US20090149519A1 - Phenylamino-benzoxazole substituted carboxylic acids, method for their production and use thereof as medicaments - Google Patents

Phenylamino-benzoxazole substituted carboxylic acids, method for their production and use thereof as medicaments Download PDF

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Publication number
US20090149519A1
US20090149519A1 US12/267,896 US26789608A US2009149519A1 US 20090149519 A1 US20090149519 A1 US 20090149519A1 US 26789608 A US26789608 A US 26789608A US 2009149519 A1 US2009149519 A1 US 2009149519A1
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United States
Prior art keywords
inhibitors
agonists
alkyl
modulators
physiologically tolerated
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Inventor
Elisabeth Defossa
Markus Follmann
Thomas Klabunde
Viktoria Dietrich
Gerhard Hessler
Siegfried Stengelin
Guido Haschke
Andreas Herling
Stefan Bartoschek
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Sanofi SA
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Sanofi Aventis France
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Assigned to SANOFI-AVENTIS reassignment SANOFI-AVENTIS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DIETRICH, VIKTORIA, HASCHKE, GUIDO, HERLING, ANDREAS, BARTOSCHEK, STEFAN, DEFOSSA, ELISABETH, HESSLER, GERHARD, KLABUNDE, THOMAS, STENGELIN, SIEGFRIED, FOLLMANN, MARKUS
Publication of US20090149519A1 publication Critical patent/US20090149519A1/en
Assigned to SANOFI reassignment SANOFI CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: SANOFI-AVENTIS
Priority to US13/938,627 priority Critical patent/US8748465B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to phenylaminobenzoxazole-substituted carboxylic acids and their physiologically tolerated salts.
  • the invention was based on the object of providing compounds which display a therapeutically utilizable effect.
  • the object was in particular to find novel compounds suitable for the treatment of hyperglycemia and diabetes.
  • the invention therefore relates to compounds of the formula I,
  • radicals or substituents may occur more than once in the compounds of the formulae I, they may all independently of one another have the stated meaning and be identical or different.
  • alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals in the radicals X, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 may be either straight-chain or branched.
  • the invention relates to compounds of the formula I in the form of their salts, racemates, racemic mixtures and pure enantiomers, and diastereomers and mixtures thereof.
  • Physiologically tolerated salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have a physiologically tolerated anion or cation.
  • Suitable physiologically tolerated acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, and organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids.
  • the chlorine salt is particularly preferably used for medical purposes.
  • Suitable physiologically tolerated basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), zinc salts, and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine, arginine, choline, meglumine or ethylenediamine salts.
  • Salts with a physiologically untolerated anion or cation likewise belong within the framework of the invention as useful intermediates for preparing or purifying physiologically tolerated salts and/or for use in nontherapeutic, for example in vitro applications.
  • a further aspect of this invention are prodrugs of the compounds of the invention.
  • Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.
  • the compounds of the invention may also exist in various polymorphous forms, e.g. as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according to the invention belong within the framework of the invention and are a further aspect of the invention.
  • the compounds of the formula (I) and the physiologically tolerated salts thereof represent ideal pharmaceuticals for the treatment of elevated lipid concentrations in the blood, the metabolic syndrome, diabetes, insulin resistance, dysregulation of LDL, HLD and VLDL or cardiovascular disorders and lipid metabolism disorders, especially hyperlipidemia.
  • the compound(s) of the formula (I) can also be administered in combination with further active ingredients.
  • the amount of a compound of formula (I) necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient.
  • the daily dose is generally in the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day and per kilogram of body weight, for example 0.1-10 mg/kg/day. Tablets or capsules may contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg.
  • the compounds of formula (I) may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health.
  • 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.
  • Other pharmaceutically active substances may likewise be present, including other compounds of formula (I).
  • the pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
  • compositions of the invention are those suitable for oral and peroral (for example sublingual) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula (I) used in each case.
  • Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contains a defined amount of the compound of formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact.
  • the compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary.
  • a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients.
  • Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one (or more) surface-active/dispersing agent(s) in a suitable machine.
  • Molded tablets can be produced by molding the compound, which is in powder form and is moistened with an inert liquid diluent, in a suitable machine.
  • compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula (I) with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • the compounds of the invention can be administered alone or in combination with one or more further pharmacologically active substances which have, for example, beneficial effects on metabolic disturbances or disorders frequently associated therewith.
  • further pharmacologically active substances which have, for example, beneficial effects on metabolic disturbances or disorders frequently associated therewith. Examples of such medicaments are
  • Administration of the active ingredient combination can take place either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.
  • active ingredients suitable for combination products are in particular: All antidiabetics which are mentioned in the Rote Liste 2006, chapter 12; all weight-reducing agents/appetite suppressants which are mentioned in the Rote Liste 2006, chapter 1; all lipid-lowering agents which are mentioned in the Rote Liste 2006, chapter 58. They may be combined with the compound of the invention of the formula I in particular for a synergistic improvement in the effect.
  • the active ingredient combination can be administered either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients is present in a pharmaceutical preparation. Most of the active ingredients mentioned hereinafter are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
  • Antidiabetics include insulin and insulin derivatives such as, for example, Lantus® (see www.lantus.com) or HMR 1964 or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see U.S. Pat. No.
  • inhalable insulins such as, for example, Exubera® or oral insulins such as, for example, IN-105 (Nobex) or Oral-lynTM (Generex Biotechnology), GLP-1 derivatives such as, for example, exenatide, liraglutide or those which have been disclosed in WO98/08871 or WO2005027978 of Novo Nordisk A/S, in WO01/04156 of Zealand or in WO00/34331 of Beaufour-Ipsen, pramlintide acetate (Symlin; Amylin Pharmaceuticals), and orally effective hypoglycemic active ingredients.
  • inhalable insulins such as, for example, Exubera® or oral insulins such as, for example, IN-105 (Nobex) or Oral-lynTM (Generex Biotechnology)
  • GLP-1 derivatives such as, for example, exenatide, liraglutide or those which have been disclosed in WO98/08871 or WO2005027978 of Nov
  • the orally effective hypoglycemic active ingredients include preferably sulfonylureas,
  • biguanidines meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, inhibitors of glycogen phosphorylase, glucagon antagonists, glucokinase activators, inhibitors of fructose-1,6-bisphosphatase, modulators of glucose transporter 4 (GLUT4), inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), GLP-1 agonists, potassium channel openers such as, for example, those which have been disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, inhibitors of dipeptidylpeptidase IV (DPP-IV), insulin sensitizers, inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, of glucose transport and of glucose reabsorption, inhibitors of 11 ⁇ -HSD1, inhibitors of protein tyrosine
  • the compound of the formula I is administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin or L-659699.
  • an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin or L-659699.
  • the compound of the formula I is administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692), MD-0727 (Microbia Inc., WO2005021497) or with compounds as described in WO2002066464 (Kotobuki Pharmaceutical Co. Ltd.), WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZeneca AB).
  • a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692), MD-0727 (Microbia Inc., WO2005021497) or with compounds as described in WO2002066464 (Kotobu
  • the compound of the formula I is administered in combination with a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, G1 262570, R-483 or CS-011 (rivoglitazone).
  • a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, G1 262570, R-483 or CS-011 (rivoglitazone).
  • the compound of the formula I is administered in combination with a PPAR alpha agonist such as, for example, GW9578, GW-590735, K-111, LY-674, KRP-101 or DRF-10945.
  • a PPAR alpha agonist such as, for example, GW9578, GW-590735, K-111, LY-674, KRP-101 or DRF-10945.
  • the compound of the formula I is administered in combination with a mixed PPAR alpha/gamma agonist such as, for example, muraglitazar, tesaglitazar, naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, or as described in PCT/US 00/11833, PCT/US 00/11490, DE10142734.4 or in J. P. Berger et al., TRENDS in Pharmacological Sciences 28(5), 244-251, 2005.
  • a mixed PPAR alpha/gamma agonist such as, for example, muraglitazar, tesaglitazar, naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, or as described in PCT/US 00/11833, PCT/US 00/11490, DE10142734.4 or in J. P. Berger e
  • the compound of the formula I is administered in combination with a PPAR delta agonist such as, for example, GW-501516.
  • the compound of the formula I is administered in combination with metaglidasen or with MBX-2044 or other partial PPAR gamma agonists/antagonists.
  • the compound of the formula I is administered in combination with a fibrate such as, for example, fenofibrate, clofibrate or bezafibrate.
  • the compound of the formula I is administered in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757 or those described in WO2005085226.
  • an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757 or those described in WO2005085226.
  • the compound of the formula I is administered in combination with a CETP inhibitor such as, for example, torcetrapib or JTT-705.
  • the compound of the formula I is administered in combination with a bile acid absorption inhibitor (see, for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 or WO00/61568), such as, for example, HMR 1741 or those as described in DE 10 2005 033099.1 and DE 10 2005 033100.9.
  • a bile acid absorption inhibitor see, for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 or WO00/61568
  • HMR 1741 such as, for example, HMR 1741 or those as described in DE 10 2005 033099.1 and DE 10 2005 033100.9.
  • the compound of the formula I is administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine or colesevelam.
  • a polymeric bile acid adsorbent such as, for example, cholestyramine or colesevelam.
  • the compound of the formula I is administered in combination with an LDL receptor inducer (see U.S. Pat. No. 6,342,512), such as, for example, HMR1171, HMR1586 or those as described in WO2005097738.
  • an LDL receptor inducer see U.S. Pat. No. 6,342,512
  • the compound of the formula I is administered in combination with Omacor® (omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and of docosahexaenoic acid).
  • Omacor® omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and of docosahexaenoic acid.
  • the compound of the formula I is administered in combination with an ACAT inhibitor such as, for example, avasimibe.
  • the compound of the formula I is administered in combination with an antioxidant such as, for example, OPC-14117, probucol, tocopherol, ascorbic acid, ⁇ -carotene or selenium.
  • an antioxidant such as, for example, OPC-14117, probucol, tocopherol, ascorbic acid, ⁇ -carotene or selenium.
  • the compound of the formula I is administered in combination with a vitamin such as, for example, vitamin B6 or vitamin B12.
  • the compound of the formula I is administered in combination with a lipoprotein lipase modulator such as, for example, ibrolipim (NO-1886).
  • a lipoprotein lipase modulator such as, for example, ibrolipim (NO-1886).
  • the compound of the formula I is administered in combination with an ATP citrate lyase inhibitor such as, for example, SB-204990.
  • the compound of the formula I is administered in combination with a squalene synthetase inhibitor such as, for example, BMS-188494 or as described in WO2005077907.
  • a squalene synthetase inhibitor such as, for example, BMS-188494 or as described in WO2005077907.
  • the compound of the formula I is administered in combination with a lipoprotein (a) antagonist such as, for example, gemcabene (CI1027).
  • a lipoprotein (a) antagonist such as, for example, gemcabene (CI1027).
  • the compound of the formula I is administered in combination with an HM74A receptor agonist such as, for example, nicotinic acid.
  • the compound of the formula I is administered in combination with a lipase inhibitor such as, for example, orlistat or cetilistat (ATL-962).
  • a lipase inhibitor such as, for example, orlistat or cetilistat (ATL-962).
  • the compound of the formula I is administered in combination with insulin.
  • the compound of the formula I is administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.
  • a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.
  • the compound of the formula I is administered in combination with a biguanide such as, for example, metformin.
  • a biguanide such as, for example, metformin.
  • the compound of the formula I is administered in combination with a meglitinide such as, for example, repaglinide or nateglinide.
  • a meglitinide such as, for example, repaglinide or nateglinide.
  • the compound of the formula I is administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
  • a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione
  • the compound of the formula I is administered in combination with an ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose.
  • 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, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • the compound of the formula I is administered 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, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • the compound of the formula I is administered in combination with an inhibitor of glycogen phosphorylase, such as, for example, PSN-357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31 or WO2005067932.
  • an inhibitor of glycogen phosphorylase such as, for example, PSN-357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31 or WO2005067932.
  • the compound of the formula I is administered in combination with glucagon receptor antagonists such as, for example, A-770077, NNC-25-2504 or as described in WO2004100875 or WO2005065680.
  • glucagon receptor antagonists such as, for example, A-770077, NNC-25-2504 or as described in WO2004100875 or WO2005065680.
  • the compound of the formula I is administered in combination with activators of glucokinase, such as, for example, RO-4389620, LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those as are described for example by Prosidion in WO2004072031, WO2004072066, WO 05103021 or WO 06016178, by Roche in WO 00058293, WO 00183465, WO 00183478, WO 00185706, WO 00185707, WO 01044216, GB 02385328, WO 02008209, WO 02014312, WO 0246173, WO 0248106, DE 10259786, WO 03095438, U.S.
  • activators of glucokinase such as, for example, RO-4389620, LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those as are described for example by Pro
  • the compound of the formula I is administered in combination with an inhibitor of gluconeogenesis, such as, for example, FR-225654.
  • the compound of the formula I is administered in combination with inhibitors of fructose-1,6-bisphosphatase (FBPase), such as, for example, CS-917.
  • FBPase fructose-1,6-bisphosphatase
  • the compound of the formula I is administered in combination with modulators of glucose transporter 4 (GLUT4), such as, for example, KST-48 (D. -O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).
  • GLUT4 glucose transporter 4
  • the compound of the formula I is administered in combination with inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), as are described for example in WO2004101528.
  • GFAT glutamine-fructose-6-phosphate amidotransferase
  • the compound of the formula I is administered in combination with inhibitors of dipeptidylpeptidase IV (DPP-IV), such as, for example, vildagliptin (LAF-237), sitagliptin (MK-0431), saxagliptin (BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964 ⁇ or as are described in WO2003074500, WO2003106456, WO200450658, WO2005058901, WO2005012312, WO2005012308, PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002, PCT/EP2005/008004, PCT/EP2005/008283, DE 10 2005 012874.2 or DE 10 2005 012873.4.
  • DPP-IV dipeptidylpeptidase IV
  • the compound of the formula I is administered in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 (11 ⁇ -HSD1), such as, for example, BVT-2733 or those as are described for example in WO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744, WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896, WO2005016877 or WO2005097759.
  • 11 ⁇ -HSD1 11-beta-hydroxysteroid dehydrogenase 1
  • the compound of the formula I is administered in combination with inhibitors of protein tyrosine phosphatase 1B (PTP1B), as are described for example in WO200119830-31, WO200117516, WO2004506446, WO2005012295, PCT/EP2005/005311, PCT/EP2005/005321, PCT/EP2005/007151, PCT/EP2005/or DE 10 2004 060542.4.
  • PTP1B protein tyrosine phosphatase 1B
  • the compound of the formula I is administered in combination with modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), such as, for example, KGA-2727, T-1095, SGL-0010, AVE 2268 and SAR 7226 or as are described for example in WO2004007517, WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237, JP2004359630 or by A. L. Handlon in Expert Opin. Ther. Patents (2005) 15(11), 1531-1540.
  • modulators of the sodium-dependent glucose transporter 1 or 2 SGLT1, SGLT2
  • KGA-2727, T-1095, SGL-0010, AVE 2268 and SAR 7226 or as are described for example in WO2004007517, WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237, JP2004359630 or by A. L. Handlon in Expert Op
  • the compound of the formula I is administered in combination with inhibitors of hormone-sensitive lipase (HSL) as described for example in WO2005073199.
  • HSL hormone-sensitive lipase
  • the compound of the formula I is administered in combination with inhibitors of acetyl-CoA carboxylase (ACC), such as, for example, those as described in WO199946262, WO200372197, WO2003072197 or WO2005044814.
  • ACC acetyl-CoA carboxylase
  • the compound of the formula I is administered in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), such as, for example, those as described in WO2004074288.
  • PPCK phosphoenolpyruvate carboxykinase
  • the compound of the formula I is administered in combination with an inhibitor of glycogen synthase kinase 3 beta (GSK-3 beta), as described for example in US2005222220, WO2005085230, PCT/EP2005/005346, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727 or WO2004046117.
  • GSK-3 beta glycogen synthase kinase 3 beta
  • the compound of the formula I is administered in combination with an inhibitor of protein kinase C beta (PKC beta), such as, for example, ruboxistaurin.
  • PLC beta protein kinase C beta
  • the compound of the formula I is administered in combination with an endothelin A receptor antagonist such as, for example, avosentan (SPP-301).
  • an endothelin A receptor antagonist such as, for example, avosentan (SPP-301).
  • the compound of the formula I is administered in combination with inhibitors of “I-kappaB kinase” (IKK inhibitors), as are described for example in WO2001000610, WO2001030774, WO2004022553 or WO2005097129.
  • IKK inhibitors inhibitors of “I-kappaB kinase”
  • the compound of the formula I is administered in combination with modulators of the glucocorticoid receptor, like those described for example in WO2005090336.
  • the compound of the formula I is administered in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9), 554-558);
  • NPY antagonists such as, for example, naphthalene-1-sulfonic acid ⁇ 4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl ⁇ amide hydrochloride (CGP 71683A); peptide YY 3-36 (PYY3-36) or analogous compounds, such as, for example, CJC-1682 (PYY3-36 conjugated with human serum albumin via Cys34), CJC-1643 (derivative of PYY3-36 which conjugates in vivo to serum albumin) or those as are described in WO2005080424; cannabinoid receptor 1 antagonists such as, for example, rimonabant, SR147778 or those as are described for example in EP 0656354, WO 00/15609, WO02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO2001
  • CRF BP antagonists e.g. urocortin
  • urocortin agonists e.g. urocortin
  • urocortin agonists e.g. urocortin
  • urocortin agonists e.g. urocortin
  • urocortin agonists e.g. urocortin
  • ⁇ 3 agonists such as, for example, 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol hydrochloride (WO 01/83451)
  • MSH melanocyte-stimulating hormone
  • MCH melanin-concentrating hormone receptor antagonists
  • NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 compounds such as
  • dexfenfluramine mixed serotoninergic and noradrenergic compounds
  • 5-HT receptor agonists e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111); 5-HT2C receptor agonists (such as, for example, APD-356, BVT-933 or those as are described in WO200077010, WO20077001-02, WO2005019180, WO2003064423, WO200242304 or WO2005082859); 5-HT6 receptor antagonists as are described for example in WO2005058858; bombesin receptor agonists (BRS-3 agonists); galanin receptor antagonists; growth hormone (e.g.
  • growth hormone human growth hormone or AOD-9604
  • growth hormone-releasing compounds tertiary butyl 6-benzyloxy-1-(2-diisopropyl-aminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695)
  • growth hormone secretagogue receptor antagonists ghrelin antagonists
  • TRH agonists see, for example, EP 0 462 884
  • leptin agonists see, for example, 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 or Doprexin); lipase/amylase inhibitors (like those described for example in WO 00/40569); inhibitors of diacylglycerol O-acyltransferases (DGATs) as described for example in US2004/0224997, WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492 or WO2005013907; inhibitors of fatty acid synthase (FAS) such as, for example, C75 or those as described in WO2004005277; oxyntomodulin; oleoyl-estrone or thyroid hormone receptor agonists such as, for example: KB-2115 or those as described in WO20058279, WO200172692, WO200194293, WO2003084915, WO200
  • the further active ingredient is leptin; see, for example, “Perspectives in the therapeutic use of leptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.
  • the further active ingredient is dexamphetamine or amphetamine.
  • the further active ingredient is fenfluramine or dexfenfluramine.
  • the further active ingredient is sibutramine.
  • the further active ingredient is mazindole or phentermine.
  • the compound of the formula I is administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, Carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 September-October), 18(5), 230-6).
  • Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt/Main).
  • Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®.
  • Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.
  • the invention further relates both to mixtures of stereoisomers of the formula I and to the pure stereoisomers of the formula I, and mixtures of diastereomers of the formula I and the pure diastereomers. Separation of the mixtures takes place chromatographically.
  • Function-testing assays were carried out by means of the FLIPR technique (“Fluorescence Imaging Plate Reader”, Molecular Devices Corp.). For this purpose, agonist-induced changes in the intracellular concentration of Ca 2+ in recombinant HEK293 cells which expressed the GPCR GPR40 were determined.
  • the compounds of the formula I may also show a corresponding effect on the GPR120 receptor.
  • the compounds of the formula I can be prepared for example by reacting suitable starting materials of the formula II (the syntheses are sufficiently well known in the literature) with isothiocyanates of the formula III to give compounds of the formula IV.
  • the compounds of the formula I can be prepared for example by converting suitable starting materials (in the case of substituted (2-hydroxyphenyl)thioureas) of the formula IV (the syntheses are sufficiently well known in the literature) by a choice of a suitable desulfurizing reagent such as, for example, yellow HgO (Journal of Chemical Research, Synopses 2001, (4), 138-139), PbO (Journal of Pharmaceutical Sciences 1964, 53 (5), 538-44), AgNO 3 /NH 4 OH (Khimiya Geterotsiklicheskikh Soedinenii 1981, (5), 604-7), KO 2 (Chemistry Letters 1986, (8), 1291-4), N,N′-dicyclohexylcarbonyldiimide (DE 3006671), methyl iodide/s-collidine (Tetrahedron Letters 2001, 42 (34), 5853-5856), or p-toluenesulfonyl chlor
  • the compounds of the formula I can also be converted by the synthesis described by Jong Yeon Hwang and Young-Dae Gong (J. Comb. Chem. 2006, in press) of polymer-bound mercaptobenzoxazoles by reacting 2-aminophenols of the formula II with CS 2 and for example Merrifield resin in the presence of diisopropylcarbonyldiimide into the compounds of the formula V,

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