Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors

Patent metadata

Field	Value
Publication number	US-9776965-B2
Application number	US-201615051717-A
Country	US
Kind code	B2
Filing date	Feb 24, 2016
Priority date	May 7, 2004
Publication date	Oct 3, 2017
Grant date	Oct 3, 2017

Abstract

The N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
n is 1 or 2; L represents a C 1-3 alkyl linker optionally substituted with one or two substituents selected from C 1-4 alkyl, C 1-3 alkyloxy-C 1-4 alkyl-, hydroxy-C 1-4 alkyl, hydroxy, C 1-3 alkyloxy- or phenyl-C 1-4 alkyl; M represents a direct bond or a C 1-3 alkyl linker optionally substituted with one or two substituents selected from hydroxy, C 1-4 alkyl or C 1-4 alkyloxy; R 1 and R 2 each independently represent hydrogen, halo, cyano, hydroxy, C 1-4 alkyl optionally substituted with halo, C 1-4 alkyloxy- optionally substituted with one or where possible two or three substituents selected from hydroxy, Ar 1 and halo; or R 1 and R 2 taken together with the phenyl ring to which they are attached form naphtyl or 1,3-benzodioxolyl, wherein said naphtyl or 1,3-benzodioxolyl are optionally substituted with halo; R 3 represents hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy-, cyano or hydroxy; R 4 represents hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy-, cyano or hydroxy; R 5 represents hydrogen, C 1-4 alkyl or Ar 2 —C 1-4 alkyl-; R 6 represents hydrogen, halo, C 1-4 alkyl or C 1-4 alkyoxy-; Ar 1 and Ar 2 each independently represent phenyl or naphtyl wherein said phenyl and naphtyl are optionally substituted with C 1-4 alkyl, C 1-4 alkyloxy-, or phenyl-C 1-4 alkyl;

for use as a medicine.

First claim

The invention claimed is:

1. A method for treating obesity, diabetes, obesity related cardiovascular diseases, dementia, cognition, osteoporosis and glaucoma, comprising administering an effective amount of a compound having formula

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
n is 2;
L represents a C 1-3 alkyl linker optionally substituted with one or two substituents selected from C 1-4 alkyl, C 1-3 alkloxy-C 1-4 alkyl-, hydroxy-C 1-4 alkyl, hydroxy,
C 1-3 alkyloxy- or phenyl-C 1-4 alkyl;
M represents a direct bond or a C 1-3 alkyl linker optionally substituted with one or two substituents selected from hydroxy, C 1-4 alkyl or C 1-4 alkyloxy;
R 1 and R 2 each independently represent hydrogen, halo, cyano, hydroxy,
C 1-4 alkyl optionally substituted with halo,
C 1-4 alkyloxy- optionally substituted with one or where possible two or three substituents selected from hydroxy, Ar 1 and halo;
or R 1 and R 2 taken together with the phenyl ring to which they are attached form naphtyl or 1,3-benzodioxolyl, wherein said naphtyl or 1,3-benzodioxolyl are optionally substituted with halo;
R 3 represents hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy-, cyano or hydroxy;
R 4 represents hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy-, cyano or hydroxy;
R 5 represents hydrogen, C 1-4 alkyl or Ar 2 —C 1-4 alky-;
R 6 represents hydrogen, halo, C 1-4 alkyl or C 1-4 alkyoxy-;
Ar 1 and Ar 2 each independently represent phenyl or naphtyl wherein said phenyl and naphtyl are optionally substituted with C 1-4 alkyl, C 1-4 alkyloxy-, or phenyl-C 1-4 alkyl, wherein the effective amount of the compound having formula (I) treats obesity, diabetes, obesity related cardiovascular diseases, dementia, cognition, osteoporosis and glaucoma.

2. The method of claim 1 wherein;
n is 2;
L represents a C 1-3 alkyl linker optionally substituted with one or two substituents selected from C 1-4 alkyl, C 1-3 alkyloxy-C 1-4 alkyl-, hydroxy-C 1-4 alkyl, hydroxy, C 1-3 alkyloxy- or phenyl-C 1-4 alkyl; in particular L represents a C 1 -linker optionally substituted with C 1-4 alkyl; preferably L represents a C 1 -linker substituted with C 1-4 alkyl, more preferably a C 1 -linker substituted with methyl;
M represents a direct bond or a C 1-2 alkyl optionally substituted with one or two substituents selected from hydroxy, C 1-4 alkyl or C 1-4 alkyloxy-; preferably M represents a C 1 -linker optionally substituted with C 1-4 alkyl;
R 1 represents hydrogen, hydroxy, halo, C 1-4 alkyl, C 1-4 alkyloxy-, or C 1-4 alkyloxy substituted with halo;
R 2 represents hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy- or Ar 1 —C 1-4 alkyloxy-;
R 3 represents hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy- or cyano;
R 4 represents hydrogen, halo, C 1-4 alkyl or C 1-4 alkyloxy-;
R 5 represents hydrogen, C 1-4 alkyl or Ar 2 —C 1-4 alkyl; in particular hydrogen;
R 6 represents hydrogen, halo, or C 1-4 alkyloxy; in particular hydrogen, chloro, fluoro, bromo or methoxy;
Ar 1 represents phenyl;
Ar 2 represents phenyl or naphtyl.

3. The method of claim 1 , wherein R 6 is at the para position, L represents a C 2 -alkyl linker and M represents a C 1 -linker.

4. The method of claim 1 , wherein L represents a C 1 -linker substituted with a C 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl-, hydroxyC 1-4 alkyl- or phenylC 1-4 alkyl- wherein said C 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl-, hydroxyC 1-4 alkyl- or
phenylC 1-4 alkyl-is in the S-configuration.

5. The method of claim 1 , wherein the administering comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective 11β-HSD1 inhibitory amount of the compound having formula (I).

6. The method of claim 5 , wherein the pharmaceutical composition is prepared by mixing a pharmaceutically acceptable carrier with an effective 11β-HSD1 inhibitory amount of the compound having formula (I).

Assignees

• Janssen Pharmaceutica Nv
• Janssen Pharmaceutica Nv

Inventors

• Jaroskova Libuse
• Linders Joannes Theodorus Maria
• Buyck Christophe Francis Robert Nestor
• Van Der Veken Louis Jozef Elisabeth
• Dimitrov Vladimir Dimtchev
• Nikiforov Theo Teofanov

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title