Heterocyclically substituted benzoylureas, process for their preparation and their use as pharmaceuticals

• US 20040152743A1
• Filed: 07/11/2003
• Published: 08/05/2004
• Est. Priority Date: 07/12/2002
• Status: Active Grant

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Aventis Pharma Deutschland GmbH (Sanofi )
• Inventors: Schoenafinger, Karl, Defossa, Elisabeth, Klabunde, Thomas, Herling, Andreas, Kadereit, Dieter, Burger, Hans-Joerg, Wendt, Karl-Ulrich, Roedern, Erich Von
• Granted Patent: US 7,138,414 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/26 1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 249/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 253/07 with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 271/10 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 271/113 with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

The invention relates to heterocyclically substituted benzoylureas and also to their physiologically tolerated salts and physiologically functional derivatives.

Compounds are described of the formula I

where the radicals are defined as specified, and also their pharmaceutically acceptable salts and processes for their preparation. The compounds are suitable, for example, for treating type 2 diabetes.

Claims

1. A compound of the formula 1,

2. The compound of claim 1 wherein

R1 and R2 are H;

R3 and R4 are each independently F, Cl or Br;

R5 is H, F, Cl, Br, OH, NO₂, CN, (C₁-C₆)-alkyl, O—

(C₁-C₄)-alkyl, CO—

(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-COOH, (C₀-C₆)-alkylene-COO—

(C₁-C₆)-alkyl, SO₂—

(C₁-C₆)-alkyl, O—

(C₂-C₆)-alkenyl or (C₂-C₆)-alkynyl, wherein said (C₁-C₆)-alkyl, O—

(C₁-C₄)-alkyl, CO—

(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-COOH, (C₀-C₆)-alkylene-COO—

(C₁-C₆)-alkyl, SO₂—

(C₁-C₆)-alkyl, 0-(C₂-C₆)-alkenyl and (C₂-C₆)-alkynyl are optionally mono- or polysubstituted by F, Cl or Br;

A is H, F, Cl, Br, OH, NO₂, CN, (C₁-C₆)-alkyl, CO—

(C₁-C₆)-alkyl, (C₁-C₆)-alkylene-COOH, (C₁-C₆)-alkylene-COO(C₁-C₆)-alkyl, SO₂—

(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—

(C₁-C₆)-alkyl, S(O)_1-2—

(C₁-C₆)-alkyl-, NH—

(C₁-C₆)-alkyl, N-[(C₁-C₆)-alkyl]₂, COOH, COO—

(C₁-C₆)-alkyl, CONH₂, CONH—

(C₁-C₆)-alkyl, CON-[(C₁-C₆)-alkyl]₂, SO₂NH₂, SO₂NH—

(C₁-C₆)-alkyl, SO₂N-[(C₁-C₆)-alkyl]₂ or NHCOR6, wherein said (C₁-C₆)-alkyl, CO—

(C₁-C₆)-alkyl, (C₁-C₆)-alkylene-COOH, (C₁-C₆)-alkylene-COO(C₁-C₆)-alkyl, SO₂—

(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—

(C₁-C₆)-alkyl, S(O)_1-2—

(C₁-C₆)-alkyl-, NH—

(C₁-C₆)-alkyl, N-[(C₁-C₆)-alkyl]₂, COO—

(C₁-C₆)-alkyl, CONH—

(C₁-C₆)-alkyl, CON-[(C₁-C₆)-alkyl]₂, SO₂NH—

(C₁-C₆)-alkyl and SO₂N-[(C₁-C₆)-alkyl]₂ are optionally mono- or polysubstituted by F, Cl, Br, COOH, COO—

(C₁-C₆)-alkyl, CONH₂, CONH—

(C₁-C₆)-alkyl, CON-[(C₁-C₆)-alkyl]₂ or OCO—

(C₁-C₆)-alkyl;

R6 is H, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkylene, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₁-C₆)-alkylene-COO—

(C₁-C₆)-alkyl, (C₁-C₆)-alkylene-CO—

(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-COOH, (C₁-C₆)-alkylene-CONH₂, (C₆-C₁₀)-aryl, (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl, heteroaryl, (C₁-C₄)-alkylene-heteroaryl or CO-heteroaryl, wherein said (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)—

cycloalkyl-(C₁-C₄)-alkylene, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₁-C₆)-alkylene-COO—

(C₁-C₆)-alkyl, (C₁-C₆)-alkylene-CO—

(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-COOH and (C₁-C₆)-alkylene-CONH₂ are optionally mono- or polysubstituted by F, Cl, Br, O—

(C₁-C₄)-alkyl, COO—

(C₁-C₄-alkyl), or N-[(C₁-C₄)-alkyl]₂, and said (C₆-C₁₀)-aryl, (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl, heteroaryl, (C₁-C₄)-alkylene-heteroaryl and CO-heteroaryl are optionally mono- or polysubstituted by F, Cl, Br, NO₂, CN, O—

(C₁-C₄-alkyl), COO—

(C₁-C₄-alkyl), S—

COO(C₁-C₄-alkyl), N-[(C₁-C₄)-alkyl]₂ or (C₁-C₆)-alkyl;

n is 0, 1 or 2;

m is 1;

o is 0 or 1;

Het is a heterocyclic 4- to 7-membered ring selected from triazolyl, tetrazolyl, oxadiazolyl, pyrazolyl, benzimidazolyl, furyl, triazinyl or

wherein said heterocyclic 4- to 7-membered ring is optionally substituted by R7, R8 and R9; and

R7, R8, and R9 are each independently H, F, Cl, Br, (C₁-C₆)-alkyl, O—

(C₁-C₆)-alkyl, O—

(C₂-C₆)-alkenyl, O—

(C₂-C₆)-alkynyl, OH, oxo, O—

(C₁-C₆)-alkyl, NH₂, NH—

(C₁-C₆)-alkyl, N-[(C₁-C₆)-alkyl]₂, COOH, CO—

(C₁-C₆)-alkyl, COO—

(C₁-C₆)-alkyl, CONH₂, CONH—

(C₁-C₆)-alkyl, CON-[(C₁-C₆)-alkyl]₂, (C₀-C₆)-alkylene-aryl or (C₁-C₆)-alkylene-COO—

(C₁-C₆)-alkyl, wherein said (C₁-C₆)-alkyl, O—

(C₁-C₆)-alkyl, O—

(C₂-C₆)-alkenyl, O—

(C₂-C₆)-alkynyl, O—

(C₁-C₆)-alkyl, N H—

(C₁-C₆)-alkyl, N-[(C₁-C₆)-alkyl]₂, CO—

(C₁-C₆)-alkyl, COO—

(C₁-C₆)-alkyl, CONH—

(C₁-C₆)-alkyl, CON-[(C₁-C₆)-alkyl]₂, (C₀-C₆)-alkylene-aryl and (C₁-C₆)-alkylene-COO—

(C₁-C₆)-alkyl are optionally substituted by COOH, CONH₂, CONH—

(C₁-C₆)-alkyl, CON-[(C₁-C₆)-alkyl]₂, OCO—

(C₁-C₆)-alkyl, F, Cl, (C₁-C₆)-alkyl or O—

(C₁-C₆)-alkyl;

and two radicals selected from said R7, R8 and R9 may optionally be bonded together to form a ring fused onto said heterocyclic 4- to 7-membered ring;

and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 wherein R1 and R2 are H;

R3 and R4 are each independently F, Cl or Br;

R5 is H, F, Cl, Br, OH, NO₂, CN, (C₁-C₆)-alkyl, O—

(C₁-C₄)-alkyl, CO—

(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-COOH, (C₀-C₆)-alkylene-COO—

(C₁-C₆)-alkyl, SO₂—

(C₁-C₆)-alkyl, O—

(C₂-C₆)-alkenyl or (C₂-C₆)-alkynyl, wherein said (C₁-C₆)-alkyl, O—

(C₁-C₄)-alkyl, CO—

(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-COOH, (C₀-C₆)-alkylene-COO—

(C₁-C₆)-alkyl, SO₂—

(C₁-C₆)-alkyl, O—

(C₂-C₆)-alkenyl and (C₂-C₆)-alkynyl are optionally mono- or polysubstituted by F, Cl or Br;

A is H, F, Cl, Br, (C₁-C₆)-alkyl, CF₃, OCF₃, NO₂, CN, O—

(C₁-C₆)-alkyl, CO—

(C₁-C₆)-alkyl, (C₀-C₆)-alkylene-COOH, (C₀-C₆)-alkylene-COO—

(C₁-C₆)-alkyl or SO₂—

(C₁-C₆)-alkyl;

n is 0, 1 or 2;

m is 1;

o is 0 or 1;

Het is a heterocyclic 4- to 7-membered ring group selected from triazolyl, tetrazolyl, oxadiazolyl, furyl, triazinyl or

wherein said 4- to 7-membered heterocyclic ring is optionally substituted by R7, R8 and R9; and

R7, R8, and R9 are each independently H, (C₁-C₆)-alkyl, OH, oxo, NH₂, COOH, COO—

(C₁-C₆)-alkyl, CONH₂, CONH—

(C₁-C₆)-alkyl or CON-[(C₁-C₆)-alkyl]₂, wherein said (C₁-C₆)-alkyl, COO—

(C₁-C₆)-alkyl, CONH—

(C₁-C₆)-alkyl and CON-[(C₁-C₆)-alkyl]₂ are optionally substituted by COOH;

and pharmaceutically acceptable salts thereof.

4. The compound of claim 1 wherein the compound has the structure Ia

5. The compound of claim 1 wherein the compound has the structure Iaa

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of claim 1.

7. A pharmaceutical composition comprising one or more compounds of claim 1 and at least one further active ingredient.

8. The pharmaceutical composition of claim 7, wherein said further active ingredient is selected from the group consisting of:

antidiabetics, hypoglycemic active ingredients, HMG-CoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate-lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α

-glucosidase inhibitors, active ingredients acting on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β

3 agonists, 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, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-β

agonists or amphetamines.

9. A method of reducing blood sugar comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

10. A method for treating lipid and carbohydrate metabolism disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

11. A method for treating type 2 diabetes comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

12. A method for treating arteriosclerotic symptoms comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

13. A method for treating insulin resistance comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

14. A process for preparing a compound of claim 1, which comprises reacting a urea of formula 2 with a compound of formula 4

15. A process for preparing a compound of claim 1, which comprises reacting an aniline derivative of formula 3 with a compound of formula 4