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EP2252592A1 - Imidazolidine-2,4-diones substitués par un arylchalcogeno-arylalkyle, procédé de production, médicaments contenant ces composés et leur utilisation - Google Patents

Imidazolidine-2,4-diones substitués par un arylchalcogeno-arylalkyle, procédé de production, médicaments contenant ces composés et leur utilisation

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Publication number
EP2252592A1
EP2252592A1 EP09708570A EP09708570A EP2252592A1 EP 2252592 A1 EP2252592 A1 EP 2252592A1 EP 09708570 A EP09708570 A EP 09708570A EP 09708570 A EP09708570 A EP 09708570A EP 2252592 A1 EP2252592 A1 EP 2252592A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
cycloalkyl
aryl
cooh
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09708570A
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German (de)
English (en)
Inventor
Gerhard Jaehne
Peter Below
Siegfried Stengelin
Matthias Gossel
Thomas Klabunde
Irvin Winkler
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Sanofi SA
Original Assignee
Sanofi Aventis France
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Priority to EP09708570A priority Critical patent/EP2252592A1/fr
Publication of EP2252592A1 publication Critical patent/EP2252592A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Arylchalcogeno-arylalkyl-substituted imidazolidine-2,4-diones process for their preparation, medicaments containing them and their use
  • the invention relates to imidazolidine-2,4-diones which are substituted by an aralkyl radical and their physiologically acceptable salts.
  • WO2004 / 031160 A2 discloses structurally similar compounds which, however, always carry a thiocarbonyl group on the imidazolidine ring.
  • the structurally similar examples 42, 90 and 116 from WO2004 / 031160A like the compounds according to the invention, were tested in the hCB1R FLIPR assay and showed an IC50 value of> 10 ⁇ M and must therefore be regarded as inactive.
  • the invention had the object to provide compounds that develop a therapeutically useful effect.
  • the object was to find new compounds which are suitable for the treatment of metabolic syndrome, type II diabetes and obesity.
  • the invention therefore relates to compounds of the formula I,
  • R, R 'independently of one another are H, (CH 2 ) n -aryl, (C] -C 6 ) -alkyl, where (C 1 -C 6 ) -alkyl or the aryl radical may be substituted by halogen, O-R 14, S ( O) m -R12 or
  • Carbon atom may be replaced by O, S (O) m , N- (CH 2 ) n -CO-NH-aryl, NRl 3 or NRl 5;
  • n 0, 1, 2, 3, 4;
  • R 1, R 2, R 3, R 4, R 5 independently of one another are H, F, Cl, Br, J, CN, N 3 , NC, NO 2 , CF 3 , (C 1 -C 8 ) -alkyl, (C 3 -C 8 ) -Cycloalkyl, (CH 2 ) q - [(C 3 -C 8 ) -cycloalkyl], (CH 2 ) n - [(C 3 -C 8 ) -cycloalkenyl], (CH 2 ) n - [(C 7 - C 12) bicycloalkyl], (CH 2) ⁇ - [(C 7- C 12) - bicycloalkenyl], (CH 2) n - [(C 7 -C i, adamantane-1-yl 2) tricycloalkyl] , Adamantan-2-yl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, O
  • Cycloalkyl [CH 2 ) n -O- (CH 2 ) n -CO- [O- (C 1 -C 8 ) -alkyl], (CH 2 ) n -O- (CH 2 ) n -CO- [O - (C 3 -C 8 ) -cycloalkyl], (CH 2 ) n -O- (CH 2 ) n -CO - [(C 1 -C 8 ) -alkyl], (CH 2 ) n -O- (CH 2 ) n -
  • Fluorine atoms may be substituted and wherein the aryl or heteroaryl substituted with halogen, CN, (C 1 -C 6) - alkyl, (C 3 -C 6) -cycloalkyl, 0- (C] -C6) - alkyl, S ( 0) m -
  • (C 1 -C 6 ) -alkyl, SO 2 -NH 2 , COOH, CONH 2 , CO- [O (C 1 -C 6 ) -alkyl], CO- (C 1 -C 6 ) - Alkyl may be substituted and wherein the alkyl radicals may be substituted with fluorine atoms; where at least one of the radicals R6, R7, R8, R9 and R10 has the meaning of X-bicyclic heterocycle, X-aryl or X-heteroaryl has, and
  • R 1 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 10 ) -alkenyl, (C 2 -C 10 ) -alkynyl, (C 3 -C 8 ) -cycloalkyl,
  • R 1 is H, (C 1 -C 8 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (CH 2 ) q - [(C 3 -C 8 ) -cycloalkyl], (CH 2 ) n - [(C 7-
  • R 14 H (C 1 -C 10 -alkyl, (C 3 -C 8 ) -cycloalkyl, (CH 2 ) q - [(C 3 -C 8 ) -cycloalkyl],
  • R 1 is H, (C 1 -C 8 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl,
  • alkyl SO 2 -NH 2 , COOH, CONH 2 , CO -O (C 1 -C 6) - alkyl, CO- (C 6 -C! - alkyl may be substituted and wherein the alkyl groups may be substituted with fluorine atoms;
  • R 1 8 (C 1 -C 8 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (CH 2 ) q - [(C 3 -C 8 ) -cycloalkyl],
  • alkyl and cycloalkyl radicals may be substituted by fluorine atoms and wherein the aryl or heteroaryl radical with halogen, CN, (C, -C 6 ) alkyl, 0 - (C 1 -C 6 ) - alkyl, SO 2 -NH 2 , COOH, CONH 2 , CO- [O (C r C 6 ) alkyl], CO- (C 1 -Ce) -AnCyI may be substituted and wherein the alkyl radicals may be substituted by fluorine atoms;
  • R20 H, (C 1 -Ce) -AnCyI, (C 3 -C 8) cycloalkyl, aryl, [(C r C6) -alkyl] -aryl;
  • Cycloalkyl O- (CH 2 ) n -aryl, O- (CO) - (C 1 -C 6 ) -alkyl, O- (CO) - (C 3 -C 8 ) -cycloalkyl, O- (CO) -O- (C 1 -C 6 ) -alkyl, O- (CO) -O- (C 3 -C 8 ) -cycloalkyl, NH - [(C 1 -C 6 ) -alkyl] -aryl , NH 2 , N H- (C 1 -Ce) -Alkyl, NH- (CO) - (C 1 -C 6 ) -alkyl;
  • R 22 is H, CF 3 , (C 1 -C 6 ) -alkyl, aryl, [(C 1 -C 6 ) -alkyl] -aryl;
  • R, R ' are independently H, (CH 2) n -aryl, (dC 6) alkyl, said (C r C6) alkyl or the aryl moiety may be substituted with halogen, or R and R' together form a ring having three to eight carbon atoms, wherein one
  • Carbon atom may be replaced by O, S (O) 01 , NRl 3 or NRl 5;
  • n 0, 1, 2, 3;
  • Rl, R2, R3, R4, R5 are independently H, F, Cl, Br, I, CN, CF 3, (C 1 -Ce) -alkyl, (C 3 - C 6) -cycloalkyl, (CH 2) q - [(C 3 -C 6) cycloalkyl], (CH 2) n - [(C 7 -C 10) bicycloalkyl], (CH 2) n - [(C 7 -C 2) tricycloalkyl] adamantane -1-yl, adamantan-2-yl, (CH 2 ) "- aryl, (CH 2 ) n -heteroaryl, OCF 3 , O-R 11, NR 13
  • Fluorine atoms can be substituted and wherein the aryl or heteroaryl radicals with halogen, CN 5 (C r C6) alkyl, (C 3 -C 6) -cycloalkyl, O- (C r C6) alkyl, S (O) m - (dC 6) -alkyl, SO 2 -NH 2, COOH, CONH 2, CO- [O (Ci-C6) alkyl], CO- (C 1 -C 6) - alkyl may be substituted and wherein the alkyl groups may be substituted with fluorine atoms; where at least one of the radicals R6, R7, R8, R9 and R10 has the meaning of X-bicyclic heterocycle, X-aryl or X-heteroaryl has, and
  • R 1 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, (C 3 -C 6 ) -cycloalkyl,
  • CO-O (dC 6 ) alkyl CO (C ! -C 6 ) alkyl may be substituted and wherein the alkyl radicals may be substituted with fluorine atoms;
  • R 12 is H, (C 1 -C 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (CH 2 ) q - [(C 3 -C 6 ) -cycloalkyl], (CH 2 ) n -
  • R 13 is H, SO 2 - [(dC 6 ) -alkyl], SO 2 - [(C 3 -C 6 ) -cycloalkyl], SO 2 - (CH 2 ) n -aryl,
  • R 1 8 (C 1 -C 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (CH 2 ) q - [(C 3 -C 6 ) -cycloalkyl],
  • alkyl and cycloalkyl radicals may be substituted by fluorine atoms and wherein the aryl or heteroaryl radical with halogen, CN, (C 1 -C 4 ) alkyl, O - (dC 4) -alkyl, SO 2 -NH 2, COOH, CONH 2, CO- [O (dC 4) alkyl], CO- (C 1 -C 4) - alkyl may be substituted and wherein the alkyl radicals having Fluorine atoms may be substituted;
  • R 20 is H, (C 1 -C 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, aryl, [(C 1 -C 4 ) -alkyl] -aryl;
  • Cycloalkyl O- (CH 2 ) n -aryl, O- (CO) - (C 1 -C 4 ) -alkyl, O- (CO) - (C 3 -C 6 ) -cycloalkyl, O- (CO) - O- (Ci-C4) - alkyl, O- (CO) -O- (C 3 -C 6) cycloalkyl, NH - [(dC 4) alkyl] - aryl, NH 2, NH- (C 1 -C 4 ) - alkyl, NH- (CO) - (C 1 -C 4 ) -alkyl;
  • R, R ' are independently H, (CH 2) n -aryl, (C 1 -CZ t) -alkyl, wherein (C! -C4) alkyl or the aryl moiety may be substituted with halogen, or R and R' together form a ring of three to eight carbon atoms, one being
  • Carbon atom may be replaced by O, S (O) m , NRl 3 or NRl 5;
  • n 0, 1, 2;
  • Fluorine atoms may be substituted and wherein the aryl or heteroaryl substituted with halogen, CN, (C 1 -C 6) - alkyl, (C 3 -C 6) -cycloalkyl, 0- (C 6 -C! - alkyl, S ( 0) m -
  • Alkyl may be substituted and wherein the alkyl radicals may be substituted with fluorine atoms; where at least one of the radicals R 6, R 7, R 8, R 9 and R 10 has the meaning of X-bicyclic heterocycle, X-aryl or X-heteroaryl has and
  • R 1 is H, (C, -C 8) alkyl, (C 2 -C 6) -alkynyl, (C 3 -C 6) -cycloalkyl, (CH 2) "- Aiyl, (CH 2) n -
  • R 12 is H, (C 1 -C 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (CH 2 ) q - [(C 3 -C 6 ) -cycloalkyl],
  • alkyl or cycloalkyl radicals may be substituted by fluorine atoms, and where the aryl or heteroaryl radical is halogen, CN, (C 1 -C 4 ) -alkyl, O- (C 1 -C 4) - alkyl, SO 2 -NH 2, COOH, CONH 2, CO-O (C 1-C 4) - alkyl, which may be substituted and wherein the alkyl groups may be substituted with fluorine atoms; R 13 is H, SO 2 - [(C 1 -C 4 ) -alkyl], SO 2 - [(C 3 -C 6 ) -cycloalkyl], SO 2 - (CH 2 ) n -aryl,
  • Rl 5 H (C 1 -C 8 ) -alkyl, where the alkyl radical may be substituted by fluorine atoms;
  • Rl 8 (Ci-C 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (CH 2 ) n -aryl, (CH 2 ) n -Heteroaryl, wherein the alkyl and cycloalkyl radicals may be substituted by fluorine atoms and wherein the aryl or heteroaryl radical with halogen, CN, (C 1 -C 4 ) -alkyl, O- (C 1 -C 4 ) -alkyl, SO 2 -NH 2 , COOH, CONH 2 , CO- [O (C 1 -C 4 ) -alkyl], and wherein the alkyl residues may be substituted by fluorine atoms;
  • R20 H, (Ci-C 4) -alkyl, (C 3 -C 6) cycloalkyl, aryl, [(C 1 -C 4) - alkyl] aryl;
  • Cycloalkyl O- (CH 2) n aryl, 0- (CO) - (C, -C 4) - alkyl, O- (CO) - (C 3 -C 6) -cycloalkyl, O- (CO) - O- (C 1 -C 4 ) -alkyl, O- (CO) -O- (C 3 -C 6 ) -cycloalkyl, NH - [(C 1 -C 4 ) -alkyl] -aryl, NH 2 , NH- (C iC 4 ) -alkyl, NH- (CO) - (C 1 -C 4 ) -alkyl;
  • R, R ' are independently H, aryl, (C 1 -C 4) - alkyl, with (Ci-C4) - alkyl or
  • Aryl may be substituted with halogen; or R and R 'together form a ring of three to eight carbon atoms, wherein a
  • Carbon atom may be replaced by O, S (0) m , NRl 3 or NRl 5;
  • n 0, 1, 2;
  • R 1, R 2, R 3, R 4, R 5 independently of one another H, F, Cl, Br, J, CN, CF 3 , (C 1 -C 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, OCF 3 , ORI 1, NRl 3Rl 5, S (O) m -R 12, SO 2 -NH 2 , SO 2 -NH-CO-R 12, SO 2 -NH -CO-NHRl 2, SO 2 -NH-CO-R 16, SO 2 -NH - [(dC 4 ) -alkyl], SO 2 -NH - [(C 3 -C 6 ) -cycloalkyl], SO 2 -NH - (CH 2 ) n - aryl, SO 2 -NH- (CH 2 ) n -heteroaryl, SO 2 -N [(C 1 -
  • R 1 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkynyl, (C 3 -C 6 ) -cycloalkyl,
  • R 12 is H, (C 1 -C 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (CH 2 ) "-aryl, (CH 2 ) n -heteroaryl, where the alkyl or cycloalkyl radicals may be substituted by fluorine atoms and wherein the aryl or heteroaryl radical with halo, CN, (C J -C 4) - alkyl, O-tQ-O-alkyl, SO 2 -NH 2, COOH, CONH 2, CO-O (C 1 -C 4 ) - alkyl may be substituted and wherein the alkyl radicals may be substituted with fluorine atoms;
  • Rl 5 H (C 1 -C 8 ) -alkyl, where the alkyl radical may be substituted by fluorine atoms;
  • Rl 8 (C 1 -C 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, where the alkyl and cycloalkyl radicals may be substituted by fluorine atoms and wherein the aryl or heteroaryl radical with halo, CN, (C 4 -C?) - alkyl, O- (! C -C 4) -alkyl, SO 2 -NH 2, COOH, CONH 2, CO- [0 (C ! -C 4 ) - alkyl] and wherein the alkyl radicals may be substituted by fluorine atoms;
  • R20 H, (Ci-GO-alkyl, (C 3 -C 6) cycloalkyl, aryl, [(C ⁇ C 4) - alkyl] aryl;
  • R 21 is H, F, CF 3 , (Q-GO-alkyl, (C 3 -C 6 ) -cycloalkyl, OH, 0- (C 1 -C 4 ) -alkyl, O- (C 3 -C 6 ) -
  • Cycloalkyl O- (CH 2 ) n -aryl, O- (CO) - (C 1 -C 4 ) -alkyl, O- (CO) - (C 3 -C 6 ) -cycloalkyl, O- (CO) - O- (! C -C 4) alkyl, O- (CO) -O- (C 3 -C 6) cycloalkyl, NH - [(C 1 -C 4) alkyl] - aryl, NH 2, NH - (C r C 4 ) alkyl, NH- (CO) - (C 1 -C 4 ) alkyl;
  • n 0, 1, 2;
  • R 1, R 2, R 3 , R 4, R 5 independently of one another are H, F, Cl, Br, J, CN, CF 3 , (C 1 -C 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (CH 2 ) n -aryl, (CH 2) n -heteroaryl, OCF 3, O-R 1, NR13R15, S (O) 01 -rl 2, SO 2 -NH 2, SO 2 -NH-CO-R 2, SO 2 -NH -CO-NHRI 2, SO 2 -NH-CO- Rl 6, SO 2 -NH- [CC 1 -C) -alkyl], SO 2 -NH - [(C 3 -C 6 ) -cycloalkyl], SO 2 -NH- (CH 2 V aryl, SO 2 -NH - (CH 2 ) n -Heteroaryl, SO 2 -N [(C 1 -C 4 ) -alkyl
  • R7, R8, R9, Rl O is independently H, F, Cl, Br, I, CN, CF 3, (C, -C 4) - alkyl, (C 2 -C 4) - alkynyl, (C 3 -C 6 ) -cycloalkyl, aryl, heteroaryl, (CH 2 ) n -CO- [O- (C 1 -C 4 ) -alkyl], (CH 2 ) n -CO - [(C 1 -C 4 ) -alkyl],
  • R 1 is H, (C 1 -C 8 ) -alkyl, (C 2 -C 6 ) -alkynyl, (C 3 -C 6 ) -cycloalkyl,
  • R30, R31, R32 independently of one another RI 1 5 F, Cl, Br, J, CN, CF 3 , (CH 2 ) n -O-Rl 1, O-
  • R31 or R32 is a substituent other than hydrogen
  • n 0, 1, 2;
  • R 1, R 2, R 3 , R 4, R 5 independently of one another are H, F, Cl, Br, J, CN, CF 3 , (C 1 -C 4 ) -alkyl, (CH 2 ) n -aryl, -O- (CH 2 ) n - Aryl, OCF 3 , O- (C 1 -C 8 ) -alkyl, S (O) m - (C 1 -C 8 ) -alkyl, CO-O [(C 1 -C 4 ) -alkyl], CO- (dC 4 ) -Alkyl, CO-aryl, CH 2 -CN; wherein the alkyl radicals may be substituted by fluorine atoms;
  • R7, R8, R9, R10 H; R30, R31, R32 independently of one another are H, (C 1 -Cg) -alkyl, F, Cl, Br, -COOH, -COO (C 1 -C 4)
  • compounds of formula I are preferred in which p is 1.
  • R 6 is S (O) m -aryl, where m can be 0, 1 or 2 and where aryl can be substituted.
  • R 7 is S (O) m -aryl, where m can be 0, 1 or 2 and where aryl can be substituted.
  • compounds of the formula I are preferred in which R and R 'is methyl.
  • compounds of formula I are preferred in which A is equal to N.
  • compounds of the formula I are preferred in which D is N. In one embodiment, compounds of the formula I are preferred in which E is CH.
  • compounds of the formula I are preferred in which E is N.
  • radicals or substituents can occur several times in the compounds of the formula I, they may all independently of one another have the meanings indicated and be identical or different.
  • the invention further provides both stereoisomer mixtures of the formula I and the pure stereoisomers of the formula I, and also diastereoisomer mixtures of the formula I and the pure diastereoisomers.
  • the separation of the mixtures takes place z. B. by chromatographic means.
  • the invention relates to compounds of the formula I, in the form of their tautomers, racemates, racemic mixtures, stereoisomer mixtures, pure stereoisomers, mixtures of diastereoisomers, pure diastereoisomers.
  • the separation of the mixtures takes place z. B. by chromatographic means.
  • alkyl radicals in the substituents Rl to Rl 8 and R and R ' can be both straight-chain and branched.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphorus, metaphosphorus, Nitric and sulfuric acid and organic acids such as acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic , Succinic, p-toluenesulfonic and tartaric acids.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphorus, metaphosphorus, Nitric and sulfuric acid
  • organic acids such as acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesul
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-l, 3-propanediol), diethanolamine, lysine or ethylenediamine.
  • Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.
  • the compounds of the invention may also be in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
  • alkyl radical a straight or branched chain hydrocarbon chain of one to eight carbons, e.g. Methyl, ethyl, isopropyl, tert -butyl, hexyl, heptyl, octyl.
  • the alkyl radicals may be monosubstituted or polysubstituted as described above.
  • a cycloalkyl radical is to be understood as meaning a ring system containing one or more rings which is saturated or partially unsaturated (having one or two double bonds) which is composed exclusively of carbon atoms, e.g. Cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
  • cycloalkyl radicals may be substituted one or more times with suitable groups as described above.
  • An aryl radical is understood as meaning a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonic, indanyl or indan-1-onyl radical.
  • the aryl radicals may be substituted one or more times with suitable groups as described above.
  • Suitable heteroaryl radicals are e.g. Furyl, imidazolyl, benzimidazolyl, benzothiazolyl, indolyl, indolinyl, pyrimidinyl, pyridyl, pyrazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, isoxazolyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl; the 2H-pyridazin-3-one, dihydropyridazine-3,6-dione, imidazolidin-2-one, 1,3-dihydro-imidazol-2-one, imidazolidine-2,5-dione, quinoline , Isoquinoline, quinoxaline, quinazoline, be
  • heteroaryl radicals may be monosubstituted or polysubstituted by suitable groups as described above.
  • the invention also includes solvates or hydrates of the compounds of the formula I.
  • the compounds of formula I are cannabinoid 1 receptor (CBIR) modulators and, as such, are useful in humans and in animals for the treatment or prevention of diseases based on a disorder of the endocannabinoid system.
  • CBDR cannabinoid 1 receptor
  • the compounds of formula I are useful as psychotropic drugs, particularly for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delirium, obsessive-compulsive disorder, general psychosis, schizophrenia, attention deficit and hyperactivity disorder (ADHD).
  • ADHD attention deficit and hyperactivity disorder
  • the compounds of the formula I according to the invention can be used as medicaments for the treatment of migraine, stress, diseases of psychosomatic origin, panic attack crises, epilepsy, movement disorders, in particular dyskinesias or Parkinson's disease, tremors and dystonia.
  • the compounds of the formula I according to the invention can furthermore also be used as medicaments for the treatment of memory disorders, mental defects, in particular for the treatment of senile dementia, Alzheimer's disease and for the treatment of diminished attention or alertness.
  • the compounds of formula I can be used as neuroprotectors, for the treatment of ischemia, cranial injuries and treatment of neurodegenerative diseases, including chorea, Huntington's disease, Tourette's syndrome.
  • the compounds of the formula I according to the invention can furthermore be used as medicaments in the treatment of pain; These include neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin.
  • the compounds of the formula I according to the invention can furthermore be used as medicaments for the treatment of eating disorders (for example, addictive eating disorders, anorexia and bulimia), for the treatment of addiction to sweets, carbohydrates, drugs, alcohol or other addictive substances.
  • the compounds of the formula I according to the invention are particularly suitable for the treatment of obesity or bulimia and for the treatment of diabetes type II as well as for the treatment of dyslipidaemias and the metabolic syndrome.
  • the compounds of the formula I according to the invention are therefore useful for the treatment of obesity and the dangers associated with obesity, in particular cardiovascular dangers.
  • the compounds of formula I according to the invention can be used as medicaments for the treatment of gastrointestinal disorders, for the treatment of diarrhea, gastrointestinal ulcers, vomiting, bladder disorders and disorders of urination, disorders of endocrine origin, cardiovascular problems, low blood pressure, hemorrhagic Shocks, septic shock, chronic liver cirrhosis, hepatic steatosis, non-alcoholic steatohepatitis, asthma, Raynaud's syndrome, glaucoma, fertility problems, abortion, premature birth, inflammatory phenomena, immune system disorders, especially autoimmune and neuroinflammatory, such as rheumatoid arthritis , reactive arthritis, diseases leading to demyelinization, multiple sclerosis, infectious diseases and viral diseases such as encephalitis, ischemic stroke and drugs For the treatment of Guillain-Barre syndrome and for the treatment of osteoporosis.
  • the compounds of the formula I according to the invention can furthermore also be used as medicaments for the treatment of the polycystic ovary syndrome (
  • the compounds of formula I are particularly useful for the treatment of psychotic disorders, especially schizophrenia, diminished attention and hyperactivity (ADHD) in hyperkinetic children, for the treatment of eating disorders and obesity, for the treatment of type II diabetes, for the treatment of Memory deficits and cognitive deficits, for the treatment of alcohol addiction, nicotine addiction, that is for alcohol and tobacco cessation.
  • psychotic disorders especially schizophrenia, diminished attention and hyperactivity (ADHD) in hyperkinetic children
  • eating disorders and obesity for the treatment of type II diabetes
  • Memory deficits and cognitive deficits for the treatment of alcohol addiction, nicotine addiction, that is for alcohol and tobacco cessation.
  • the compounds of the formula I according to the invention for the treatment and prevention of eating disorders, appetite disorders, metabolic disorders, gastrointestinal disorders, inflammatory phenomena, disorders of the immune system, psychotic disorders, alcohol addiction and nicotine addiction.
  • the invention relates to the use of a compound of formula I, its pharmaceutically acceptable salts and its solvates or hydrates for the treatment of the disorders and disorders indicated above.
  • the compound (s) of the formula I can also be administered in combination with other active substances.
  • the amount of a compound of Formula I required to achieve the desired biological effect is dependent upon a number of factors, eg, the specific compound chosen, the intended use, the mode of administration, and the clinical condition of the patient.
  • the daily dose ranges from 0.3 mg to 100 mg (typically 3 mg and 50 mg) per day per kilogram of body weight, eg 3-10 mg / kg / day.
  • an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may conveniently be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
  • Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.
  • Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
  • injectable ampoules, and orally administrable unit dose formulations such as tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
  • the compounds according to formula I can themselves be used as compound, but they are preferably present with a compatible carrier in the form of a pharmaceutical composition.
  • the carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Further pharmaceutical Active substances may also be present, including other compounds according to formula ⁇ .
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients.
  • compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is of the type and severity of the treatment to be treated State and on the nature of the particular compound used in accordance with formula I is dependent.
  • coated formulations and coated slow release formulations are within the scope of the invention.
  • Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
  • the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary.
  • a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients.
  • Pressed tablets may be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or a surfactant / dispersing agent in a suitable machine.
  • Molded tablets can be prepared by molding the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • compositions suitable for peroral (sublingual) administration include lozenges containing a compound of Formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
  • Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil.
  • Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used as the carrier.
  • the active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
  • Transdermal administration is also possible.
  • Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%.
  • the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
  • active substances for the combined preparations are: All antidiabetics mentioned in the Red List 2007, Chapter 12; all weight loss / appetite suppressants listed in the Red List 2007, Chapter 1; all diuretics mentioned in the Red List 2007, chapter 36; all lipid lowering drugs mentioned in the Red List 2007, chapter 58. They can be combined with the compound of the formula I according to the invention in particular for the synergistic effect improvement.
  • the administration of the active ingredient combination can be carried out either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. If the administration of the active ingredients by separate administration of the active ingredients, so this can be done simultaneously or sequentially.
  • Most of the drugs listed below are disclosed in the USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville, 2006.
  • Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir), Humalog (R) (insulin lispro), Humulin (R), VIAject TM, SuliXen (R) or those as described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633), inhalable insulins such.
  • Lantus ® see www.lantus.com
  • HMR 1964 Levemir® (insulin detemir), Humalog (R) (insulin lispro), Humulin (R), VIAject TM, SuliXen (R) or those as described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633), inhalable insulins such.
  • Levemir® insulin detemir
  • Humalog (R) insulin lispro
  • Humulin R
  • IN-105 Nobex
  • Oral-lyn TM Geneex Biotechnology
  • Technosphere (R) insulin MannKind
  • Cobalamin TM oral insulin or insulins as described in WO2007128815, WO2007128817, WO2008034881, WO2008049711 or insulins
  • GLP-I derivatives and GLP-I agonists such as exenatides or 'special preparations thereof, as described, for example, in WO2008061355, liraglutide, Taspoglutide (R-1583), albiglutide, lixisenatide or those described in WO 98/08871, WO2005027978, WO2006037811, WO2006037810 of Novo Nordisk A / S, in WO 01/04156 of Zealand or in WO 00/34331 of Beaufour-Ipsen, Pramlintide acetate (Symlin; Amylin Pharmaceuticals),
  • Antidiabetic agents also include agonists of the glucose-dependent insulinotropic polypeptide (GIP) receptor as described e.g. in WO2006121860 are described.
  • GIP glucose-dependent insulinotropic polypeptide
  • Antidiabetics also include the glucose-dependent insulinotropic polypeptide (GIP) as well as analogous compounds as described e.g. in WO2008021560 are described.
  • GIP glucose-dependent insulinotropic polypeptide
  • Antidiabetics also include analogs and derivatives of fibroblast growth factor 21 (FGF-21, fibroblast growth factor 21).
  • the orally active hypoglycans are preferably sulfonylureas
  • Potassium channel opener e.g. Pinacidil, cromakalim, diazoxide or those as described by R. D.
  • DPP-IV dipeptidyl peptidase-IV
  • PTP-IB protein tyrosine phosphatase-1B
  • Nicotinic receptor agonists
  • Inhibitors of acetyl-CoA carboxylase ACCl and / or ACC2
  • lipid metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents.
  • FXR Farnesoid X Receptor
  • SST5 receptor Antagonists of the somatostatin 5 receptor
  • the compound of the formula I is administered in combination with insulin.
  • the compound of the formula I is administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, e.g. Sulfonylureas, e.g. Tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride.
  • an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, e.g. Sulfonylureas, e.g. Tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride.
  • the compound of formula I is administered in combination with a tablet containing both glimepride which is rapidly released and contains metformin which is released over a prolonged period of time (as described, for example, in US2007264331, WO2008050987, WO2008062273).
  • the compound of formula I is used in combination with a biguanide, e.g. Metformin, administered.
  • a biguanide e.g. Metformin
  • the compound of formula I is used in combination with a meglitinide, e.g. Repaglinide, nateglinide or mitiglinide administered.
  • a meglitinide e.g. Repaglinide, nateglinide or mitiglinide administered.
  • the compound of formula I is administered with a combination of mitiglinides with a glitazone, eg, pioglitazone hydrochloride.
  • the compound of the formula I is administered with a combination of mitiglinides with an alpha-glucosidase inhibitor.
  • the compound of the formula I is administered in combination with antidiabetic compounds, as described in WO2007095462, WO2007101060, WO2007105650.
  • the compound of the formula I is administered in combination with antihypoglycemic compounds, as described in WO2007137008, WO2008020607.
  • the compound of formula I is used in combination with a thiazolidinedione, e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
  • a thiazolidinedione e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl]
  • the compound of formula I is used in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-Ol 1 (rivoglitazone), DRL-17564, DRF-2593 (balaglitazone), INT-131, T-2384 or those as described in WO2005086904, WO2007060992 administered, WO2007100027, WO2007103252, WO2007122970, WO2007138485, WO2008006319, WO2008006969, WO2008010238, WO2008017398, WO2008028188, WO2008066356, WO2008084303, WO2008089464 WO2008089461-, WO2008093639, WO2008096769, WO2008096820, WO2008096829, US2008194617, WO2008099944, WO200810860
  • the compound of the formula I is administered in combination with Competact TM, a solid combination of pioglitazone hydrochloride with metformin hydrochloride.
  • the compound of the formula I is administered in combination with Tandemact TM, a solid combination of pioglitazone with glimepride.
  • the compound of the formula I is administered in combination with a solid combination of pioglitazone hydrochloride with an angiotensin II agonist such as TAK-536.
  • the compound of the formula I is administered in combination with a PPAR alpha agonist or mixed PPAR alpha / PPAR delta agonists, such as e.g. GW9578, GW-590735, KH1, LY-674, KRP-101, DRF-10945, LY-518674, CP-900691, BMS-687453, BMS-711939 or those as described in WO2001040207, WO2002096894, WO2005097076, WO2007056771, WO2007087448 , WO2007089667, WO2007089557, WO2007102515, WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043, WO2008006043, WO2008006044, WO2008012470, WO2008035359, WO2008087365, WO2008087366, WO2008087367, WO2008117982.
  • the compound of formula I is used in combination with a mixed PPAR alpha / gamma agonist, e.g. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD-501 (Lobeglitazone Sulfate), MBX-213, KY-201 or as in WO 00/64888, WO 00/64876 WO03 / 020269, WO2004024726, WO2007099553, US2007276041, WO2007085135, WO2007085136, WO2007141423, WO2008016175, WO2008053331, WO2008109697, WO2008109700, WO2008108735 or JP Berger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005, administered.
  • a mixed PPAR alpha / gamma agonist e.g. Naveglitazar
  • the compound of the formula I is used in combination with a PPAR delta agonist such as GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887, WO2007141423, US2008004281, WO2008016175, WO2008066356, WO2008071311, WO2008084962, US2008176861.
  • a PPAR delta agonist such as GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887, WO2007141423, US2008004281, WO2008016175, WO2008066356, WO2008071311, WO2008084962,
  • the compound of the formula I is administered in combination with a pan-SPPARM (selective PPAR modulator alpha, gamma, delta), such as, for example, GFT-505 or those as described in WO2008035359.
  • a pan-SPPARM selective PPAR modulator alpha, gamma, delta
  • the compound of formula I is administered in combination with metaglidases or with MBX-2044 or other partial PPAR gamma agonist / antagonist.
  • the compound of formula I is administered in combination with an ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose or those as described e.g. in WO2007114532, WO2007140230, US2007287674, US2008103201, WO2008065796, WO2008082017.
  • an ⁇ -glucosidase inhibitor e.g. Miglitol or acarbose or those as described e.g. in WO2007114532, WO2007140230, US2007287674, US2008103201, WO2008065796, WO2008082017.
  • the compound of formula I is used in combination with a glycogen phosphorylase inhibitor, e.g. PSN-357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932, WO2008062739, WO2008099000, WO2008113760.
  • a glycogen phosphorylase inhibitor e.g. PSN-357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932, WO2008062739, WO2008099000, WO2008113760.
  • the compound of formula I is administered in combination with glucagon receptor antagonists, such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488, WO2007047177, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577, WO2008042223, WO2008098244.
  • glucagon receptor antagonists such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488, WO2007047177, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577, WO2008042223, WO2008098244.
  • the compound of formula I is used in combination with an antisense compound, e.g. ISIS-325568, which inhibits the production of the glucagon receptor.
  • an antisense compound e.g. ISIS-325568
  • the compound of the formula I in combination with activators of glucokinase such as. LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50, or those as described e.g. In WO2004072031, WO2004072066, WO2005080360, WO2005044801, WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549, WO2007017649, WO2007007910, WO2007007040-42, WO2007006760-61, WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365, WO2007041366, WO2007037534, WO2007043638, WO2007053345, WO2007051846, WO2007051845, WO2007053765, WO2007051847, WO2007061923, WO20070758
  • the compound of the formula I in combination with an inhibitor of gluconeogenesis as z.
  • an inhibitor of gluconeogenesis as described in FR-225654, WO2008053446.
  • the compound of formula I is used in combination with inhibitors of fructose-1,6-bisphosphatase (FBPase), e.g. MB-07729, CS-917 (MB-06322) or MB-07803 or those as described in WO2006023515, WO2006104030, WO2007014619, WO2007137962, WO2008019309, WO2008037628.
  • FBPase fructose-1,6-bisphosphatase
  • the compound of the formula I in combination with modulators of the glucose transporter-4 (GLUT4), such as. KST-48 (D.O. Lee et al .: Arzneim.-Forsch.drug Res. 54 (12), 835 (2004)).
  • the compound of formula I is used in combination with inhibitors of glutamine-fructose 6-phosphate amidotransferase (GFAT), as described e.g. As described in WO2004101528 administered.
  • GFAT glutamine-fructose 6-phosphate amidotransferase
  • the compound of formula I in combination with inhibitors of dipeptidyl peptidase-IV in combination with inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as. Vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptin phosphate, saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200 (melogliptin), GW-825964X, KRP-104, DP-893, ABT-341, ABT-279, or another salt thereof, S-40010, S- 40755, PF-00734200, BI-1356, PHX-1149, alogliptin benzoate, linagliptin, melogliptin or such compounds as described in WO2003074500, WO2003106456, WO2004037169,
  • the compound of formula I is administered in combination with Janumet TM, a solid combination of sitagliptin phosphate with metformin hydrochloride.
  • the compound of the formula I is administered in combination with Eucreas, a solid combination of vildagliptin with metformin hydrochloride.
  • the compound of the formula I is administered in combination with a solid combination of alogliptin benzoate with pioglitazone.
  • the compound of formula I is administered in combination with a solid combination of a salt of sitagliptin with metformin hydrochloride. In one embodiment, the compound of the formula I is administered in combination with a combination of a DPP-IV inhibitor with omega-3 fatty acids or omega-3 fatty acid esters, as described, for example, in WO2007128801.
  • the compound of formula I is administered in combination with a solid combination of a salt of sitagliptin with metformin hydrochloride.
  • the compound of formula I in combination with an insulin secretion enhancing substance, such as. KCP-265 (WO2003097064) or those as described in WO2007026761, WO2008045484, US2008194617.
  • an insulin secretion enhancing substance such as. KCP-265 (WO2003097064) or those as described in WO2007026761, WO2008045484, US2008194617.
  • the compound of the formula I in combination with agonists of the glucose-dependent insulinotropic receptor (GDIR) such.
  • GDIR glucose-dependent insulinotropic receptor
  • the compound of formula I is used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990 administered.
  • an ATP citrate lyase inhibitor e.g. SB-204990 administered.
  • the compound of formula I is used in combination with modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2) such as KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083 , SGL-5085, SGL-5094, ISIS-388626, sergliflozin or dapagliflozin or as such.
  • modulators of the sodium-dependent glucose transporter 1 or 2 such as KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083 , SGL-5085, SGL-5094, ISIS-388626, sergliflozin or dapagliflozin or as such.
  • the compound of the formula I in combination with inhibitors of 1 1-beta-hydroxysteroid dehydrogenase-l (1 Iß-HSDI), such as.
  • Iß-HSDI 1 1-beta-hydroxysteroid dehydrogenase-l
  • the compound of the formula I in combination with inhibitors of protein tyrosine phosphatase-1B in combination with inhibitors of protein tyrosine phosphatase-1B (PTP-IB), as z.
  • PTP-IB protein tyrosine phosphatase-1B
  • WO200119830-31 WO200117516, WO2004506446, WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE 10 2004 060542.4, WO2007009911, WO2007028145, WO2007067612-615, WO2007081755, WO2007115058, US2008004325, WO2008033455, WO2008033931, WO2008033932, WO2008033934, WO2008089581 are described, administered.
  • the compound of formula I is administered in combination with an agonist of GPR10A (HM74A receptor agonists; NAR agonists (nicotinic acid receptor agonists)), e.g. Nicotinic acid or "extended release niacin" in association with MK-0524A (laropiprant) or MK-0524 or such compounds as described in WO2004041274, WO2006045565, WO2006045564, WO2006069242, WO2006085108, WO2006085112, WO2006085113, WO2006124490, WO2006113150, WO2007017261, WO2007017262, WO2007017265 , WO2007015744, WO2007027532, WO2007092364, WO2007120575, WO2007134986, WO2007150025, WO2007150026, WO2008016968, WO2008051403, WO2008086949, WO200809
  • GPR10A
  • the compound of formula I is administered in combination with a solid combination of niacin with simvastatin.
  • the compound of formula I is administered in combination with nicotinic acid or extended release niacin in association with MK-0524A (laropiprant).
  • the compound of the formula I is administered in combination with nicotinic acid or extended release niacin in conjunction with MK-0524A (laropiprant) and with simvastatin.
  • the compound of the formula I is used in combination with nicotinic acid or another nicotinic acid receptor agonist and a prostaglandin DP receptor antagonists such as those as described in WO2008039882 administered.
  • the compound of formula I is used in combination with an agonist of GPR16, as described, e.g. in WO2006067531, WO2006067532.
  • the compound of formula I is used in combination with modulators of GPR40, as described, e.g. in WO2007013689, WO2007033002, WO2007106469, US2007265332, WO2007123225, WO2007131619, WO2007131620, WO2007131621, US2007265332, WO2007131622, WO2007136572, WO2008001931, WO2008030520, WO2008030618, WO2008054674, WO2008054675, WO2008066097, US2008176912.
  • the compound of Formula I is used in combination with modulators of GPR19 (G protein-coupled glucose dependent insulinotropic receptor), such as e.g. PSN-119-1, PSN-821, PSN-119-2, MBX-2982 or such.
  • GPR19 G protein-coupled glucose dependent insulinotropic receptor
  • the compound of formula I is used in combination with modulators of the GPR120, e.g. in EP1688138, WO2008066131, WO2008066131, WO2008103500, WO2008103501.
  • the compound of the formula I in combination with inhibitors of hormone-sensitive lipase (HSL) and / or phospholipases, such.
  • HSL hormone-sensitive lipase
  • phospholipases such as described in WO2005073199, WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837, WO2008122352, WO2008122357.
  • the compound of the formula I in combination with inhibitors of endothelial lipase such as. As described in WO2007110216 administered.
  • the compound of formula I is used in combination with a phospholipase A2 inhibitor, e.g. Darapladib or A-002 or those as described in WO2008048866, WO20080488867 administered.
  • a phospholipase A2 inhibitor e.g. Darapladib or A-002 or those as described in WO2008048866, WO20080488867 administered.
  • the compound of the formula I is administered in combination with myricitrin, a lipase inhibitor (WO2007119827).
  • the compound of the formula I in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), such as. B. in US2005222220, WO2005085230, WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727, WO2004046117, WO2007073117, WO2007083978, WO2007120102, WO2007122634, WO2007125109, WO2007125110, US2007281949 , WO2008002244, WO2008002245, WO2008016123, WO2008023239, WO2008044700, WO2008056266, WO2008057940, WO2008077138, EP193919
  • the compound of formula I is used in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), e.g. such as described in WO2004074288 administered.
  • PPCK phosphoenolpyruvate carboxykinase
  • the compound of formula I is administered in combination with an inhibitor of phosphoinositide kinase-3 (PI3K), such as those described in WO2008027584, WO2008070150, WO2008125833, WO2008125835, WO2008125839.
  • PI3K phosphoinositide kinase-3
  • SGK Giucocorticoid regulated kinase
  • the compound of the formula I in combination with a modulator of the glucocorticoid receptor, such.
  • a modulator of the glucocorticoid receptor such as WO2008057855, WO2008057856, WO2008057857, WO2008057859, WO2008057862, WO2008059867, WO2008059866, WO2008059865, WO2008070507, WO2008124665, WO2008124745.
  • the compound of formula I in combination with a modulator of the mineralocorticoid receptor (MR), such as.
  • MR mineralocorticoid receptor
  • drospirenones or those as described in WO2008104306, WO2008119918 administered.
  • the compound of formula I in combination with an inhibitor of protein kinase C beta (PKC beta), such as. Ruboxistaurin, or those as described in WO2008096260, WO2008125945 administered.
  • PLC beta protein kinase C beta
  • the compound of formula I in combination with an inhibitor of protein kinase D such as. B. Doxazosin (WO2008088006) administered.
  • the compound of the formula I in combination with an activator of AMP-activated protein kinase (AMPK), as described, for.
  • AMPK AMP-activated protein kinase
  • the compound of the formula I in combination with an inhibitor of ceramide kinase, as z.
  • an inhibitor of ceramide kinase as described in WO2007112914, WO2007149865.
  • the compound of the formula I is used in combination with an inhibitor of the MAPK-interacting kinase 1 or 2 (MNK1 or 2), as described, for example, in US Pat WO2007104053, WO2007115822, WO2008008547, WO2008075741.
  • MNK1 or 2 an inhibitor of the MAPK-interacting kinase 1 or 2
  • the compound of the formula I is used in combination with inhibitors of "I-kappaB kinase" (IKK inhibitors), as described, for example, in WO2001000610, WO2001030774, WO2004022057, WO2004022553, WO2005097129, WO2005113544, US2007244140, WO2008099072, WO2008099073, WO2008099073, WO2008099074, WO2008099075 described, administered.
  • IKK inhibitors inhibitors of "I-kappaB kinase”
  • the compound of formula I in combination with inhibitors of NF-kappaB (NFKB) activation as described, for. As salsalates administered.
  • the compound of the formula I in combination with inhibitors of ASK-I (apoptosis signal-regulating kinase 1), as described, for. As described in WO2008016131 administered.
  • ASK-I apoptosis signal-regulating kinase 1
  • the compounds of formula I are used in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin, L-659699, BMS-644950 or those described in US2007249583 , WO2008083551.
  • an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin, L-659699, BMS-644950 or those described in US2007249583 , WO2008083551.
  • the compound of formula I in combination with a farnesoid X receptor (FXR) modulator e.g. WAY-362450 or those described in WO2003099821, WO2005056554, WO2007052843, WO2007070796, WO2007092751, JP2007230909, WO2007095174, WO2007140174, WO2007140183, WO2008000643, WO2008002573, WO2008025539, WO2008025540, JP2008214222.
  • FXR farnesoid X receptor
  • the compound of the formula I is administered in combination with a ligand of the liver X receptor (LXR), as described, for example, in WO2007092965, WO2008041003, WO2008049047, WO2008065754, WO2008073825, US2008242677.
  • LXR liver X receptor
  • the compound of formula I is administered in combination with a fibrate, such as fenofibrate, clofibrate, bezafibrate, or those as described in WO2008093655.
  • the compound of formula I is used in combination with fibrates, e.g. the choline salt of fenofibrate (SLV-348).
  • fibrates e.g. the choline salt of fenofibrate (SLV-348).
  • the compound of formula I is used in combination with fibrates, e.g. the choline salt of fenofibrate and a HMGCoA reductase inhibitor, e.g. Rosuvastatin, administered.
  • fibrates e.g. the choline salt of fenofibrate and a HMGCoA reductase inhibitor, e.g. Rosuvastatin, administered.
  • the compound of the formula I is administered in combination with bezafibrate and difiunisal.
  • the compound of formula I is administered in combination with a fixed combination of fenofibrate or a salt thereof with simvastatin, rosuvastatin, fluvastatin, lovastatin, cerivastatin, pravastatin, pitavastatin or atorvastatin.
  • the compound of formula I is administered in combination with Synordia (R), a fixed combination of fenofibrate with metformin.
  • the compound of the formula I is administered in combination with a cholesterol absorption inhibitor, such as ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate, Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with compounds as described in WO2002066464, WO2005000353 (Kotobuki Pharmaceutical Co.
  • a cholesterol absorption inhibitor such as ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate, Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with compounds as described in WO2002066464, WO2005000353 (Kotobuki Pharmaceutical Co.
  • the compound of formula I is administered in combination with an NPC ILl antagonist, e.g. those as described in WO2008033464, WO2008033465, administered.
  • an NPC ILl antagonist e.g. those as described in WO2008033464, WO2008033465, administered.
  • the compound of formula I is administered in combination with Vytorin TM, a fixed combination of ezetimibe with simvastatin.
  • the compound of formula I is administered in combination with a fixed combination of ezetimibe with atorvastatin.
  • the compound of formula I is administered in combination with a fixed combination of ezetimibe with fenofibrate.
  • the further active ingredient is a diphenylazetidinone derivative, e.g. in US 6,992,067 or US 7,205,290.
  • the further active ingredient is a diphenylazetidinone derivative, e.g. in US 6,992,067 or US 7,205,290 combined with a statin such as e.g. Simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin, pitavastatin or rosuvastatin.
  • a statin such as e.g. Simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin, pitavastatin or rosuvastatin.
  • the compound of formula I is administered in combination with a solid combination of Lapaquistat, a squalene synthase inhibitor, with atorvastatin.
  • the compound of the formula I is used in combination with a CETP inhibitor, such as torcetrapib, anacetrapib or JTT-705 (dalcetrapib) or those described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154, US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243, WO2007120621, US2007265252, US2007265304, WO2007128568, WO2007132906, WO2008006257, WO2008009435, WO2008018529, WO20080589
  • the compound of formula I is used in combination with bile acid resorption inhibitors (inhibitors of the intestinal bile acid transporter (IBAT)) (see for example US 6,245,744, US 6,221,897 or WO00 / 61568), e.g. HMR 1741 or those described in DE 10 2005 033099.1 and DE 10 2005 033100.9, DE 10 2006 053635, DE 10 2006 053637, WO2007009655-56, WO2008058628, WO2008058629, WO2008058630, WO2008058631.
  • IBAT intestinal bile acid transporter
  • the compound of Formula I is used in combination with agonists of GPBAR1 (G-protein-coupled bile-acid receptor-1; TGR5), as described, e.g. in US20060199795, WO2007110237, WO2007127505, WO2008009407, WO2008067219, WO2008067222, FR2908310, WO2008091540, WO2008097976.
  • GPBAR1 G-protein-coupled bile-acid receptor-1
  • the compound of formula I is used in combination with inhibitors of the TRPM5 channel (TRP cation channel M5), e.g. in WO2008097504.
  • the compound of formula I is administered in combination with a polymeric bile acid adsorber such as cholestyramine, colesevelam hydrochloride. In one embodiment of the invention, the compound of the formula I is administered in combination with coleseviram hydrochloride and metformin or a sulfonylurea or insulin.
  • the compound of formula I is administered in combination with a phytosterol-containing chewing gum (Reductol TM).
  • the compound of formula I is used in combination with an inhibitor of the microsomal triglyceride transfer protein (MTP inhibitor), e.g. Implitapide, BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR-733 or those as described in WO2005085226, WO2005121091, WO2006010423, WO2006113910, WO2007143164, WO2008049806, WO2008049808, WO2008090198, WO2008100423.
  • MTP inhibitor microsomal triglyceride transfer protein
  • the compound of formula I is used in combination with a combination of a cholesterol absorption inhibitor, e.g. Ezetimibe, and an inhibitor of the triglyceride transfer protein (MTP inhibitor), such as. Implitapide as described in WO2008030382 or WO2008079398 described.
  • a cholesterol absorption inhibitor e.g. Ezetimibe
  • MTP inhibitor an inhibitor of the triglyceride transfer protein
  • the compound of formula I is administered in combination with an antihypertriglyceridemic agent, e.g. such as those described in WO2008032980 administered.
  • an antihypertriglyceridemic agent e.g. such as those described in WO2008032980 administered.
  • the compound of formula I is administered in combination with an antagonist of the somatostatin 5 receptor (SST5 receptor), e.g. such as those described in WO2006094682 administered.
  • SST5 receptor somatostatin 5 receptor
  • the compound of formula I is administered in combination with an ACAT inhibitor, e.g. Avasimibe, SMP-797 or KY-382 or those as described in WO2008087029, WO2008087030, WO2008095189 administered.
  • an ACAT inhibitor e.g. Avasimibe, SMP-797 or KY-382 or those as described in WO2008087029, WO2008087030, WO2008095189 administered.
  • the compound of the formula I in combination with an inhibitor of hepatic carnitine palmitoyltransferase-1 (L-CPTl), as for example in WO2007063012, WO2007096251 (ST-3473), WO2008015081, US2008103182, WO2008074692.
  • L-CPTl hepatic carnitine palmitoyltransferase-1
  • the compound of formula I is used in combination with a modulator of serine-palmitoyltransferase (SPT), as described e.g. in WO2008031032, WO2008046071, WO2008083280, WO2008084300.
  • SPT serine-palmitoyltransferase
  • the compound of formula I is used in combination with a squalene synthetase inhibitor, e.g. BMS-188494, TAK-475 (Lapaquistat acetate) or as described in WO2005077907, JP2007022943, WO2008003424.
  • a squalene synthetase inhibitor e.g. BMS-188494, TAK-475 (Lapaquistat acetate) or as described in WO2005077907, JP2007022943, WO2008003424.
  • the compound of formula I is administered in combination with ISIS-301012 (mipomersen), an antisense oligonucleotide capable of regulating the apolipoprotein B gene.
  • the compound of formula I is used in combination with a stimulator of the ApoA-1 gene, e.g. in WO2008092231 is administered.
  • the compound of formula I is used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMRI 171, HMRI 586, or those described in WO2005097738, WO2008020607.
  • an LDL receptor inducer see US 6,342,512
  • the compound of formula I is administered in combination with an HDL cholesterol increasing agent, e.g. those as described in WO2008040651, WO2008099278 administered.
  • an HDL cholesterol increasing agent e.g. those as described in WO2008040651, WO2008099278 administered.
  • the compound of the formula I is administered in combination with an ABCA1 expression enhancer, as described, for example, in WO2006072393, WO2008062830.
  • the compound of formula I is administered in combination with a lipoprotein-lipase modulator, such as ibrolipim (NO-1886).
  • the compound of formula I in combination with a lipoprotein (a) antagonist such as e.g. Gemcabene (CI-1027).
  • the compound of formula I is administered in combination with a lipase inhibitor, e.g. Orlistat or cetilistat (ATL-962).
  • a lipase inhibitor e.g. Orlistat or cetilistat (ATL-962).
  • the compound of the formula I is administered in combination with an adenosine A1 receptor agonist (adenosine Al R), as described e.g. in EP 1258247, EP1375508, WO2008028590, WO2008077050.
  • an adenosine A1 receptor agonist as described e.g. in EP 1258247, EP1375508, WO2008028590, WO2008077050.
  • the compound of formula I is used in combination with adenosine A2B receptor agonist (adenosine A2B R), e.g. ATL-801 administered.
  • adenosine A2B receptor agonist e.g. ATL-801 administered.
  • the compound of the formula I in combination with a modulator of the adenosine A2A and / or adenosine A3 receptors such. in WO2007111954, WO2007121918, WO2007121921, WO2007121923, WO2008070661.
  • the compound of the formula I is administered in combination with an agonist of the adenosine A1 / A2B receptors, such as e.g. in WO2008064788, WO2008064789, administered.
  • the compound of the formula I is administered in combination with an adenosine A2B receptor antagonist (adenosine A2B R), as described in US2007270433, WO2008027585, WO2008080461.
  • an adenosine A2B receptor antagonist as described in US2007270433, WO2008027585, WO2008080461.
  • the compound of the formula I in combination with inhibitors of acetyl-CoA carboxylase such as in WO 199946262, WO200372197, WO2003072197, WO2005044814, WO2005108370, JP2006131559, WO2007011809, WO2007011811, WO2007013691, WO2007095601-603, WO2007119833, WO2008065508, WO2008069500, WO2008070609, WO2008072850, WO2008079610, WO2008088688, WO2008088689, WO2008088692, US2008171761, WO2008090944, JP2008179621, US2008200461, WO2008102749 , WO2008103382, WO2008121592.
  • the compound of the formula I is used in combination with modulators of the microsomal acyl-CoA: glycerol-3-phosphate acyltransferase 3 (GP AT3, described in WO2007100789) or with modulators of the microsomal acyl-CoA: glycerol-3-phosphate - Acyltransferase 4 (GP AT4, described in WO2007100833) administered.
  • modulators of the microsomal acyl-CoA glycerol-3-phosphate acyltransferase 3
  • modulators of the microsomal acyl-CoA glycerol-3-phosphate - Acyltransferase 4
  • the compound of the formula I is administered in combination with modulators of xanthine oxidoreductase (XOR).
  • the compound of formula I is used in combination with soluble epoxide hydrolase (sEH) inhibitors, e.g. in WO2008051873, WO2008051875, WO2008073623, WO2008094869, WO2008112022.
  • SEH soluble epoxide hydrolase
  • the compound of the formula I is used in combination with CART modulators (see “cocaine-amphetamine-regulated transcript-influenced transient-energy metabolism, anxiety and gastric emptying in mice” Asakawa, A. et al .: Hormone and Metabolism Research (2001 ), 33 (9), 554-558);
  • NPY antagonists e.g. Naphthalene-l-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl ⁇ -amide hydrochloride (CGP 71683A) or Velneperite;
  • NPY-5 receptor antagonists such as L-152804 or the compound "NPY-5-BY” from Banyu or as described, for example, in WO2006001318, WO2007103295, WO2007125952, WO2008026563, WO2008026564, WO2008052769, WO2008092887, WO2008092888, WO2008092891; NPY-4 receptor antagonists as they are e.g. As described in WO2007038942;
  • NPY-2 receptor antagonists such as. As described in WO2007038943;
  • Peptide YY 3-36 PYY3-36 or analogous compounds such.
  • CJC-1682 PYY3-36 conjugated to human serum albumin via Cys34
  • CJC-1643 derivative of PYY3-36 conjugated to serum albumin in vivo
  • CBIR Cannabinoid Receptor 1 antagonists such as Rimonabant, Surinabant (SR147778), SLV-319 (Ibipinabant), AVE-1625, Taranabant (MK-0364) or salts thereof, Otenabant (CP-945,598), Rosonabant, V-24343 or such compounds as in z.
  • Cannabinoid Receptor 1 / Cannabinoid Receptor 2 (CB1 / CB2) modulating compounds e.g. delta-9-tetrahydrocannabivarin or those as described e.g. in WO2007001939, WO2007044215, WO2007047737, WO2007095513, WO2007096764, WO2007112399, WO2007112402, WO2008122618 are described;
  • FAAH fatty acid amide hydrolase
  • Inhibitors of fatty acid synthase e.g. in WO2008057585, WO2008059214, WO2008075064, WO2008075070, WO2008075077 are described;
  • Modulators, antagonists or inverse agonists of opioid receptors such as e.g. GSK-982 or such as e.g. WO2007047397, WO2008021849, WO2008021851, WO2008032156, WO2008059335;
  • Agonists of the prostaglandin receptor e.g. Bimatoprost or such compounds as described in WO2007111806;
  • MC4 receptor agonists (melanocortin-4 receptor agonists, MC4R agonists such as 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo) 2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chloro-phenyl) -2-oxo-ethyl] -amide; (WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141, MK-0493 or those as described in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793, W
  • Histamine H3 receptor antagonists / inverse agonists eg 3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) - propan-1-one oxalic acid salt (WO 00/63208) or those as described in WO200064884, WO2005082893, US2005171181 (eg PF-00389027), WO2006107661, WO2007003804, WO2007016496, WO2007020213, WO2007049798, WO2007055418, WO2007057329, WO2007065820, WO2007068620, WO2007068641, WO2007075629, WO2007080140, WO2007082840, WO2007088450, WO2007088462, WO2007094962, WO2007099423, WO2007100990, WO2007105053, WO2007106349,
  • Histamine Hl / histamine H3 modulators such as. B. Betahistine or its dihydrochloride;
  • Histamine H4 modulators as described, for example, in WO2007117399; CRF antagonists (eg [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-l, 3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585) or those CRF1 antagonists, as described in WO2007 / 0515, WO2007133756, WO2008036541, WO2008036579, WO2008083070);
  • CRF antagonists eg [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-l, 3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585) or those CRF1 antagonists, as described in WO2007 / 0515, WO2007133756, WO2008036541, WO2008036579, WO2008083070;
  • CRF BP antagonists e.g., urocortin
  • Modulators of the beta-3 adrenoceptor such as e.g. 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) -ethyl-amino] -ethanol hydrochloride (WO 01/83451) or solabegron (GW -427,353) or N-5984 (KRP-204) or those as described in JP2006111553, WO2002038543, WO2002038544, WO2007048840-843, WO2008015558, EP 1947103;
  • MSH melanocyte-stimulating hormone
  • MCH (melanin-concentrating hormone) receptor antagonists such as NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71 (AMG-071, AMG-076 ), GW-856464, NGD-4715, ATC-0453, ATC-0759, GW-803430 or such compounds as described in WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2004092181, WO2003033476, WO2002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279,
  • Serotonin reuptake inhibitors e.g., dexfenfluramines
  • mixed serotonin / dopamine reuptake inhibitors e.g., bupropion
  • mixed reuptake inhibitors such as e.g. DOV 21,947;
  • mixed sertonine and noradrenergic compounds e.g., WO 00/71549
  • 5-HT receptor agonists e.g. 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111);
  • mixed dopamine / norepinephrine / acetylcholine reuptake inhibitors e.g., tesofensins
  • those as described e.g. in WO2006085118 e.g., WO2006085118;
  • Norepinephrine reuptake inhibitors as described e.g. in US2008076724;
  • 5-HT2A receptor antagonists as described e.g. in WO2007138343 are described;
  • 5-HT2C receptor agonists such as Lorcaserin hydrochloride (APD-356) or BVT-933 or those as described in WO200077010, WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533, WO2005082859, WO2006004937, US2006025601, WO2006028961, WO2006077025, WO2006103511, WO2007028132, WO2007084622, US2007249709; WO2007132841, WO2007140213, WO2008007661, WO2008007664, WO2008009125, WO2008010073, WO2008108445 are described);
  • 5-HT6 receptor modulators e.g. E-6837, BVT-74316 or PRX-07034 or such as e.g. in WO2005058858, WO2007054257, WO2007107373, WO2007108569, WO2007108742-744, WO2008003703, WO2008027073, WO2008034815, WO2008054288, EP1947085, WO2008084491, WO2008084492, WO2008092665, WO2008092666, WO2008101247, WO2008110598, WO2008116831, WO2008116833;
  • estrogen receptor gamma e.g. in WO2007131005, WO2008052709;
  • estrogen receptor alpha (ERR ⁇ / ERR1 agonists), as described e.g. in WO2008109727 are described;
  • Muscarinic 3 receptor (M3R) antagonists as described e.g. in WO2007110782, WO2008041184 are described;
  • Bombesin receptor agonists (BRS-3 agonists), as described e.g. in WO2008051404, WO2008051405, WO2008051406, WO2008073311 are described;
  • Growth hormone e.g., human growth hormone or AOD-9604
  • human growth hormone e.g., human growth hormone or AOD-9604
  • Growth hormone releasing compounds (6-Benzyloxy-l- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)); Growth Hormone Secretagogue Receptor Antagonists (ghrelin antagonists) such as A-778193 or those as described in WO2005030734, WO2007127457, WO2008U08286;
  • ghrelin modulators e.g. JMV-2959, JMV-3002, JMV-2810, JMV-2951 or those as described in WO2006012577 (e.g., YIL-781 or YIL-870), WO2007079239, WO2008092681;
  • TRH agonists see, e.g., EP 0 462 884;
  • decoupling protein 2 or 3 modulators
  • Leptin agonists see, eg, Lee, Daniel W, Leinung, Matthew C, Rozhavskaya Arena, Marina, Grasso, Patricia, Leptin agonists as a Potential Approach to the Treatment of Obesity, Drugs of the Future (2001), 26 (9), 873-881);
  • DA agonists bromocriptine, doprexin
  • Lipase / amylase inhibitors e.g., WO 00/40569, WO2008107184
  • Inhibitors of diacylglycerol O-acyltransferases such.
  • Inhibitors of fatty acid synthase e.g. C75 or those as described in WO2004005277, WO2008006113;
  • Inhibitors of stearoyl-CoA delta9 desaturase as described e.g. in WO2007009236, WO2007044085, WO2007046867, WO2007046868, WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457, WO2007136746, WO2007143597, WO2007143823, WO2007143824, WO2008003753, WO2008017161, WO2008024390, WO2008029266, WO2008036715, WO2008043087, WO2008044767, WO2008046226, WO2008056687, WO2008062276, WO2008064474, WO2008074824 , WO2008074832, WO2008074833, WO2008074834, WO2008074835, WO2008089580, WO2008096746, WO2008104524, WO2008
  • hypoglycemic / hypertriglyceridemic indoline compounds as described in WO2008039087;
  • Activators of adiponectin secretion e.g. in WO2006082978, WO2008105533;
  • Promoters of adiponectin production e.g. in WO2007125946, WO2008038712 described; modified adiponectins such as e.g. described in WO2008121009;
  • KB-2115 Eprotirome
  • QRX-431 Sobetirome
  • DITPA DITPA
  • WO20058279 WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419, WO2007009913, WO2007039125, WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864, WO2008001959, WO2008106213;
  • TR-beta thyroid hormone receptor beta
  • the compound of the formula I is administered in combination with a combination of Ezetimibe Eprotiromes.
  • the compound of formula I is used in combination with an inhibitor of Site-1 protease (SlP), e.g. PF-429242 administered.
  • SlP Site-1 protease
  • the compound of the formula I is used in combination with a modulator of the "Trace Amine-Associated-Receptor-1" (TAAR1), as described e.g. in US2008146523, WO2008092785.
  • TAAR1 Race Amine-Associated-Receptor-1
  • the compound of formula I is used in combination with an inhibitor of growth factor receptor Bound protein-2 (GRB2), e.g. in WO2008067270, administered.
  • GRB2 growth factor receptor Bound protein-2
  • the compound of the formula I is administered in combination with an RNAi (siRNA) therapeutic which is directed against PCSK9 (proprotein convertase subtilisin / kexin type 9).
  • RNAi siRNA
  • PCSK9 proprotein convertase subtilisin / kexin type 9
  • the compound of the formula I is administered in combination with Omacor® or Levavaza TM (omega-3 fatty acid esters, highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).
  • the compound of the formula I is administered in combination with lycopene.
  • the compound of formula I is used in combination with an antioxidant, e.g. OPC-14117, AGI-1067 (succinobucol), probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
  • an antioxidant e.g. OPC-14117, AGI-1067 (succinobucol), probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
  • the compound of the formula I in combination with a vitamin, such as. As vitamin B6 or vitamin B12 administered.
  • the compound of formula I is used in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin (PrandiMet (TM)), insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • a sulfonylurea and metformin e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin (PrandiMet (TM)), insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • TM repaglinide and metformin
  • the compound of formula I is used in combination with an inhibitor of carbonic anhydrase type 2, such as carbonic anhydrase type 2, e.g. such as described in WO2007065948 administered.
  • an inhibitor of carbonic anhydrase type 2 such as carbonic anhydrase type 2, e.g. such as described in WO2007065948 administered.
  • the compound of the formula I is administered in combination with topiramate or a derivative thereof, as described in WO2008027557.
  • the compound of the formula I is administered in combination with a solid combination of topiramate with phentermine (Qnexa TM).
  • the compound of formula I is administered in combination with an antisense compound, eg ISIS-377131, which inhibits the production of the glucocorticoid receptor.
  • the compound of the formula I is administered in combination with an aldosterone synthase inhibitor and an antagonist of the glucocorticoid receptor, a cortisol synthesis inhibitor and / or an antagonist of the corticotropin releasing factor, such as corticotropin releasing factor. described in EP 1886695, WO2008119744.
  • the compound of formula I in combination with an agonist of the RUP3 receptor, such.
  • an agonist of the RUP3 receptor such as described in WO2007035355, WO2008005576.
  • the compound of the formula I in combination with an activator of the gene coding for the Ataxia Telangiectasia mutated (ATM) protein kinase such as. As chloroquine administered.
  • ATM Ataxia Telangiectasia mutated
  • the compound of formula I in combination with a tau protein kinase 1 inhibitor (TPKl inhibitor), such as. As described in WO2007119463 administered.
  • TPKl inhibitor tau protein kinase 1 inhibitor
  • the compound of the formula I is administered in combination with a "c-Jun N-terminal kinase” inhibitor (JNK inhibitor), as described, for example, in WO2007125405, WO2008028860, WO2008118626.
  • JNK inhibitor c-Jun N-terminal kinase inhibitor
  • the compound of the formula I in combination with an endothelin A receptor antagonists such.
  • the compound of formula I is used in combination with modulators of the glucocorticoid receptor (GR), such as KB-3305 or such compounds as described, for example, in US Pat. B. in WO2005090336, WO2006071609, WO2006135826, WO2007105766, WO2008120661.
  • GR glucocorticoid receptor
  • the other active ingredient is varenicline tartrate, a partial agonist of the alpha 4-beta 2 nicotinic acetylcholine receptor.
  • the other active ingredient is trodusquemine.
  • the further active ingredient is a modulator of the enzyme SIRT1 and / or SIRT3 (an NAD + -dependent protein deacetylase); this active substance may be, for example, resveratrol in suitable formulations, or such compounds as mentioned in WO2007019416 (eg SRT-1720), WO2008073451.
  • the further active ingredient is DM-71 (N-acetyl-L-cysteine with bethanechol).
  • the compound of formula I is used in combination with anti-hypercholesterolemic compounds, such as those described e.g. in WO2007107587, WO2007111994, WO2008106600, WO2008113796.
  • the compound of the formula I is used in combination with inhibitors of the SREBP (sterol regulatory element-binding protein), as described, for example, in US Pat. in WO2008097835.
  • SREBP sterol regulatory element-binding protein
  • the compound of formula I is used in combination with a cyclic peptide agonist of the VPAC2 receptor, as described e.g. in WO2007101146, WO2007133828.
  • the compound of the formula I is administered in combination with an agonist of the endothelin receptor, as described, for example, in WO2007112069.
  • the compound of the formula I is administered in combination with AKP-Ü20 (bis (ethylmaltolato) oxovanadium-IV).
  • the compound of formula I is administered in combination with tissue-selective androgen receptor modulators (SARM) as described, for example, in WO2007099200, WO2007137874.
  • SARM tissue-selective androgen receptor modulators
  • the compound of formula I is used in combination with an AGE (advanced glycation endproduct) inhibitor, e.g. in JP2008024673.
  • an AGE advanced glycation endproduct
  • the further active ingredient is leptin; see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi,
  • the further active ingredient is metreleptin (recombinant methionyl-leptin) combined with pramlintide.
  • the further active ingredient is the tetrapeptide ISF-402.
  • the other active ingredient is dexamphetamine or amphetamine.
  • the other active ingredient is fenfluramine or dexfenfluramine.
  • the other active ingredient is sibutramine or such derivatives as described in WO2008034142.
  • the other active ingredient is mazindol or phentermine.
  • the further active ingredient is geniposidic acid (geniposidic acid, WO2007100104) or derivatives thereof (JP2008106008).
  • the further active ingredient is a nasally administered calcium channel blocker such as diltiazem or those described in US 7,138,107.
  • the further active ingredient is an inhibitor of sodium-calcium ion exchange, e.g. those as described in WO2008028958, WO2008085711.
  • the further active ingredient is a blocker of calcium channels, e.g. of the CaV3.2 or CaV2.2 as described in WO2008033431, WO2008033447, WO2008033356, WO2008033460, WO2008033464, WO2008033465, WO2008033468, WO2008073461.
  • the further active ingredient is a modulator of a calcium channel, e.g. those as described in WO2008073934, WO2008073936.
  • the further active ingredient is a blocker of the "T-type calcium channel" as described, for example, in WO2008033431, WO2008110008.
  • the further active ingredient is an inhibitor of KCNQ potassium channel-2 or -3, e.g. those as described in US2008027049, US2008027090.
  • the further active ingredient is an inhibitor of the potassium KvI.3 ion channel, e.g. those as described in WO2008040057, WO2008040058, WO2008046065.
  • the further active ingredient is a modulator of the MCP-1 receptor (monocyte chemoattractant protein-1 (MCP-I)), e.g. those as described in WO2008014360, WO2008014381.
  • MCP-1 receptor monocyte chemoattractant protein-1 (MCP-I)
  • the further active ingredient is a modulator of somatostatin receptor 5 (SSTR5) such as those described in WO2008019967, US2008064697, US2008249101, WO2008000692.
  • the further active ingredient is a modulator of somatostatin receptor 2 (SSTR2) such as those described in WO2008051272.
  • the further active ingredient is an erythropoietin-mimetic peptide which acts as an erythropoietin (EPO) receptor agonist.
  • EPO erythropoietin
  • the further active ingredient is an anorectic / hypoglycemic compound, e.g. those as described in WO2008035305, WO2008035306, WO2008035686.
  • the further active ingredient is an inducer of lipoic acid synthetase, e.g. those as described in WO2008036966, WO2008036967.
  • the further active ingredient is a stimulator of endothelial nitric oxide synthase (eNOS), e.g. those as described in WO2008058641, WO2008074413.
  • eNOS endothelial nitric oxide synthase
  • the further active ingredient is a modulator of carbohydrate and / or lipid metabolism, e.g. those as described in WO2008059023, WO2008059024, WO2008059025, WO2008059026.
  • the further active ingredient is an angiotensin II receptor antagonist, such as e.g. those as described in WO2008062905, WO2008067378, WO2008062905.
  • the further active ingredient is an agonist of the sphingosine-1 phosphate receptor (SLP), such as e.g. those as described in WO2008064315, WO2008074820. WO2008074821 are described.
  • SLP sphingosine-1 phosphate receptor
  • the further active ingredient is an agent which retards gastric emptying, for example 4-hydroxyisoleucine (WO2008044770).
  • the further active ingredient is a muscle-relaxing substance as described, for example, in WO2008090200.
  • the further active ingredient is an inhibitor of monoamine oxidase B (MAO-B), e.g. those as described in WO2008092091.
  • MAO-B monoamine oxidase B
  • the further active ingredient is an inhibitor of the binding of cholesterol and / or triglycerides to the SCP-2 protein (sterol carrier protein-2), e.g. those as described in US2008194658.
  • the other active ingredient is lisofylline, which prevents autoimmune damage to insulin-producing cells.
  • the compound of formula I in combination with bulking agents preferably insoluble bulking agents
  • bulking agents preferably insoluble bulking agents
  • Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)) administered.
  • Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®.
  • Caromax ® can also be administered in the form of food, such as in baked goods or muesli bars.
  • the invention furthermore relates to a process for the preparation of the compounds of general formula I, characterized in that the compounds of formula I are so obtained that the procedure is analogous to the following reaction schemes.
  • This reaction can be carried out, for example with isocyanate in toluene or with diphosgene or triphosgene
  • the isocyanate B is then reacted with the methyl ester or another ester (eg tert-butyl) of the amino acid J, in which R and R 'have the meanings given in formula I, or a salt of an ester of the amino acid / with the addition of base (for example triethylamine) to give a urea of the formula K.
  • This urea can be converted into imidazolidine-2,4-dione of the formula under basic or acidic conditions, preferably acidic conditions
  • the further conversion into a compound of the formula H which represents the ortho-substituted special case of a compound of the formula I can be carried out, for example, by adding a suitable substituent Compounds Q, wherein Z may be one or more substituents as described above in formula I, and Y is either a protected hydroxyl OR, where R z.
  • Acetyl, tert.butyl, benzyl or p -methoxybenzyl, or Y is a halogen radical such as chloro or bromo
  • V is either a halogen atom, preferably a chloro or bromo, or for example an O-SO 2 -C 6 H 4 -4 -CH 3 radical or a 0-SO 2 - CH 3 -ReSt or a 0-SO 2 -CF 3 radical, to give the compound M is alkylated.
  • M can be copper-catalyzed under Ullmann conditions (eg R. Frian, D.
  • Kikelj Synthesis 2006, 2271-2285
  • aryl or heteroaryl halides preferably bromides
  • W in R 19-W of the formula O has, for example, the meaning -Br .
  • this reaction may be carried out in such a way that the radical Y in the compound Q is a halogen atom (eg bromine or chlorine).
  • This compound of formula M can then be reacted in a next step with a compound of formula Rl 9-W, wherein W is -OH, under the above-described copper-catalyzed conditions to give a compound of formula H.
  • the palladium-catalyzed diaryl ether coupling reaction can also be used (for example: A. Aranyos et al .: J. Am. Chem. Soc. 121 (1999) 4369-4378).
  • a further variant is the intermolecular nucleophilic substitution (see, for example: F. Li et al .: Synthesis 2005, 1305, M. Chaouchi et al .: Eur. J. Org. Chem. 2002, 1278; S.-L. Cui et al .: Synlett 2004, 1829).
  • a further variant is the cross-coupling of phenols with aryl or heteroaryl boronic acids or trifluoroborates into consideration (see, for example: DMT Chan et al .: Tetrahedron Lett. 39 (1998) 2933, DMT Chan et al .: Tetrahedron Lett ) 3863; TD Quach et al .: Org. Lett. 5 (2003) 1381).
  • This reaction can be conducted so that either a compound of formula M wherein Y 'is OH, with a compound of formula O, wherein W is -B (OH) 2 or -BF 3 " K + , to a compound of formula H wherein Y "is oxygen.
  • a compound of the formula M in which Y 'is -B (OH) 2 or BF 3 " K + is reacted with a compound of the formula O in which W is hydroxy.
  • the formula H shown here represents a special case of the formula I in which the radical Y "- R 19 in formula I is in the ortho position, this radical may also be located in the meta or para position.
  • Y is either a protected hydroxyl radical OR, wherein R z.
  • Acetyl, tert-butyl, benzyl or p-methoxybenzyl, or Y represents a halogen radical such as chlorine or bromine, with the addition of a base (eg., Triethylamine) converted to a urea of the formula F.
  • the amino acid ester derivative C may be prepared from the compound D, wherein Z may be one or more substituents as described above in formula I, and wherein Y is either protected Hydroxyl radical OR, where R z. Acetyl, tert.butyl, benzyl or p -methoxybenzyl, or Y is a halogen radical such as chloro or bromo, and X is a (CH 2 ) P -U moiety, where U is Cl, Br, J, O-SO 2 -C 6 H 4 ⁇ -CH 3 , 0-SO 2 -CH 3 or 0-SO 2 -CF 3 may have, with an amino acid ester of the formula E, wherein R and R 'in the formula I.
  • the urea F may be ring-closed under basic or acidic conditions, preferably acidic conditions, to the imidazolidine-2,4-dione of the formula G.
  • acetyl, tert.Butyl, benzyl or p-methoxybenzyl, in the compounds of formula G can be converted with standard reactions in an -OH function, depending on whether Y in the compound of formula G is -OH or halogen (eg Cl or Br), compounds of formula H can be prepared by reaction with compounds of formula O wherein W is either boronic acid (boronic acid ester) or -OH.
  • W is either boronic acid (boronic acid ester) or -OH.
  • Any existing protecting groups of compound H can be removed at the end of the reaction sequence.
  • the formula H shown here represents a special case of the formula I in which the radical Y "- R 19 in formula I is in the ortho position, this radical may also be located in the meta or para position.
  • the urea K ' may be ring-closed under basic or acidic conditions, preferably acidic conditions, to the imidazolidine-2,4-dione of the formula L'.
  • the compounds M ' are obtained by reacting the compounds L' with the compounds Q under alkylating conditions.
  • Z, V and Y of the compounds Q have the meanings as mentioned in process "A.”
  • the p-methoxybenzyl group in the compounds M ' can be removed by oxidation to give the compounds T.
  • Rl 9 is in the ortho position in formula I; this remainder may also be located in the meta or para position.
  • HPLC-MS measurements were carried out on a Waters LCT device.
  • Trifluoroacetic acid (water + 0.05% trifluoroacetic acid) 5:95 (0 minutes) to 95: 5 (3.4
  • the compound 1.1 can be represented by method "B”. To this was added 3.21 g (76.7 mmol) of lithium hydroxide hydrate in 125 ml of dry dimethylformamide, mixed with 20 g of 4 ⁇ molecular sieve and stirred for 30 minutes at room temperature. Thereafter, 7.5 g (38.3 mmol) of tert-butyl 2-amino-2-methylpropionate hydrochloride were added and stirred for 15 minutes at room temperature before dissolving 11.09 g (42.16 mmol) of the bromide 1.2 in 25 ml of dry dimethylformamide were added dropwise at room temperature. Of the Reaction mixture was stirred for 20 h at room temperature.
  • the compound 75.1 can be represented by method "A".
  • A For this purpose, 3.2 ml phosgene solution (20% in toluene) were placed under argon. Then, at 75 ° C., 3-amino-2-chloro-6-trifluoromethyl-pyridine (0.62 g) dissolved in 10 ml of dry acetonitrile was slowly added dropwise and then stirred at 75 ° C. for a further 90 minutes. The mixture was concentrated in vacuo, the residue was treated with toluene and concentrated again in vacuo. The solid residue was dissolved in 10 ml of tetrahydrofuran and treated with 0.46 g of methyl 2-amino-2-methylpropionate hydrochloride.
  • Example 77 Reaction of 77.1 with compound 1.2;
  • Example 78 Reaction of 78.1 with 3- (4-fluorophenoxy) benzyl bromide (76.2);
  • Example 79 Reaction of 78.1 with 3- (2-fluorophenoxy) benzyl bromide (79.2);
  • Example 83 Reaction of 83.1 with compound 1.2;
  • Example 84 4- [2,5-Dioxo-3- (2-phenoxybenzyl) -4-phenyl-imidazolidin-1-yl] -2-trifluoromethyl-benzonitrile
  • Example 95 The compound of Example 95 was obtained by reacting 84.1 with 2-bromomethyl-1-chloro-3-phenoxybenzene analogously to the procedure for the preparation of 84.
  • Example 97 4- ⁇ 2- [3- (4-Cyano-3-trifluoromethyl-phenyl) -5,5-dimethyl-2,4-dioxo-imidazolidin-1-ylmethyl-phenoxy ⁇ -benzoic acid
  • Example 98 4- ⁇ 2- [3- (4-Cyano-3-trifluoromethyl-phenyl) -5,5-dimethyl-2,4-dioxo-imidazolidin-1-ylmethyl] -phenoxy ⁇ -benzamide
  • Example 105 4- ⁇ 3- [2- (4-Chloro-phenylsulfanyl) -benzyl] -4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl ⁇ -2-trifluoromethylbenzonitrile
  • Example 106 4- ⁇ 3- [2- (4-Chlorobenzenesulfonyl) benzyl] -4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl ⁇ -2-trifluoromethylbenzonitrile and
  • Example 107 4- ⁇ 3 - [2- (4-chloro-benzenesulfinyl) -benzyl] -4,4-dimethyl-2,5-dioxo-imidazolidine
  • Example 105 150 mg of the compound of Example 105 were dissolved in a mixture of 10 ml of methanol and 2 ml of water, treated with 2 equivalents of potassium peroxodisulfate and stirred for 4 h at room temperature.
  • the methanol was removed in vacuo, the residue was combined with water and dichloromethane, the organic phase separated and dried over magnesium sulfate. After filtration, the separated organic phase, concentrated in vacuo and the residue was purified by chromatography (method [RPl]).
  • ligand-induced changes in the intracellular concentration of Ca 2+ in recombinant HEK293 cells were determined, which expressed both a cannabinoid receptor (CBl or CB2) and G-protein galphal ⁇ .
  • CBl or CB2 cannabinoid receptor
  • G-protein galphal ⁇ a cannabinoid receptor
  • cells were seeded in 96-well microtiter plates (60,000 cells / well) and grown overnight. The medium was removed and the cells incubated in buffer containing the fluorescent dye fluo-4. After this loading with dye, the cells were washed, test substance dissolved in buffer was added, incubated for 20 minutes, a known cannabinoid receptor agonist was added as the reference agonist in buffer, and finally the changes in intracellular Ca 2+ concentration in the FLIPR device were measured.
  • Results were expressed as percentage change relative to control (0%: analog experiment without test blank and no reference agonist, ie buffer only, 100% analog experiment without test substance but with reference agonist in excess), used for calculation of dose / effect curves and IC 50 - values determined. Results:
  • Table 3 gives the values of the functional assay against the cannabinoid 1 receptor including exemplary selectivities to the cannabinoid 2 receptor.
  • Test compounds The compounds (3 ⁇ l, 10 mM, 100% DMSO), pipetted into 96-well PP microtiter plates, were diluted with 27 ⁇ l of 100% DMSO (dimethyl sulfoxide). Starting from this solution, a further 3-fold dilution steps were carried out by transferring 10 ⁇ l in each case to a new PP microtiter plate and adding another 20 ⁇ l of 100% DMSO. In each case 6 ⁇ l of these solutions were transferred to new 96-well PP microtiter plates and filled up with 144 ⁇ l assay buffer. The final concentrations ranged from 10 ⁇ M to 0.005 ⁇ M.
  • Negative control AM 251, dissolved in assay buffer containing 1% DMSO, was added to the serial dilutions in the microtiter plates as a control. The final concentration was 1 ⁇ M.
  • the values listed were obtained as average values of a duplicate determination.
  • the IC 50 values were calculated from the measured values with the program Xlfit, formula 205. Ki values were obtained from the IC 50 and Kd values using the Cheng-Prusoff equation:
  • the compounds of the formula I according to the invention act as CBIR antagonists and are therefore suitable for the treatment of metabolic syndrome, type II diabetes and obesity.
  • the test is used to study the anorexigenic potency of the test substances.
  • Female NMRI mice weighing 25-35 g are used. The mice are accustomed to the keeping conditions for at least one week and to the offered condensed milk for 2 days.
  • mice are fasted for 24 hours but have constant access to water.
  • the test is used to measure the potency of cannabinoid CBI receptor (CB I) antagonists. It is measured to what extent the CBl antagonists to be tested are able to prevent or antagonize the CBL agonist-induced hypothermia.
  • CB I cannabinoid CBI receptor
  • mice Female NMRI mice weighing 25-35 g are used. The mice are accustomed to the housing conditions for at least one week.
  • mice are treated orally, intravenously or intraperitoneally with the CBl antagonist to be tested. 30 min. later the mice become the CBl agonist
  • Body temperature at 5-6 ° C within 30 min. The body temperature will be the first time
  • the potency of the test substances is expressed as the percentage reduction of the area under the test
  • Temperature-time curve which is formed on the one hand by the average basal body temperature, on the other hand by the temperature-time curve, which is exclusively treated with the CBl antagonist animals.
  • mice Female NMRI mice weighing 25-35 g are used. The mice are accustomed to the housing conditions for at least one week.
  • mice are fasted for 24 hours but have constant access to water.
  • test substances are administered orally, intravenously, subcutaneously but not intraperitoneally.
  • test substance is 30-120 min. administered before the specific effector. 30 min. After this application, a defined Amount of a colored, non-caloric filler introduced by gavage into the stomach. After another 30 min, the colored filler has filled to about 80% of the small intestine at this point in time, the animals are sacrificed and the small intestine is prepared. The intestinal motility is expressed as the passage of the colored filler in comparison to the total length of the small intestine in percent. A treatment effect is also given as the difference of this passage to the vehicle control also in percent.

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Abstract

L'invention concerne des composés de formule (I) dans laquelle les groupes R et R' A, D, E, G, L, p et R1 à R10 ont les significations indiquées, ainsi que leurs sels physiologiquement acceptables. Ces composés servent par ex. d'agents anti-adipeux.
EP09708570A 2008-02-07 2009-01-30 Imidazolidine-2,4-diones substitués par un arylchalcogeno-arylalkyle, procédé de production, médicaments contenant ces composés et leur utilisation Withdrawn EP2252592A1 (fr)

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EP09708570A EP2252592A1 (fr) 2008-02-07 2009-01-30 Imidazolidine-2,4-diones substitués par un arylchalcogeno-arylalkyle, procédé de production, médicaments contenant ces composés et leur utilisation

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AR070523A1 (es) 2010-04-14
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WO2009097998A1 (fr) 2009-08-13
CL2009000261A1 (es) 2009-06-26
UY31643A1 (es) 2009-08-31

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