IP Library › Granted Patent US 8,673,917

Granted Patent B2

US 8,673,917 · App. 13/063,088 · Granted Mar 18, 2014

2-heteroaryl-pyrrolo [3,4-C]pyrrole derivatives, and use thereof as SCD inhibitors

Inventors: Gerhard Zoller (Schöneck, DE); Marc Dietrich Voss (Frankfurt am Main, DE); Hans Matter (Frankfurt am Main, DE); Andreas Herling (Frankfurt am Main, DE)

Assignee: Sanofi

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Quick Facts

Patent No.: US 8,673,917
App. No.: 13/063,088
Granted: Mar 18, 2014
Kind: B2

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Abstract

The invention relates to compounds of the formula (I), where the groups R1, M, A, B, D, L, and R have the specified meanings, and to the physiologically compatible salts thereof. The compounds are suitable, for example, for treating metabolic syndrome, insulin resistance, obesity, and diabetes.

Claims (88)

1. A compound of the formula I

in which

R is hydrogen, (C 1 -C 16 )-alkyl, (C 1 -C 5 )-alkyloxy, (C 1 -C 5 )-alkylthio, (C 1 -C 5 )-alkylamino, di-(C 2 -C 8 )-alkylamino, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 0 -C 4 )-alkylene-(C 5 -C 12 )-heteroaryl, (C 0 -C 4 )-alkylene-(C 3 -C 12 )-heterocyclyl, (C 0 -C 4 )-alkylene-(C 3 -C 12 )-cycloalkyl, a bicyclic (C 8 -C 14 ) ring system,

where aryl, heteroaryl, heterocyclyl, cycloalkyl or the bicyclic (C 8 -C 14 ) ring system may be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl;

R1 is hydrogen, (C 1 -C 10 )-alkyl, 13 (C 6 -C 10 )-aryl, —(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl, —(C 3 -C 12 )-cycloalkyl;

where alkyl may be substituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, —(C 6 -C 10 )-aryl, —(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl or —(C 3 -C 12 )-cycloalkyl,

where aryl, heteroaryl, heterocyclyl or cycloalkyl may optionally be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino;

R2 is hydrogen, (C 1 -C 16 )-alkyl, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl;

R3 is hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, cyano, (C 1 -C 6 )-alkylcarbonyl, halogen, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl;

A is O, S, N(R2), C(R3), C(R3)=C(R3);

B is C(R3), N;

D is C(R3), N;

where at least one of the members A, B or D must be nitrogen;

n is 1;

L is a bond, —C(═O)—, —C(═S)—, —C(═O)—N(R2)-, —C(═O)—O—, —S(O) 0-2 —, —S(O) 0-2 —N(R2)-, a mono- or bicyclic ring system in which one or more ring members may be N(R3), O, S or —C(═O)—;

M is —O—, —CH 2 —O—, —O—CH 2 —;

and physiologically compatible salts thereof.

2. A compound of the formula Ia

in which

R1 is (C 1 -C 10 )-alkyl, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl; (C 0 -C 4 )-alkylene-(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl, —(C 3 -C 12 )-cycloalkyl,

R2 is hydrogen, (C 1 -C 16 )-alkyl, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl;

A is O, S, N(R2), C(R3), C(R3)=C(R3);

B is C(R3), N;

D is C(R3), N;

where at least one of the members A, B or D must be nitrogen;

M is —O—, —O—CH 2 —;

and physiologically compatible salts thereof.

3. A compound of the formula Ia as claimed in claim 2 , wherein

R1 is (C 1 -C 10 )-alkyl, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 0 -C 4 )-alkylene-(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl, —(C 3 -C 12 )-cycloalkyl,

R2 is hydrogen, (C 1 -C 16 )-alkyl, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl;

A is S, C(R3)=C(R3);

B is C(R3), N;

D is N;

M is —O—, —O—CH 2 ;

and physiologically compatible salts thereof.

4. A compound of the formula Ia as claimed in claim 2 , wherein

R is (C 1 -C 16 )-alkyl, (C 1 -C 5 )-alkyloxy, (C 0 -C 4 ) -alkylene-(C 6 -C 10 )-aryl, a bicyclic (C 8 -C -14 ) ring system,

where aryl or the bicyclic (C 8 -C 14 ) ring system may be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl;

R1 is (C 1 -C 10 -alkyl, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 0 -C 4 -alkylene-(C 5 -C 12 )-heteroaryl, —(C 3 -C 12 )-heterocyclyl, —(C 3 -C 12 )-cycloalkyl,

R2 is hydrogen, (C 1 -C 6 )-alkyl, (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl;

A is S, C(R3)=C(R3);

B is C(R3), N;

D is N;

L is a bond, —C(═O)—:

M is —O—;

and physiologically compatible salts thereof.

5. A compound of the formula Ia as claimed in claim 2 , wherein

R is (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl,

where aryl may be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl;

R1 is (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 0 -C 4 )-alkylene-(C 5 -C 12 )-heteroaryl,

where aryl or heteroaryl may optionally be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino;

R3 is hydrogen;

A is C(R3)=C(R3);

B is C(R3), N;

D is N;

L is —C(═O)—:

M is —O—;

and physiologically compatible salts thereof.

6. A compound of the formula Iaa

in which

R1 is (C 0 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 0 -C 4 )-alkylene-(C 5 -C 12 )-heteroaryl,

B is CH, N;

and physiologically compatible salts thereof.

7. A compound of the formula Iaa as claimed in claim 6 , wherein

R1 is (C 1 -C 4 )-alkylenephenyl, (C 1 -C 4 )-alkylene-(C 5 -C 6 )-heteroaryl, where heteroaryl is a monocyclic aromatic ring with one or two ring heteroatoms selected from N, O or S and

where phenyl or heteroaryl may optionally be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxyl, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino;

B is CH, N;

and physiologically compatible salts thereof.

8. A pharmaceutical composition comprising one or more compounds as claimed in claim 1 , 2 or 6 and a pharmaceutically compatible carrier and/or assistant.

9. The pharmaceutical composition according to claim 8 , further comprising at least one active ingredient.

10. The pharmaceutical composition as claimed in claim 9 , wherein said active ingredient is chosen from the group consisting of one or more antidiabetics, active hypoglycemic ingredients, HMG-CoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, activators of glucokinase, inhibitors of gluconeogenesis, inhibitors of fructose 1,6-biphosphatase, modulators of glucose transporter 4, inhibitors of glutamine:fructose-6-phosphate amidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of 11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B, modulators of the sodium-dependent glucose transporter 1 or 2, modulators of GPR40, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A receptor antagonists, inhibitors of I kappaB kinase, modulators of the glucocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB 1 receptor antagonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR-β-agonists and amphetamines.

11. A process for producing a pharmaceutical comprising one or more of the compounds as claimed in claim 1 , 2 or 6 , which comprises mixing the active ingredient with a pharmaceutically suitable carrier and bringing this mixture into a form suitable for administration.

Assignments (2)

CHANGE OF NAME Recorded Jun 20, 2012

From: SANOFI-AVENTIS

To: SANOFI

Reel/Frame 028413/0927 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 30, 2011

From: ZOLLER, GERHARD; VOSS, MARC DIETRICH; MATTER, HANS; HERLING, ANDREAS

To: SANOFI-AVENTIS

Reel/Frame 026830/0123 →

Priority Claims (1)

EP 08290845 · Sep 9, 2008 · regional

Continuity (1)

Related Publication 20120028986A1 · Feb 2, 2012