WO2010000401A1 - Utilisation de dérivés d'acide pyridinone-carboxylique substitués pour la production de médicaments destinés au traitement de la dyslipidémie - Google Patents

Utilisation de dérivés d'acide pyridinone-carboxylique substitués pour la production de médicaments destinés au traitement de la dyslipidémie Download PDF

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Publication number
WO2010000401A1
WO2010000401A1 PCT/EP2009/004477 EP2009004477W WO2010000401A1 WO 2010000401 A1 WO2010000401 A1 WO 2010000401A1 EP 2009004477 W EP2009004477 W EP 2009004477W WO 2010000401 A1 WO2010000401 A1 WO 2010000401A1
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alkyl
aryl
formula
heterocyclyl
compound
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PCT/EP2009/004477
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German (de)
English (en)
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Harm Brummmerhop
Matthias Urmann
Siegfried Stengelin
Thomas Klabunde
Hubert Heuer
Andreas Herling
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Sanofi-Aventis
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Publication of WO2010000401A1 publication Critical patent/WO2010000401A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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

Definitions

  • the invention relates to the use of substituted Pyridinoncarbonklaivaten and their physiologically acceptable salts for the preparation of medicaments for the treatment of dislipidemia.
  • FFA free fatty acids
  • the invention therefore relates to the use of the compounds of the formula I,
  • R (Ci-Co) alkyl, (C 2 -C 10) alkenyl, (C 2 -C 10) -alkynyl, where in the (Ci-Cio) alkyl, (C 2 -C i O) - Alkenyl or (C 2 -C 10) -alkynyl radicals, one or more individual CH 2 groups may be replaced by O and where the alkyl, alkenyl and alkynyl radicals may be monosubstituted or polysubstituted by F, Cl, Br, I, CF 3 , (C 3 -Ci 2 ) - Carbocycle, aryl, where aryl may be mono or polysubstituted with F, Cl, Br, I, CF 3, (Ci-C 6) alkyl;
  • R (C 1 -Co) -AUCyI, (C 2 -C 10 ) -alkenyl, wherein in the (Ci -C 10 ) -AUCyI- or (C 2 -C 10 ) -AUcenylresten one or more individual CH 2 groups O may be replaced and wherein the alkyl radicals may be monosubstituted or polysubstituted with F, Cl, Br, I, (C 3 -C 2 ) -carbocycle, aryl;
  • R (C 1 -Co) -AlkVl wherein in the (Ci-Cio) alkyl radical one or more individual CH 2 groups may be replaced by O and wherein the alkyl radicals may be mono- or polysubstituted with F, Cl, Br, I, (C 3 -C 12 ) -Cyclocycle , Aryl;
  • R (C, -C O) -alkyl where in the (C 1 -C 0) alkyl one or more individual CH 2 groups can be replaced by O and wherein said alkyl radicals can be mono or polysubstituted with F, Cl, Br, I, (C 3 -C 12 ) -carbocycle, phenyl;
  • compounds of formula I are preferred, wherein R is (C 1 - C ö) alkyl, wherein in the (Ci-C] o) alkyl one or more individual CH 2 groups can be replaced by O and wherein the alkyl radical may be monosubstituted or polysubstituted with F, Cl, Br, I, CF 3 .
  • R is (C 2 -C 10) -alkenyl, where in the (C 2 -d0) -alkenyl radical one or more individual CH 2 groups may be replaced by O and where the alkenyl radical may be monosubstituted or polysubstituted with F, Cl, Br, I, CF 3 .
  • compounds of formula I are preferred, wherein R is (C 2 - Cio) -alkynyl, where in the (C 2 -C io) - 2 groups may be replaced by O alkynyl group one or more individual CH.
  • the invention relates to the use of the compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
  • alkyl radical is meant a straight or branched hydrocarbon chain having one or more carbons, e.g. Methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, neopentyl, tert-butyl, hexyl.
  • the alkyl radicals may be mono- or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C ! -C 6 ) ADCyI, CONH 2 , CONH (C 1 - C 6) alkyl, CON [(C r C6) alkyl] 2> carbocycle, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, aryl, heterocyclyl, 0- ( C 1 -C 6 ) -alkyl, 0-COO- (C 1 -C 6 ) -alkyl, 0-CO- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, 0-CO (C r C 6 ) heterocyclyl, PO 3 H 2 , P (O) (Oalkyl) 2, (C 1 -C
  • N (heterocyclyl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N (aryl) 2 , N (heterocyclyl) -CO-N (aryl) 2 , aryl, O - (CH 2 ) n -aryl, O- (CH 2 ) n -heterocyclyl, where n 0-6, where the aryl or heterocyclyl radical may be substituted one to three times by F, Cl, Br , I, OH, CF 3, NO 2, CN, OCF 3, 0- (C 1 -C 6) - alkyl, (Ci-C6) - alkyl, NH 2, NH (C, -C6) - alkyl , N ((QC 6 ) -alkyl) 2 , SF 5 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alky
  • alkenyl radical is understood as meaning a straight-chain or branched hydrocarbon chain having two or more carbons and one or more double bonds, such as, for example, vinyl, allyl, pentenyl.
  • the alkenyl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2; Carbocycle, (C, -C 0) - alkyl, (C 2 -C 6) alkynyl, aryl, heterocyclyl, 0- (C, -C 6) - alkyl 0-CO- (Ci-C6) - alkyl, 0-CO- (C 1 -C 6 ) -aryl, O
  • alkynyl radical is understood to mean a straight-chain or branched hydrocarbon chain having two or more carbons and one or more triple bonds, such as ethynyl, propynyl, hexynyl.
  • the alkynyl radicals may be mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (Ci-C6) alkyl, CONH 2, CONH ( C, - C 6) alkyl, conf (Ci-C 6) -alkyl] 2, carbocycle, (C 2 -C 6) alkenyl, (Ci -C 0) - alkyl, 0- (Ci-C 6) - alkyl O-CO- (Ci-C 6) -alkyl, 0-CO- (Ci-C6) - aryl, 0-CO- (C 1 -C 6) -Heterozyklyl; PO
  • 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 mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, SF 5, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2; Carbocycle, (Ci -C 0) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) - alkynyl, O- (C, -C6) - alkyl 0-CO- (C, - C 6 ) - alkyl, 0-CO- (C 1 -C 6 ) -aryl, 0-CO- (C 1 -C 6 ) -heterocyclyl;
  • suitable groups for example: F, Cl, Br, I, CF 3, NO 2, SF 5, N 3, CN, COOH, COO (
  • 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 monosubstituted or polysubstituted by suitable groups, such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH ( C, -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2, carbocycle, (C 1 -C 10 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) - alkynyl, 0- (C 1 -C 6) - alkyl 0-CO- (C 1 -C 6) - alkyl, 0-CO- (C, -C6) - aryl, 0-CO- (Ci-C 6 ) - heterocyclyl; PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C
  • a carbocycle radical is meant a ring system containing one or more rings which is saturated or partially unsaturated (with one or two Double bonds) understood, which is composed exclusively of carbon atoms, such as cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
  • the Carbocyclusreste may be one or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C 1 - C 6) alkyl, CON [(C, -C 6) alkyl] 2> carbocycle, (C 1 -C 10) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6 ) - alkynyl, O - (CC 6 ) - alkyl 0-CO- (C, -C 6 ) -alkyl, 0-CO- (C, -C 6 ) -aryl, 0-CO- (C 1 -C 6 ) - heterocyclyl; PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C 6) -alkylene-P (O) (O-alkyl)
  • Heterocycle, heterocyclyl or heterocyclic radical are understood as meaning rings and ring systems which, in addition to carbon, also contain heteroatoms, such as, for example, nitrogen, oxygen or sulfur. Furthermore, ring systems also belong to this definition, in which the heterocyclic or the heterocyclic radical is condensed with benzene nuclei.
  • Suitable heterocyclic or "heterocyclic radicals” are acridinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, Chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] -tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, hidazolyl, IH-indazolyl
  • Pyridyl is both 2-, 3- and 4-pyridyl.
  • Thienyl is both 2- and 3-thienyl.
  • Furyl is both 2- and 3-furyl.
  • N-oxides of these compounds eg 1-oxy-2-, 3- or 4-pyridyl.
  • heterocyclic rings or heterocyclic radicals may be mono- or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) AUCyI , CONH 2, CONH (C 1 -C 6) AUCyI, cont (C 1 -C 6) AUCyI] 2, carbocycle, (C, - C O) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) -alkynyl, O- (C, -C6) alkyl 0-CO- (C, -C6) - alkyl, O- CO- (C 1 -C 6) aryl, 0-CO - (C, -C 6) -Heterozyklyl;
  • suitable groups such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of formula I are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulfuric and organic acids, e.g.
  • the chloro salt is used in a particularly preferred manner.
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).
  • 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 formula I can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of formula I are within the scope of the invention and are a further aspect of the invention.
  • all references to "compound (s) according to formula (I)" refer to compound (s) of formula (I) as described above, as well as their salts and solvates as described herein.
  • the compound (s) of formula (I) may also be administered in combination with other active ingredient.
  • the amount of a compound of formula (I) required to achieve the desired biological effect depends on a number of factors, e.g. the specific compound chosen, the intended use, the type of
  • the daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg and 50 mg) per day per kilogram of body weight, e.g. 3-10 mg / kg / day.
  • An intravenous dose may e.g. in the range of 0.3 mg to 1.0 mg / kg, which can be suitably administered as an infusion of 10 ng to 100 ng per kilogram per minute.
  • 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 abovementioned weights are based on the weight of the benzothiazepine ion derived from the salt.
  • the compounds according to formula (I) may themselves be used as compound, but they are preferably present with a tolerable 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.
  • Other pharmaceutically active substances may also be present, including further compounds according to formula (I).
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which are essentially lent consist 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 the nature and severity of the treatment State and on the nature of the particular compound used according to formula (I) is dependent.
  • coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate,
  • Hydroxypropylmethylcellulosephthalat and anionic polymers of methacrylic acid and methyl methacrylate are examples of hydroxypropylmethylcellulosephthalat and anionic polymers of methacrylic acid and methyl methacrylate.
  • 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.
  • Compressed 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 surfactant / dispersing agent in a suitable machine.
  • Molded tablets can be made by molding the powdered, moistened with an inert liquid diluent compound can be prepared in a suitable machine.
  • compositions suitable for peroral (sublingual) administration include lozenges comprising a compound of formula (I) having a
  • Flavoring usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerin or
  • 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.
  • Preparations are preferably administered intravenously, although the
  • Administration can also be administered subcutaneously, intramuscularly or intradermally as an injection.
  • compositions according to 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 be present as single patches for long-term close contact with the epidermis of the patient are suitable.
  • 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).
  • 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 ⁇ (insulin lispro), Humulin (R), VIAj ect TM or those 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 ⁇ (insulin lispro), Humulin (R), VIAj ect TM or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633), inhalable insulins such.
  • Levemir® insulin detemir
  • Humalog ⁇ insulin lispro
  • R Humulin
  • VIAj ect TM those described in WO200500
  • DSf-105 Nobex
  • Oralyn TM Geneex Biotechnology
  • Technosphere (R) insulin MannKind
  • Cobalamin TM oral insulin or insulins as described in WO2007128815, WO2007128817 or insulins which can be administered transdermally ;
  • GLP-I derivatives and GLP-I agonists such as exenatide, liraglutide or those described in WO 98/08871, WO2005027978, WO2006037811, WO2006037810 by Novo Nordisk A / S, in WO 01/04156 of Zealand or in WO 00/34331 of Beaufour-Ipsen, Pramlintide acetate (Symlin; Amylin Pharmaceuticals), AVE-0010, BIM-51077 (R-1583, ITM-077), PC-DAC: exendin-4 (an exendin-4 analogue covalently linked to recombinant human albumin), CVX-73, CVX-98 and CVx-96 (GLP-I analogs covalently linked to a monoclonal antibody, having specific binding sites for the GLP-I peptide), CNTO-736 (a GLP-I analog bound to a domain containing the Fc portion of an antibody), PGC-GLP-I (G
  • 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 analogs and derivatives of fibroblast growth factor 21 (FGF-21, fibroblast growth factor 21).
  • the orally active hypoglycemic agents preferably comprise sulfonylureas
  • Glucokinase activators inhibitors of fructose 1, 6-bisphosphatase, Glucose Transporter 4 Modulators (GLUT4),
  • Potassium channel opener e.g. Pinacidil, cromakalim, diazoxide, or those described in R.D. Carr et al., Diabetes 52, 2003, 2513, 2518, in J. B. Hansen et al, Current Medicinal
  • DPP-IV dipeptidyl peptidase-IV
  • PTP-IB protein tyrosine phosphatase-1B
  • Nicotinic acid receptor agonists inhibitors of hormone-sensitive or endothelial lipases,
  • Inhibitors of acetyl-CoA carboxylase ACCl and / or ACC2
  • lipid metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents, HMGCoA reductase inhibitors,
  • FXR Farnesoid X receptor
  • CETP inhibitors bile acid resorption inhibitors
  • Sigma-1 receptor antagonists Antagonists of the somatostatin 5 receptor (SST5 receptor); Compounds that reduce food intake and compounds that increase thermogenesis.
  • the compound of the formula I is administered in combination with insulin.
  • the compound of formula I is administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, e.g. Sulfonylureas, e.g. Tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride.
  • an agent that acts on the ATP-dependent potassium channel of 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).
  • 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 treated with a combination of mitiglinides with a glitazone, e.g. Pioglitazone hydrochloride, administered.
  • a glitazone e.g. Pioglitazone hydrochloride
  • the compound of 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. In a further embodiment, the compound of the formula I is administered in combination with antihypoglycemic compounds, as described in WO2007137008.
  • 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, especially 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, especially 5- [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2
  • a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-ol (rivoglitazone), DRL-17564, DRF-2593 (balaglitazone) or those as described in WO2007060992, WO2007100027, WO2007103252, WO2007122970 ,
  • the compound of formula I is administered in combination with Competact TM, a solid combination of pioglitazone hydrochloride with metformin hydrochloride.
  • the compound of formula I in combination with a solid combination of pioglitazone hydrochloride with an angiotensin II agonist, e.g. TAK-536 administered.
  • the compound of formula I is in combination with a PPAR alpha agonist or mixed PPAR alpha / PPAR delta agonists, such as GW9578, GW-590735, KH1, LY-674, KRP-101, DRF-10945 , LY-518674, CP-900691, BMS-687453, BMS-711939 or those as described in WO2001040207, WO2007096894, WO2005097076, WO2007056771, WO2007087448, WO2007089667, WO2007089557, WO2007102515, WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043.
  • a PPAR alpha agonist or mixed PPAR alpha / PPAR delta agonists such as GW9578, GW-590735, KH1, LY-674, KRP-101, DRF-10945 , LY-518674, CP
  • 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 or as in WO 00/64888, WO 00/64876, WO03 / 020269 , WO2007099553, US2007276041, WO2007085135, WO2007085136 or JPBerger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005.
  • 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),
  • the compound of formula I is used in combination with a PPAR delta agonist, e.g. GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887.
  • a PPAR delta agonist e.g. GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887.
  • the compound of the formula I is used in combination with a pan-SPPARM (selective PPAR modulator alpha, gamma, delta), such as e.g. GFT-505 administered.
  • a pan-SPPARM selective PPAR modulator alpha, gamma, delta
  • the compound of the formula I is administered in combination with metaglidases or with MBX-2044 or other partial PPAR gamma agonists / antagonists.
  • 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.
  • an ⁇ -glucosidase inhibitor e.g. Miglitol or acarbose or those as described e.g. in WO2007114532, WO2007140230.
  • the compound of the formula I in combination with an inhibitor of glycogen phosphorylase, such as PSN-357 or FR-258900 or such as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
  • an inhibitor of glycogen phosphorylase such as PSN-357 or FR-258900 or such as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
  • the compound of formula I is used in combination with glucagon receptor antagonists, such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577.
  • glucagon receptor antagonists such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577.
  • 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. B. 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, WO200707
  • the compound of the formula I in combination with an inhibitor of gluconeogenesis, such as. FR-225654.
  • the compound of formula I is used in combination with inhibitors of fructose-l, 6-bisphosphatase (FBPase) such as CS-917 (MB-06322) or MB-07803 or those as described in WO2006023515, WO2006104030, WO2007014619, WO2007137962.
  • FBPase 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, GW-825964X, KRP-104, DP-893, ABT-341, ABT-279 or other salt thereof, S-40010, S-40755, PF-00734200, BM 356, PHX-1149, alogliptin or such compounds as described in WO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005037828, WO2005058901, WO20050
  • the compound of formula I is administered in combination with Janumet TM, a solid combination of sitagliptin phosphate with metformin hydrochloride. In one embodiment, the compound of formula I is administered in combination with Eucreas (R) , a solid combination of vildagliptin with metformin hydrochloride.
  • the compound of 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, e.g. in WO2007128801, administered.
  • the compound of formula I in combination with an insulin secretion enhancing substance, such as. KCP-265 (WO2003097064) or those as described in WO2007026761.
  • an insulin secretion enhancing substance such as. KCP-265 (WO2003097064) or those as described in WO2007026761.
  • 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 modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), e.g. KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083, SGL-5085, SGL-5094, ISIS-388626, sergliflozin or dapagliflozin, or as described e.g. B.
  • modulators of the sodium-dependent glucose transporter 1 or 2 SGLT1, SGLT2
  • SGLT1 sodium-dependent glucose transporter 1 or 2
  • 11-beta-hydroxysteroid dehydrogenase-1 (1 lß-HSDl)
  • 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.
  • the compound of the formula I is administered in combination with an agonist of GPR10A (HM74A receptor agonists; NAR agonists (nicotinic acid receptor agonists)), such as, for example, nicotinic acid or extended release niacin in combination with MK-0524A (Laropiprant ) or MK-0524 or such compounds as described in WO2006045565, WO2006045564, WO2006069242, WO2006085108, WO2006085112, WO2006085113, WO2006124490, WO2006113150, WO2007017261, WO2007017262, WO2007017265, WO2007015744, WO2007027532, WO2007092364, WO2007120575, WO2007134986.
  • GPR10A HM74A receptor agonists
  • NAR agonists nicotinic acid receptor agonists
  • the compound of formula I is administered in combination with a solid combination of niacin with simvastatin.
  • the compound of the formula I is administered in combination with nicotinic acid or "extended release niacin" in conjunction with MK-0524 A (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.
  • cyclooxygenase-1 or cyclooxygenase-2 e.g. Acetylsalicylic acid, diclofenac, celecoxib, rofecoxib, valdecoxib, etoricoxib, or lumiracoxib.
  • the invention of formula I 1 is used in combination with a DPl receptor antagonist, e.g. Laropiprant, SAR389644 or such compounds as described in WO2008039882 administered.
  • a DPl receptor antagonist e.g. Laropiprant, SAR389644 or such compounds 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 the formula I is administered in combination with modulators of the GPR40, as described, for example, in WO2007013689, WO2007033002, WO2007106469, US2007265332, WO2007123225, WO2007131619, WO2007131620, WO2007131621, US2007265332, WO2007131622, WO2007136572.
  • the compound of formula I is used in combination with modulators of GPR19 (G protein-coupled glucose-dependent insulinotropic receptor), e.g. PSN-119-1 or such as z.
  • GPR19 G protein-coupled glucose-dependent insulinotropic receptor
  • PSN-119-1 G protein-coupled glucose-dependent insulinotropic receptor
  • WO2005061489 PSN-632408
  • WO2004065380 WO2004065380
  • WO2006018662 WO2007003960-62
  • WO2007003964 WO2007116229
  • WO2007116230 WO2007116230.
  • the compound of formula I is used in combination with modulators of the GPR120, e.g. in EP1688138.
  • 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 WO2005073199, WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837.
  • 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. Administered darapladib or A-002.
  • 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 in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), such as.
  • an inhibitor of glycogen synthase kinase-3 beta such as.
  • GSK-3 beta glycogen synthase kinase-3 beta
  • GSK-3 beta glycogen synthas
  • 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 the formula I in combination with an inhibitor of serum / glucocorticoid-regulated kinase (SGK), such as.
  • SGK serum / glucocorticoid-regulated kinase
  • the compound of the formula I in combination with an inhibitor of protein kinase C beta such as. B. Ruboxistaurin administered.
  • PLC beta protein kinase C beta
  • the compound of the formula I in combination with an activator of the AMP-activated protein kinase (AMPK), as described, for. As described in WO2007062568 administered.
  • AMPK AMP-activated protein kinase
  • the compound of the formula I in combination with an inhibitor of ceramide kinase, as z. As described in WO2007112914 administered.
  • the compound of the formula I is used in combination with an inhibitor of MAPK-interacting kinase 2 (MNK2), as described e.g. in WO2007104053, WO2007115822 are administered.
  • MNK2 MAPK-interacting kinase 2
  • the compound of the formula I is administered in combination with inhibitors of the "I-kappaB kinase" (IKK inhibitors), as described, for example, in WO2001000610, WO2001030774, WO2004022057, WO2004022553, WO2005097129, WO2005113544, US2007244140.
  • the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699 or those as described in US2007249583.
  • the compound of formula I is used in combination with a farnesoid X receptor (FXR) antagonist, such as e.g. in WO2007052843, WO2007070796, WO2007092751, JP2007230909, WO2007095174, WO2007140174, WO2007140183.
  • FXR farnesoid X receptor
  • the compound of the formula I is used in combination with a liver X receptor (LXR) ligand, e.g. described in WO2007092965.
  • LXR liver X receptor
  • a fibrate e.g. Fenofibrate, clofibrate, bezafibrate.
  • 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 diflunisal.
  • 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 or atorvastatin.
  • the compound of the formula I is administered in combination with Synordia (R), a fixed combination of fenofibrate with metformin.
  • a cholesterol resorption inhibitor e.g. 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.
  • 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 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
  • Diphenylazetidinonderivat as described for example in US 6,992,067 or US 7,205,290.
  • the further active ingredient is a diphenylazetidinone derivative as described, for example, in US Pat. No. 6,992,067 or US Pat. No. 7,205,290 combined with a statin such as simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin or rosuvastatin.
  • a statin such as simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin or rosuvastatin.
  • the compound of formula I is administered in combination with a solid combination of Lapaquistat, a squalene synthase inhibitor, with atorvastatin.
  • a CETP inhibitor e.g. Torcetrapib, anacetrapib or JTT-705 or those as are described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154, US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243, WO2007120621, US2007265252, US2007265304, WO2007128568 WO2007132906 described, administered.
  • a CETP inhibitor e.g. Torcetrapib, anacetrapib or JTT-705 or those as are described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2007088996, WO2007088999, US2007185058, US2007185113
  • the compound of formula I is used in combination with bile acid resorption inhibitor (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, WO2007009655-56.
  • bile acid resorption inhibitor see, for example, US 6,245,744, US 6,221,897 or WO00 / 61568
  • HMR 1741 e.g. HMR 1741 or those described in DE 10 2005 033099.1 and DE 10 2005 033100.9, WO2007009655-56.
  • 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 WO2007110237, WO2007127505.
  • GPBAR1 G-protein-coupled bile-acid receptor-1
  • the compound of formula I is used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam hydrochloride.
  • a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam hydrochloride.
  • the compound of formula I is administered in combination with a phytosterol-containing chewing gum (Reductol TM).
  • the compound of the formula I is used in combination with an inhibitor of the microsomal triglyceride transfer protein (MTP inhibitor), for example Implitapide, BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR -733 or those as described in WO2005085226, WO2005121091, WO2006010423, WO2006113910.
  • MTP inhibitor microsomal triglyceride transfer protein
  • 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 the formula I is administered in combination with an ACAT inhibitor, e.g. Avasimibe, SMP-797 or KY-382.
  • ACAT inhibitor e.g. Avasimibe, SMP-797 or KY-382.
  • the compound of the formula I in combination with an inhibitor of hepatic carnitine palmitoyltransferase-1 (L-CPTl), as described e.g. in WO2007063012, WO2007096251 (ST-3473).
  • L-CPTl hepatic carnitine palmitoyltransferase-1
  • 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.
  • a squalene synthetase inhibitor e.g. BMS-188494, TAK-475 (Lapaquistat acetate) or as described in WO2005077907, JP2007022943.
  • the compound of the formula I is administered in combination with ISIS-301012 (mipomersen), an antisense oligonucleotide which is capable of regulating the apolipoprotein B gene.
  • 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 as described in WO2005097738.
  • an LDL receptor inducer see US 6,342,512
  • the compound of the formula I is administered in combination with an ABCA1 expression enhancer, as described, for example, in WO2006072393. In one embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein-lipase modulator such as ibrolipim (NO-1886).
  • a lipoprotein-lipase modulator such as ibrolipim (NO-1886).
  • the compound of formula I is used in combination with a lipoprotein (a) antagonist, e.g. Gemcabene (CI-1027).
  • a lipoprotein (a) antagonist e.g. Gemcabene (CI-1027).
  • the compound of the formula I is administered in combination with an adenosine A2B receptor agonist (adenosine A2B R), e.g. ATL-801 administered.
  • an 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.
  • the compound of the formula I is administered in combination with an adenosine A2B receptor antagonist (adenosine A2B R), as described in US2007270433.
  • adenosine A2B receptor antagonist adenosine A2B R
  • the compound of the formula I in combination with inhibitors of acetyl-CoA carboxylase (ACCl and / or ACC2) such.
  • inhibitors of acetyl-CoA carboxylase ACCl and / or ACC2
  • 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 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-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl ⁇ -amide hydrochloride (CGP 71683A);
  • 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;
  • 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
  • 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 are described;
  • FAAH fatty acid amide hydrolase modulators as described, for example, in WO2007140005
  • Vanilloid-1 receptor modulators modulators of the TRPV1
  • 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-tetrahydro-naphthalene-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
  • Orexin receptor 1 antagonists (OXlR antagonists), orexin receptor 2 antagonists (OX2R antagonists) or mixed OX1R / OX2R antagonists (eg l- (2-methylbenzoxazol-6-yl) -3- [l, 5] naphthyridine 4-yl urea hydrochloride (SB-334867-A) or those described, for example, in WO200196302, WO200185693, WO2004085403, WO2005075458, WO2006067224, WO2007085718, WO2007088276, WO2007116374, WO2007122591, WO2007126934, WO2007126935);
  • 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;
  • 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 WO2007105113, WO2007133756);
  • CRF BP antagonists e.g., urocortin
  • Agonists 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;
  • 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, GW-803430 or such compounds, as are 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 WO2006118320, WO2006130075, WO2007018248, WO2007012661, WO2007029847, WO
  • CCK-A (CCK-I) agonists such as ⁇ 2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl-t-thiazole) -ylcarbamoyl-SJ-dimethyl indole-1-yl ⁇ -acetic acid trifluoroacetic acid salt (WO 99/15525) or SR-146131 (WO 0244150) or SSR-125180) or those as described in WO2005116034, WO2007120655, WO2007120688, WO2007120718;
  • Serotonin reuptake inhibitors e.g., dexfenfluramines
  • mixed serotonin / dopamine reuptake inhibitors e.g., bupropion
  • bupropion or fixed combinations of bupropion with naltrexone or bupropion with zonisamide;
  • 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;
  • 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 are described); 5-HT6 receptor modulators, such as E-6837, BVT-74316 or PRX-07034 or those as described, for example, in WO2005058858, WO2007054257, WO2007107373, WO2007108569, WO2007108742-744;
  • 5-HT6 receptor modulators such as E-6837, BVT-74316 or PRX-07034 or those as described, for example
  • estrogen receptor gamma e.g. in WO2007131005
  • Muscarinic 3 receptor (M3R) antagonists as described e.g. in WO2007110782 are described;
  • BTS-3 agonists Bombesin receptor agonists
  • Growth hormone e.g., human growth hormone or AOD-9604
  • human growth hormone e.g., human growth hormone or AOD-9604
  • Growth Hormone Secretagogue Receptor Antagonists such as A-778193 or those as described in WO2005030734, WO2007127457;
  • Growth Hormone Secretagogue Receptor 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;
  • TRH agonists see, e.g., EP 0 462 884;
  • 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
  • Inhibitors of diacylglycerol O-acyltransferases such.
  • Inhibitors of fatty acid synthase e.g. C75 or those as described in WO2004005277;
  • Inhibitors of stearoyl-CoA delta9 desaturase as described e.g. in WO2007009236, WO2007044085, WO2007046867, WO2007046868, WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457, WO2007136746 are described;
  • KB-2115 or DITPA or such as in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419, WO2007009913, WO2007039125, WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864
  • TR-beta thyroid hormone receptor beta
  • 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 administered in combination with an RNAi therapeutic which is directed against PCSK9 (proprotein convertase subtilisin / kexin type 9).
  • the compound of formula I is administered in combination with Omacor® or Lovaza TM (omega-3 fatty acid esters, highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).
  • Omacor® or Lovaza 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, succinobucol, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
  • an antioxidant e.g. OPC-14117, 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 B 12 administered.
  • the compound of the formula I is used in combination with more than one of the abovementioned compounds, for example 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. administered.
  • 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.
  • the compound of formula I is administered in combination with a solid combination of topiramate with phentermine (Qnexa TM).
  • the compound of formula I is used in combination with an antisense compound, e.g. ISIS-377131, which inhibits the production of the glucocorticoid receptor.
  • an antisense compound e.g. ISIS-377131
  • the compound of formula I in combination with an agonist of the RUP3 receptor, such. As described in WO2007035355 administered.
  • 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 the 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.
  • JNK inhibitor c-Jun N-terminal kinase inhibitor
  • the compound of the formula I in combination with an endothelin A receptor antagonists, such as. B. avosentan (SPP-301).
  • the compound of formula I is used in combination with modulators of the glucocorticoid receptor (GR), e.g. KB-3305 or such compounds as e.g. As described in WO2005090336, WO2006071609, WO2006135826, WO2007105766.
  • 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 SIRTI (an NAD + -dependent protein deacetylase); this active substance may be, for example, resveratrol in suitable formulations, or such compounds as are mentioned in WO2007019416 (eg SRT-1720).
  • SIRTI an NAD + -dependent protein deacetylase
  • the further active ingredient is DM-71 (N-acetyl-L-cysteine with bethanecho 1).
  • the compound of formula I is used in combination with anti-hypercholesterolemic compounds, such as those described e.g. in WO2007107587, WO2007111994.
  • 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-020 (bis (ethylmaltolato) oxovanadium-IV).
  • the compound of formula I is administered in combination with tissue-selective androgen receptor modulators (SARMs) as described, for example, in WO2007099200.
  • SARMs tissue-selective androgen receptor modulators
  • the further active ingredient is leptin; see, e.g. "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 metreleptin (recombinant methionyl-leptin) combined with pramlintide.
  • the further active ingredient is the tetrapeptide ISF-402.
  • the further active ingredient is dexamphetamine or amphetamine.
  • the other active ingredient is fenfluramine or dexfenfluramine.
  • the further active ingredient is sibutramine.
  • the other active ingredient is mazindol or phentermine.
  • the further active ingredient is geniposidic acid (geniposidic acid, WO2007100104).
  • the compound of formula I in combination with dietary fiber, insoluble fiber insoluble fiber
  • 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.RTM ® can in this case in the form of food, such as administered in bakery products or muesli bars.
  • the compounds of formula I are useful in the treatment of dislipidemia for prediabetes treatment, in the prevention of type 2 diabetes and in the treatment of metabolic syndrome (see Datamonitor 11/2002, Chapter 2, pages 19-32). They are especially for the treatment of diabetic dislipidemia.
  • Diabetic dyslipidemia manifests as an increase in plasma triglycerides, a decrease in HDL cholesterol, and often in elevated LDL levels. Due to the increased occurrence of small, dense LDL-cholesterol particles with high atherogenic potency, diabetic dyslipidaemia is a strong cardiovascular risk factor.
  • the compounds are also suitable for the reduction of free fatty acids in the blood.
  • the compounds of the formula I can be formulated, for example, in the following formulations:
  • Dragees containing 50 mg of active ingredient per coated tablet: per Dragee active ingredient 50 mg corn starch 100 mg
  • Example F The following formulations are suitable for the preparation of the contents of hard gelatine capsules: a) Active ingredient 100 mg
  • the substance is administered (zBpo, iv., Ip, sc) and with or without additional stimulation of endogenous lipolysis (eg by bolus injection of 2 mg / kg ip isoprenaline) the effect of the test substance on the lipolysis on the basis of the released free fatty acids (FFA), glycerol and triglycerides determined, for example, 15 min, 30, 60, 120, etc. minutes after po application a blood sample (eg by retroorbital blood sampling) is obtained and analyzed according to standard clinical-chemical methods (eg L. Thomas: Laboratory and Diagnostics, 2nd edition, Medical Publishing Company, Marburg / L., 1984; ISBN 3-921320-10-9)). The inhibition of lipolysis by the inhibitors is evaluated in comparison to the lipolysis rate of appropriately treated control animals.
  • zBpo, iv., Ip, sc endogenous lipolysis
  • endogenous lipolysis eg by bolus injection of 2 mg / kg
  • Example 1 was administered at the dose of 10 mg / kg po, which markedly lowered lipolysis, as shown by the reduction of free fatty acids (FFA), glycerol and triglycerides.
  • FFA free fatty acids
  • n stands for the number of animals. Wistar rats were tested. The effectiveness of the compounds of the formula I was also tested in the following assays:
  • Functional assays were performed by the FLIPR technique ("Fluorescence Imaging Plate Reader", Molecular Devices Corp.) for which agonist-induced changes in the intracellular concentration of Ca + in recombinant HEK293 cells were determined which include both the GPCR FJM74A (niacin receptor ), as well as the hybrid G-protein GD6qi4myr (see, for example, patent application DE10033353) express.
  • Agonists of the G protein-coupled receptor HM74a lead to a decrease of cyclic adenosine monophosphate (cAMP) and to the inhibition of lipolysis in adipocytes (S. Tunaru et al., Nat. Med. 2003, 9, 352-355. ).
  • the inhibition of lipolysis by agonists of the receptor HM74a results in a lowering of free fatty acids and triglycerides in the blood. (Offermanns, Trends in Pharm Sciences 2006, 27, 384-390.).
  • Substances that are identified as agonists of the receptor HM74a are thus suitable for the treatment of dislipidaemia.

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Abstract

La présente invention concerne l'utilisation de dérivés d'acide pyridinone-carboxylique substitués et de leurs sels physiologiquement tolérés, pour la production de médicaments destinés au traitement de la dyslipidémie. L'invention a également pour objet l'utilisation des composés de formule (I), le radical R ayant les correspondances indiquées, ainsi que de leurs sels physiologiquement tolérés pour la production d'un médicament destiné au traitement de la dyslipidémie.
PCT/EP2009/004477 2008-07-04 2009-06-20 Utilisation de dérivés d'acide pyridinone-carboxylique substitués pour la production de médicaments destinés au traitement de la dyslipidémie WO2010000401A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08290662.9 2008-07-04
EP08290662 2008-07-04

Publications (1)

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WO2010000401A1 true WO2010000401A1 (fr) 2010-01-07

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PCT/EP2009/004477 WO2010000401A1 (fr) 2008-07-04 2009-06-20 Utilisation de dérivés d'acide pyridinone-carboxylique substitués pour la production de médicaments destinés au traitement de la dyslipidémie

Country Status (1)

Country Link
WO (1) WO2010000401A1 (fr)

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BEAK P, SIEGEL B: "Mechanism of decarboxylation of 1,3-dimethylorotic acid. A model for orotidine 5'-phosphate decarboxylase", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 98, no. 12, 9 June 1976 (1976-06-09), pages 3601 - 3606, XP002506278 *
FRONK H M, MOSHER H S: "Ethyl N-methyl-2-pyridone-4-carboxylate and derivatives", JOURNAL OF ORGANIC CHEMISTRY, vol. 24, February 1959 (1959-02-01), pages 196 - 198, XP002506279 *
POLLEX R L; JOY T R; HEGELE R A: "Emerging antidyslipidemic drugs", EXPERT OPINION ON EMERGING DRUGS, vol. 13, no. 2, June 2008 (2008-06-01), pages 363 - 381, XP009109184 *
SUGASAWA SHIGEHIKO; KIRISAWA MAKOTO: "Oxidation of 4-(1,1-Ethylenedioxyethyl)-and 4-(Ethylenedioxymethyl)-1-methylpyridinium Salts", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 6, no. 6, 15 December 1958 (1958-12-15), pages 615 - 618, XP009109199 *
YUYAMA S; SUZUKI T: "The excretion of N1-methyl-2-pyridone-5-carboxylic acid and related compounds in human subjects after oral administration of nicotinic acid, trigonelline and N1-methyl-2-pyridone-5-carboxylic acid", ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY, vol. 294, 1991, pages 475 - 479, XP009109158 *

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