20 is substituted with ═O, and R4 denotes that C16 is substituted with —H.

10 . The compound according to claim 6 , wherein said compound has the formula (D):

wherein
R1 denotes that C3 is substituted with
Halogen, Bn-0 or, —N 3 ,
—R2 denotes that C17 is substituted with —H,
R3 denotes that C20 is substituted with ═O, and
R4 denotes that C16 is substituted with —H.

11 . The compound according to any one of claim 1 , 2 , 4 or 5 , wherein:
the bond between C16 and C17 and the bond between C17 and C20 are single bonds and wherein:
R3 denotes that C20 is substituted with ═O,
R4 denotes that C16 is substitute

Assignees

• Inst Nat Sante Rech Med
• Univ Bordeaux

Inventors

• Piazza Pier Vincenzo
• Vallee Monique
• Marsicano Giovanni
• Felpin Francois-Xavier
• Bellocchio Luigi
• Cota Daniela
• Revest Jean-Michel
• Vitiello Sergio
• Spampinato Umberto
• Maldonado Rafael

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title