Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors

Patent metadata

Field	Value
Publication number	US-9422284-B2
Application number	US-201514841741-A
Country	US
Kind code	B2
Filing date	Sep 1, 2015
Priority date	Aug 30, 2004
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

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 N;
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 NR7R8;
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 phenyl.

2. A compound according to claim 1 wherein;
X represents C;
Y represents N;
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 phenyl.

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 phenyl.

4. A compound according to claim 1 wherein;
A represents phenyl 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 , wherein said pharmaceutically acceptable carrier is intimately mixed with said effective 11β-HSD1 inhibitory amount of said compound.

7. A compound of claim 1 selected from the group consisting of:

Assignees

• Janssen Pharmaceutica Nv
• Janssen Pharmaceutica Nv

Inventors

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

Classifications

• C07D209/64 Primary

  with an oxygen atom in position 1 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• 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

• C07D209/58

  [b]- or [c]-condensed · CPC title

• C07D209/60

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