Urea- and urethane-substituted acylureas, process for their preparation and their use

• US 20040087659A1
• Filed: 07/11/2003
• Published: 05/06/2004
• Est. Priority Date: 07/11/2002
• Status: Active Grant

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis 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 7,262,220 B2
• Time in Patent Office: Days
• US Class Current: 514/586
• 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 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07C 275/54 Y being a carbon atom of a six-membered aromatic ring, e.g. benzoylureas
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 239/96 Two oxygen atoms
• CPC Class Codes: C07D 295/135 with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Abstract

The invention relates to urea- and urethane-substituted acylureas and to their physiologically tolerated salts and physiologically functional derivatives. In particular, the invention relates to the compounds of the formula I

wherein the radicals have meanings described herein, and to their physiologically tolerated salts and to processes for their preparation. The compounds are suitable for example as antidiabetics.

Claims

1. A compound of the formula 1,

2. A compound of the formula I as claimed in claim 1, wherein said compound has the structure of compound Ia:

3. A compound of the formula 1a as claimed in claim 2, wherein

R9, R10, R11 independently of one another are F or Cl;

R12 is H;

R13 is H, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl or (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl;

R6 is F, Cl, CF₃, OCF₃, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—

(C₁-C₁₀)-alkyl, O—

(C₂-C₁₀)-alkenyl, O—

(C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, N(R14)(R15) or Cl;

heteroalkyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, COOR13, CON(R14)(R15) or N(R₁₄)(R₁₅);

R14, R15 are independently of one another H, (C₁-C₆)-alkyl, where alkyl may be substituted by N(R13)₂;

heteroalkyl is a 3-7-membered, saturated or up to triunsaturated heterocyclic ring which may comprise up to 4 heteroatoms which correspond to N, O or S, where the heterocyclic ring may be substituted up to three times by F, Cl, Br, CN, oxo, (C₁-C₄)-alkyl, —

COOR13, (C₁-C₄)-alkylene-COOR13, CON(R14)(R15), OR13 or N(R14)(R15) or phenyl, where phenyl may be substituted by COOR13;

R8 is N(R18)(R19) or OR20;

or R8 and R4 together form the group —

NH—

CO—

;

R18, R19 are independently of one another H, (C₁-C₁₀)-alkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl, (C₆-C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl, (C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl, (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl, heteroaryl, heteroaryl-(C₁-C₄)-alkyl, heteroaryl-(C₂-C₄)-alkenyl, heteroaryl-(C₂-C₄)-alkynyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted more than once by F, Cl, CN, OR13, R13, CF₃, OCF₃, (C₆-C₁₀)-aryl, NH—

C(═

NR14)-N(R14)(R15), N(R14)(R15), C(═

NR14)—

N(R14)(R15), COOR13 or CON(R14)(R15), and where aryl may be substituted more than once by F, Cl, CN, O—

(C₁-C₆)-alkyl, O—

(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl, (C₂-C₆yalkenyl, CO—

(C₁-C₆)-alkyl, CO—

(C₂-C₆)-alkenyl, where alkyl and alkenyl may be substituted more than once by F, Cl, CH₃, OCH₃ or CN, or NH—

C(═

NR14)-N(R14)(R15), N(R14)(R15), C(═

NR14)-N(R14)(R15), COOR13, CON(R14)(R15), O-phenyl, phenyl or pyridyl;

COOR13, CON—

(R14)(R15), CO-heteroalkyl, CO—

(C₆-C₁₀)-aryl or SO₂—

(C₆-C₁₀)-aryl, where aryl may be substituted up to twice by F, Cl, CN, OH, (C₁-C₆)-alkyl, O—

(C₁-C₆)-alkyl, CF₃, OCF₃, COOR13 or CON(R14)(R15);

or the radicals R18 and R19 form together with the nitrogen atom to which they are bonded a 3-7-membered, saturated heterocyclic ring which may comprise up to 2 further heteroatoms from the group of N, O or S, where the heterocyclic ring may be substituted up to three times by F, Cl, Br, OH, oxo, N(R16)(R17) or (C₁-C₄)-alkyl;

R20 is (C₁-C₁₀)-alkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl, (C₆-C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl, (C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl or (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl, where aryl may be substituted more than once by F, Cl, CN, or O—

(C₁-C₆)-alkyl.

4. A pharmaceutical composition comprising one or more of the compounds as claimed in claim 1.

5. A pharmaceutical composition comprising one or more of the compounds as claimed in claim 1 and at least one other active ingredient.

6. A pharmaceutical composition as claimed in claim 5, wherein the other active ingredient comprises one or more 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, (x-glucosidase inhibitors, active ingredients which act 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, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-β

agonists or amphetamines.

7. A process for producing a pharmaceutical composition comprising mixing one or more of the compounds as claimed in claim 1 with an active ingredient and a pharmaceutically suitable carrier and converting this mixture into a form suitable for administration.

8. A method for reducing blood glucose, comprising administering to a subject in need thereof, one or more compounds claimed in claim 1.

9. A method for treating type 2 diabetes, comprising administering to a subject in need thereof, one or more compounds claimed in claim 1.

10. A method for treating disturbances of lipid and carbohydrate metabolism, comprising administering to a subject in need thereof, one or more compounds claimed in claim 1.

11. A method for treating arteriosclerotic manifestations, comprising administering to a subject in need thereof, one or more compounds claimed in claim 1.

12. A method for treating insulin resistance, comprising administering to a subject in need thereof, one or more compounds claimed in claim 1.