Antagonists of CB1 receptor

Patent metadata

Field	Value
Publication number	US-10040816-B2
Application number	US-201615012471-A
Country	US
Kind code	B2
Filing date	Feb 1, 2016
Priority date	May 20, 2011
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

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

The invention claimed is:

1. A method for the treatment of a pathologic condition or disorder selected from the group consisting of addiction, dependence, abuse and relapse related disorders; in a subject in need thereof comprising administering to said subject an effective amount of a pregnenolone derivative compound chosen among:
a compound of formula (B)

or a pharmaceutically acceptable salt thereof
wherein
R1 denotes that C3 is substituted with —OH or ═O,
—R2 denotes that C17 is substituted with —OH, C1-8 alkyl, halogen or Bn,
R3 denotes that C20 is substituted with —OH or ═O, and
R4 denotes that C16 is substituted with —H,
a compound of formula (C):

or a pharmaceutically acceptable salt thereof,
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,
a compound of formula (D):

or a pharmaceutically acceptable salt thereof,
wherein
R1 denotes that C3 is substituted with halogen, NH2, Bn-O 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,
or
R1 denotes that C3 is substituted with C1-8 alkoxy, halogen, Bn-O—, or N 3
—R2 denotes that C17 is substituted with -Bn, —CH 3 or C2-6 alkenyl,
R3 denotes that C20 is substituted with ═O, and
R4 denotes that C16 is substituted with —H,
or
R1 denotes that C3 is substituted with —OH,
—R2 denotes that C17 is substituted with C1-8 alkyl, C1-8 alkoxy or Bn-,
R3 denotes that C20 is substituted with ═O, and
R4 denotes that C16 is substituted with —H,
or
R1 denotes that C3 is substituted with —OH,
—R2 denotes that C17 is substituted with —H,
R3 denotes that C20 is substituted with —H, —OH or —NR8R9 wherein R8 and R9 each independently is H or C1-8 alkyl, and
R4 denotes that C16 is substituted with —H,
or
a compound of formula (E):

or a pharmaceutically acceptable salt thereof,
wherein:
R1 denotes that C3 is substituted with —H, —OH or ═O,
R3 denotes that C20 is substituted with —H, —OH or ═O, and
—R4 denotes that C16 is substituted with —H,
provided that in formulas B, C, D, and E when the bond between C3 and R1 is single, R1 is in β position.

2. The method according to claim 1 , wherein said compound is not substantially converted into active pregnenolone down stream derivatives after administration to a subject.

3. The method according to claim 1 , wherein said compound is of formula (B)

or a pharmaceutically acceptable salt thereof wherein:
R1 denotes that C3 is substituted with —OH in β position 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, and
R4 denotes that C16 is substituted with —H
or
R1 denotes that C3 is substituted with ═O,
—R2 denotes that C17 is substituted with —OH, C1-8 alkyl, halogen or -Bn,
R3 denotes that C20 is substituted with ═O, and
R4 denotes that C16 is substituted with —H.

4. The method according to claim 3 , wherein said compound is 4-Pregnen-17,20α-diol-3-one, 17α-Methylprogesterone. or 17α-Benzylprogesterone.

5. The method according to claim 1 , wherein said compound is of formula (C):

or a pharmaceutically acceptable salt thereof,
wherein
R1 denotes that C3 is substituted with ═O or —OH in βposition,
—R2 denotes that C17 is substituted with —H,
R3 denotes that C20 is substituted with ═O,
R4 denotes that C16 is substituted with —H and
C5 is substituted with H is in β position.

6. The method according to claim 5 , wherein said compound is 5β-Pregnan-3β-ol-20-one or 5β-Pregnan-3,20-dione.

7. The method according to claim 1 , wherein said compound is of formula (D):

or a pharmaceutically acceptable salt thereof,
wherein
R1 denotes that C3 is substituted with NH2, Bn-O or —N 3 in β position,
—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.

8. The method according to claim 7 , wherein said compound is 5-pregnen-3β-O-benzyl-20-one or 5-pregnen-3β-azido-20-one.

9. The method to claim 1 , wherein said compound is of formula (D):

or a pharmaceutically acceptable salt thereof,
wherein
R1 denotes that C3 is substituted with C1-8 alkoxy, halogen Bn-O— or N 3 in β position,
—R2 denotes that C17 is substituted with Bn, —CH 3 or C2-6 alkenyl,
R3 denotes that C20 is substituted with ═O, and
R4 denotes that C16 is substituted with —H.

10. The method according to claim 9 , wherein said compound is 17α-Allyl-3β-methoxypregnenolone, 17α-Benzyl-3β-fluoropregnenolone, 3β-Fluoro-17α-methylpregnenolone, 3β-Methoxy-17α-methylpregnenolone, 17α-Benzyl-3β-methoxypregnenolone, 3β-Benzyloxy-17α-methylpregnenolone or 17α-Benzyl-3β-benzyloxypregnenolone.

11. The method according to claim 1 , wherein said compound is of formula (D):

or a pharmaceutically acceptable salt thereof,
wherein:
R1 denotes that C3 is substituted with —OH in β position,
—R2 denotes that C17 is substituted with C1-8 alkyl, C1-8 alkoxy or Bn-,
R3 denotes that C20 is substituted with ═O, and
R4 denotes that C16 is substituted with —H.

12. The method according to claim 11 , wherein said compound is 17α-Benzylpregnenolone, 17α-Ethylpregnenolone, 17α-Methylpregnenolone or 17-Methoxypregnenolone.

13. The method according to claim 1 , wherein said compound is of formula (D):

or a pharmaceutically acceptable salt thereof,
wherein:
R1 denotes that C3 is substituted with —OH in β position,
—R2 denotes that C17 is substituted with —H,
R3 denotes that C20 is substituted with —H, —OH or —NR8R9 wherein R8 and R9 each independently is H or C1-8 alkyl,
and
R4 denotes that C16 is substituted with —H.

14. The method according to claim 13 , w

Assignees

• Inst Nat Sante Rech Med
• Univ Bordeaux
• Inst Nat Sante Rech Med

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

• A61P43/00

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

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title