Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors

Patent metadata

Field	Value
Publication number	US-9630921-B2
Application number	US-201615208671-A
Country	US
Kind code	B2
Filing date	Jul 13, 2016
Priority date	Aug 30, 2004
Publication date	Apr 25, 2017
Grant date	Apr 25, 2017

Abstract

Compounds of the formula (I) useful as 11-Beta Hydroxysteroid Dehydrogenase Inhibitors

First claim

The invention claimed is:

1. A compound having the formula

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
X represents C;
Y represents C;
L represents a methyl or a direct bond;
Z 1 represents a direct bond, C 1-2 alkyl- or a divalent radical of formula —CH 2 —CH═ (a) or —CH═ (b);
Z 2 represents a direct bond, C 1-2 alkyl- or a divalent radical of formula —CH 2 —CH═ (a) or —CH═ (b);
R 1 represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C 1-4 alkyloxycarbonyl, —O—(C═O)—C 1-4 alkyl, hydroxycarbonyl, NR 3 R 4 or C 1-4 alkyl wherein said C 1-4 alkyl or —O—(C═O)—C 1-4 alkyl are optionally substituted with one or more substituents selected from halo, hydroxycarbonyl, phenyl, C 1-4 alkyloxy or NR 5 R 6 or
R 1 represents C 1-4 alkyloxy- optionally substituted with one or more substituents selected from halo, hydroxycarbonyl, phenyl, C 1-4 alkyloxy or NR 7 R 8 ;

R 2 represents hydrogen, halo, C 1-4 alkyl or C 1-4 alkyloxy-;
R 3 and R 4 each independently represent hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl-;
R 5 and R 6 each independently represent hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl-;
R 7 and R 8 each independently represent hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl-;
A represents a monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrridinyl, pyridazinyl, pyrimidinyl and piperazinyl.

2. A compound according to claim 1 wherein;
X represents C;
Y represents C;
L represents a methyl or a direct bond;
Z 1 represents a direct bond, C 1-2 alkyl- or a divalent radical of formula —CH 2 —CH═ (a) or —CH═ (b);
Z 2 represents a direct bond, C 1-2 alkyl- or a divalent radical of formula —CH 2 —CH═ (a) or —CH═ (b);
R 1 represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C 1-4 alkyloxycarbonyl, hydroxycarbonyl, NR 3 R 4 or C 1-4 alkyl optionally substituted with one or more substituents selected from hydroxycarbonyl, phenyl, C 1-4 alkyloxy or NR 5 R 6 or R 1 represents C 1-4 alkyloxy- optionally substituted with one or more substituents selected from hydroxycarbonyl, phenyl, C 1-4 alkyloxy or NR 7 R 8 ;
R 2 represents hydrogen, halo, C 1-4 alkyl or C 1-4 alkyloxy-;
R 3 and R 4 each independently represent hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl-;
R 5 and R 6 each independently represent hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl-;
R 7 and R 8 each independently represent hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl-;
A represents a monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrridinyl, pyridazinyl, pyrimidinyl and piperazinyl.

3. A compound according to claim 1 wherein;
L represents methyl or a direct bond;
R 1 represents hydrogen, halo or hydroxy;
R 2 represents hydrogen, halo or C 1-4 alkyloxy-;
A represents a monocyclic heterocycle selected from the group consisting of pyridinyl and thiophenyl.

4. A compound according to claim 1 wherein;
A represents pyridinyl and wherein L represents a direct bond; and/or
R 1 represents halo, cyano, amino, phenyl, hydroxy, C 1-4 alkyloxycarbonyl-, hydroxycarbonyl, NR 3 R 4 or C 1-4 alkyl substituted with one or more substituents selected from hydroxycarbonyl, phenyl, C 1-4 alkyloxy or NR 5 R 6 .

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, an effective 11β-HSD1 inhibitory amount of a compound as described in claim 1 .

6. A process of preparing a pharmaceutical composition as defined in claim 5 , characterized in that, a pharmaceutically acceptable carrier is intimately mixed with an effective 11β-HSD1 inhibitory amount of a compound as described in claim 1 .

7. A compound of formula

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
X represents C;
Y represents C;
L represents a methyl or a direct bond;
Z 1 represents a direct bond, C 1-2 alkyl- or a divalent radical of formula —CH 2 —CH═ (a) or —CH═ (b);
Z 2 represents a direct bond, C 1-2 alkyl- or a divalent radical of formula —CH 2 —CH═ (a) or —CH═ (b);
R 1 represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C 1-4 alkyloxycarbonyl, —O—(C═O)—C 1-4 alkyl, hydroxycarbonyl, NR 3 R 4 or C 1-4 alkyl wherein said C 1-4 alkyl or —O—(C═O)—C 1-4 alkyl are optionally substituted with one or more substituents selected from halo, hydroxycarbonyl, phenyl, C 1-4 alkyloxy or NR 5 R 6 or
R 1 represents C 1-4 alkyloxy- optionally substituted with one or more substituents selected from halo, hydroxycarbonyl, phenyl, C 1-4 alkyloxy or NR 7 R 8 ;

R 2 represents hydrogen, halo, C 1-4 alkyl or C 1-4 alkyloxy-;
R 3 and R 4 each independently represent hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl-;
R 5 and R 6 each independently represent hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl-;
R 7 and R 8 each independently represent hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl-;
A represents a monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrridinyl, pyridazinyl, pyrimidinyl and piperazinyl.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as described in claim 7 .

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Jaroskova Libuse
• Linders Joannes Theodorus Maria
• Van Der Veken Louis Jozef Elisabeth
• Willemsens Gustaaf Henri Maria

Classifications

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D209/60

  Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title