MXPA06008403A - 7-phenylamino-4-quinolone-3-carboxylic acid derivatives, methods for production and use thereof as medicaments - Google Patents

Abstract

The invention relates to 7-phenylamino-4-quinolone-3-carboxylic acid derivatives, the physiologically-acceptable salts and physiologically-functional derivatives thereof, also compounds of formula (I), where the groups have the given meanings and the physiologically-acceptable salts thereof. Said compound are suitable for use, for example, as medicaments for the prevention and treatment of type 2 diabetes.

Description

DERIVATIVES OF 7-FFNILAMINO-4-QUINOLONA-3-CARROXILICO ACID, METHODS FOR ITS PRODUCTION AND ITS USE AS MEDICINES This invention relates to 7-phenylamino-4-quinolone-3-carboxylic acid derivatives and to physiologically tolerable salts and physiologically functional derivatives thereof. Compounds of similar structure have already been described in the art (Link, Helmut, Bernauer, Karl, Englert Gerhard, Helvetica Chimica Acta 65 (8), 1982, 2645-2667 and Bennet et al., J. Chem. Soc, 1949, 227 -229). The invention is based on the object of providing compounds that show a therapeutically useful blood glucose lowering effect. Therefore, the invention relates to compounds of the formula I wherein the meanings are R 1 OH, O-(C 1 -C 6) alkyl or O-C 1 -C 6 alkyl-OCO-(C 1 -C 6) alkyl; R2 H, (C1-C6) alkyl or phenyl; R3 H, (C1-C8) alkyl, (C3-C7) cycloalkyl, pyridyl or phenyl, wherein the alkyl may be substituted with R9 and wherein the phenyl or pyridyl may be substituted with R10; R9 NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2; COOH, COO- (C1-C6) alkyl, (C3-C7) cycloalkyl, heteroalkyl, heteroaryl, O-phenyl or phenyl, wherein phenyl and heteroaryl may be substituted with R11; R10 F, Cl, Br, (C1-C6 alkyl), O-(C1-C6) alkyl, COOH, COO- (C1-6) alkyl, NH2, NH- (C1-C6) alkyl or N- (alkyl) C1-C6)) 2; R11 F, Cl, (C1-C6 alkyl), O-(C1-C6) alkyl, NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2, COOH or COO-alkyl ( C1-C4); X C-R4 or N; R 4 H, F, Cl, Br, OH, NO 2, CN, (C 1 -C 6) alkyl or O-C 1 -C 6 alkyl, wherein the alkyl may be substituted more than once with F, Cl or Br; R 5 H, F, Cl, Br, OH, NO 2, CN, (C 1 -C 6) alkyl or O-C 1 -C 6 alkyl, wherein the alkyl may be substituted more than once with F, Cl or Br; R6 H, F, Cl, Br, NO2, CN or (C1-C6) alkyl, where the alkyl may be substituted more than once with F, Cl or Br; R7 H or (C1-C6) alkyl; R8 phenyl, wherein the phenyl may be substituted up to five times with F, Cl, Br, CN, NO2, (C1-C8) alkyl, O-(C1-C8) alkyl, S- (C1-C8) alkyl, alkenyl ( C2-C8), (C3-C7) cycloalkyl, (C1-C4) alkyl, phenyl, benzyl, benzoyl, NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2, P (O) - (O- (C 1 -C 4) alkyl) 2 or heteroalkyl, wherein alkyl and alkenyl may be substituted more than once with F, Cl, Br, COOH or COO- (C 1 -C 4) alkyl; heteroalkyl a 4 to 7 membered heterocyclic, saturated or unsaturated ring which may comprise up to 3 N, O or S heteroatoms as ring members, wherein the ring may be substituted with F, Cl, Br, CN, NO2, alkyl (C1-) C4), OH, COOH, COO-(C1-C4) alkyl; with the exception of the compounds of the formula I in which the radicals have simultaneously the following meanings: X is equal to N, R1 is equal to OH, R2, R3, R4, R5 and R7 are equal to H and R8 is equal to unsubstituted phenyl; and the physiologically acceptable salts thereof. Preference is given to compounds of the formula I in which one or more radicals have the following meanings: R 1 OH, O-C 1 -C 6 alkyl or O-C 1 -C 6 alkyl-OCO-C 1 -C 6 alkyl ); R2 H, (C1-C6) alkyl or phenyl; R3 (C1-C8) alkyl, (C3-C7) cycloalkyl, pyridyl or phenyl, wherein the alkyl may be substituted with R9 and wherein the phenyl or pyridyl may be substituted with R10; R9 NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2; COOH, COO- (C1-C6) alkyl, (C3-C7) cycloalkyl, heteroalkyl, heteroaryl, O-phenyl or phenyl, wherein phenyl and heteroaryl may be substituted with R11; R10 F, Cl, Br, (C1-C6 alkyl), O-(C1-C6) alkyl, COOH, COO- (C1-6) alkyl, NH2, NH- (C1-C6) alkyl or N- (alkyl) C1-C6)) 2; R11 F, Cl, (C1-C6 alkyl), O-(C1-C6) alkyl, NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2, COOH or COO-alkyl ( C1-C4); X C-R4 or N; R 4 H, F, Cl, Br, OH, NO 2, CN, (C 1 -C 6) alkyl or O (C 1 -C 6) alkyl, wherein the alkyl may be substituted more than once with F, Cl or Br; R 5 H, F, Cl, Br, OH, NO 2, CN, (C 1 -C 6) alkyl or O (C 1 -C 6) alkyl, where the alkyl may be substituted more than once with F, Cl or Br; R6 H, F, Cl, Br, NO2, CN or (C1-C6) alkyl, where the alkyl may be substituted more than once with F, Cl or Br; R7 H or (C1-C6) alkyl; R8 phenyl, wherein the phenyl may be substituted up to five times with F, Cl, Br, CN, NO2, (C1-C8) alkyl, O-(C1-C8) alkyl, S- (C1-C8) alkyl, alkenyl ( C2-C8), (C3-C7) cycloalkyl, (C1-C4) alkyl, phenyl, benzyl, benzoyl, NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2, P (O) - (O- (C 1 -C 4) alkyl) 2 or heteroalkyl, wherein alkyl and alkenyl may be substituted more than once with F, Cl, Br, COOH or COO- (C 1 -C 4) alkyl; heteroalkyl a 4 to 7 membered heterocyclic, saturated or unsaturated ring which may comprise up to 3 N, O or S heteroatoms as ring members, wherein the ring may be substituted with F, Cl, Br, CN, NO2, alkyl (C1-) C4), OH, COOH, COO-(C1-C4) alkyl; and the physiologically acceptable salts thereof. Particular preference is given to compounds of the formula I in which one or more radicals have the following meanings: R 1 OH, O-C 1 -C 6 alkyl or O-C 1 -C 6 alkyl-OCO-C 1 -C 6 alkyl ); R2 H; R3 phenyl, wherein the phenyl may be substituted with R10; R10 F, Cl, Br, (C1-C6 alkyl), O-(C1-C6) alkyl, COOH, COO- (C1-6) alkyl, NH2, NH- (C1-C6) alkyl or N- (alkyl) C1-C6)) 2; X C-R4; R 4 H, (C 1 -C 6) alkyl; R 5 H, F, Cl, (C 1 -C 6) alkyl; R6 H; R7 H; R8 phenyl, wherein the phenyl may be substituted up to five times with F, Cl; and the physiologically acceptable salts thereof. A particular preference is given to compounds of the formula I in which one or more radicals have the following meanings: R 1 OH, O-(C 1 -C 6) alkyl; R2 H; R3 phenyl, wherein the phenyl is substituted with R10; R10COOH, COO- (C1-C6) alkyl; X C-R4; R 4 H, (C 1 -C 6) alkyl; R5 F, Cl, (C1-C6) alkyl; R6 H; R7 H; R8 phenyl, wherein the phenyl is substituted one to five times with F, Cl; and the physiologically tolerable salts thereof. In addition, preference is given to compounds of the formula I in which R8 is phenyl and the latter is substituted twice with F or Cl in the ortho and para positions or substituted three times with F or Cl in the ortho, ortho and para positions. . In addition, particular preference is given to compounds of the formula I in which R8 is phenyl and the latter is substituted three times with F or Cl in the ortho, ortho and para positions. The invention relates to compounds of the formula I in the form of their racemates, racemic mixtures and pure enantiomers and to their diastereomers and mixtures thereof. The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and heteroalkyl can be both straight-chain and branched. If the radicals or substituents can appear more than once in the compounds of the formula I, they can all, independently of one another, have the indicated meanings and be different or different. The pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initiating or basic compounds, particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and organic acids such as, for example, acetic acid, benzenesulfonic acid , benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1). , 3-propanediol), diethanolamine, lysine or ethylenediamine. Analogously, within the scope of the invention salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate, are included as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for their use in non-therapeutic applications, example, in vitro. The term "physiologically functional derivative" used herein refers to any physiologically tolerable derivative of a compound of formula I of the invention, for example an ester which, after administration to a mammal such as, for example, a human , is capable of forming (directly or indirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives include prodrugs of the compounds of the invention. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs can be, in themselves, active or not. The compounds of the invention can also exist in various forms of polymorphs, for example, as amorphous and crystalline polymorph forms. All forms of polymorphs of the compounds of the invention are within the scope of the invention and are an additional aspect of the invention. All references to "compound (s) of formula I" hereinafter refer to compound (s) of formula I as described above, and salts, solvates and physiologically functional derivatives thereof as described above. A "heteroaryl radical" refers to a pyridinyl, pyrrolyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, imidazolyl, pyrazolyl, thiazolyl, thiophenyl or furanyl radical. The compound (s) of the formula I can also be administered in combination with more active ingredients. The amount of a compound of formula I necessary to achieve the desired biological effect depends on various 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 of 0.3 mg to 100 mg (typically 3 mg to 50 mg) per day and per kilogram of body weight, for example 3-10 mg / kg / day. An intravenous dose can be, for example, in the range of 0.3 mg to 1.0 mg, which can be suitably administered as an infusion of 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, 0.1 ng to 10 mg, typically 1 ng to 10 mg, per milliliter. The individual doses may contain, for example, from 1 mg to 10 g of the active ingredient. In this way, ampoules for injection may contain, for example, 1 mg to 100 mg, and individual dose formulations that can be administered orally, such as, for example, tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the therapy of the aforementioned conditions, the compounds of formula I can be used as the compound itself, but preferably in the form of a pharmaceutical composition with an acceptable carrier. Of course, the vehicle must be acceptable in the sense that it is compatible with the other ingredients of the composition and that it is not detrimental to the health of the patient. The vehicle must be a solid or a liquid or both and preferably is formulated with the compound as a single dose, for example, a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Analogously, there may be other pharmacologically active substances, including other compounds of formula I. The pharmaceutical compositions of the invention may be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with vehicles and / or pharmacologically excipients. acceptable The pharmaceutical compositions of the invention are suitable for oral, rectal, topical, peroral (e.g., sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most appropriate mode of administration depends in each individual case of the nature and severity of the condition to be treated and of the nature of the compound of formula I used in each case. Coated formulations and slow release coated formulations are also within the scope of the invention. Preference is given to formulations resistant to acids and gastric juices. Suitable gastric juice resistant coatings comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. Pharmaceutical compounds suitable for oral administration may be in the form of separate units such as, for example, capsules, seals, lupus tablets or tablets, each of which contains a defined amount of the compound of formula (I); as powders 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. As already mentioned, these compositions can be prepared by any suitable pharmaceutical method including a step in which the active ingredient and the vehicle (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced 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. In this way, for example, a tablet can be produced by compression or molding of a powder or granules of the compound, when appropriate with one or more additional ingredients. Compression tablets may be produced by compressing the compound in a fluid form such as, for example, in the form of a powder or granules, where appropriate in admixture with a binder, glidant, inert diluent and / or one or more surface active agent (s). (s) / dispersant (s) in a suitable machine. Molded tablets can be produced by molding the compound, which is in powder form and moistened with an inert liquid diluent, in a suitable machine. Pharmaceutical compositions that are suitable for peroral (sublingual) administration comprise liposome tablets containing a compound of formula I with a flavorant, typically sucrose and gum arabic or tragacanth, and lozenges comprising the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the recipient for which they are intended. These preparations are preferably administered intravenously, although administration can also be performed by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with the blood. The injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound. Pharmaceutical compositions suitable for rectal administration preferably are in the form of single dose suppositories. These can be produced by mixing a compound of the formula I with one or more conventional solid carriers, for example, cocoa butter, and molding the resulting mixture. Pharmaceutical compositions suitable for topical use in the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols and oils. The vehicles that can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal use may be in the form of individual strips which are suitable for direct contact for a long time with the epidermis of the patient. Such strips adequately contain the active ingredient in an aqueous solution which is suitably buffered when appropriate, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable concentration of the active ingredient is from about 1% to 35%, preferably from about 3% to 15%. A particular possibility for the active ingredient is to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986). Additional suitable active ingredients for combination products are: all the antidiabetics mentioned in Rote Liste 2003, Chapter 12. These can be combined with the compounds of the formula I of the invention, in particular for a synergistic improvement of the effect. The administration of combination of active ingredients may be carried out 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 a pharmaceutical preparation. Most of the active ingredients mentioned above are described in USP Dictionary of USAN and International Drug Ñames, US Pharmacopeia, Rockville 2001. Antidiabetics include insulin and insulin derivatives such as, for example, Lantus® (see www.lantus. .com) or HMR 1964, fast-acting insulins (see US 6,221,633), GLP-1 derivatives such as, for example, those described in WO 98/08871 of Novo Nordisk A / S, and ingredients effective oral hypoglycemic agents.

The effective oral hypoglycaemic active ingredients preferably include sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel opening agents such as, for example, those described in WO 97/26265 and WO 99/03861 of Novo Nordisk A / S, insulin sensitizers, hepatic enzyme inhibitors involved in the stimulation of gluconeogenesis and / or glycogenolysis, glucose uptake modulators, compounds that alter the metabolism lipid, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, compounds that reduce food intake, PPAR and PXR agonists and active ingredients that act on the ATP-dependent potassium channel of beta cells. In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin or rosuvastatin. In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside or pamaqueside. In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501 or Gl 262570.

In one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR alpha agonists such as, for example, GW 9578 and GW 7647. In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha / gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 11833, PCT / US 11490 and DE 10142734.4. In an embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, clofibrate and bezafibrate. In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757. In one embodiment of the invention, the compounds of the formula I are administered in combination with an inhibitor of bile acid absorption (see, for example, US 6,245,744 or US 6,221,897), such as, for example, example, HMR 1741. In one embodiment of the invention, the compounds of formula I are administered in combination with a CETP inhibitor, such as, for example, JTT-705. In one embodiment of the invention, the compounds of formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine and colesevelam. In one embodiment of the invention, the compounds of the formula I are administered in combination with an inducer of the LDL receptor (see US 6,342,512), such as, for example, HMR1171 and HMR1586. In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor such as, for example, avasimibe. In an embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant such as, for example, OPC-14117. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor such as, for example, NO-1886. In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP-citrate lyase inhibitor such as, for example, SB-204990. In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor such as, for example, BMS-188494. In an embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein (a) antagonist such as, for example, CI-1027 or nicotinic acid.

In an embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor such as, for example, orlistat. In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin. In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride. In one embodiment, the compounds of the formula I are administered in combination with a biguanide such as, for example, metformin. In a further embodiment, the compounds of the formula I are administered in combination with a meglitinide such as, for example, repaglinide. In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone, or the compounds described in WO 97/41097 of Dr. Reddy's Research Foundation, in in particular, 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl-methoxy] phenyl] methyl] -2,4-thiazolidinedione In one embodiment, the compounds of the formula I are administered in combination with an α-glucosidase inhibitor such as, for example, miglitol or acarbose.

In one embodiment, the compounds of formula I are administered in combination with an active ingredient that acts on the ATP-dependent potassium channel of beta cells such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide. In one embodiment, the compounds of formula I are administered in combination with more than one of the aforementioned compounds, for example, in combination with a sulfonylurea and metformin, with a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. In a further embodiment, the compounds of formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying n mice" Asakawa, A, et al., M. : Hormone and Metabolic Research (2001), 33 (9), 554-558), NPY antagonists, for example, hydrochloride. { 4 - [(4-aminoquinazolin-2-ylamino) methyl] cyclohexylmethyl} Naphthalene-1-sulfonic acid amide; (CGP 71683A)), MC4 agonists (eg, [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyra) 1-amino-1, 2,3,4-tetrahydronaphthalene-2-carboxylic acid din-5-yl) -1- (4-chlorophenyl) -2-oxoethyl] -amide (WO 01/91752)), orexin antagonists (eg, 1- (2-methylbenzoxazol-6-yl) -3- [1,5] naphthyridin-4-ylurea hydrochloride (SB-334867-A)), H3 agonists (acid salt Oxalic acid of 3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl) propan-1-one (WO 00/63208 )); TNF agonists, CRF antagonists (for example, [2-methyl-9- (2,4,6-trimethylphenyl) -9H-1,3,9-triazafluoren-4-yl] dipropylamine (WO 00 / 66585)), CRF BP antagonists (eg, urocortin), urocortin agonists, β3 agonists (eg, 1- (4-chloro-3-methanesulfonicmethylphenyl) -2- [2- (2,3- methylmethyl-1H-indol-6-yloxy) -ethalamine] -ethanol (WO 01/83451), MSH (melanocyte stimulating hormone) agonists, CCK-A agonists (e.g. , salt of trifluoroacetic acid acid. {2- 2- [4- (4-Chloro-2,5-dimethoxyphenyl) -5- (2-cyclohexylethyl) thiazol-2-ylcarbonyl] -5,7-dimethylindole-1-yl .) acetic (WO 99/15525)), serotonin reuptake inhibitors (eg, dexfenfluramine), mixed serotonergic and noradrenergic compounds (eg, WO 00/71549), 5HT agonists, eg, salt of the oxalic acid of 1- (3-ethylbenzofuran-7-yl) piperazine (WO 01/09111), bombesin agonists, galanin antagonists, hormone of growth (eg, human growth hormone), compounds that release growth hormone (6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3,4-dihydro-1 H-isoquinoline tert-butyl ester -2-carboxylic acid (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), modulators of decoupling protein 2 or 3, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential strategy for 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), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-β agonists. In one embodiment of the invention, the other 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. In a further embodiment, the other active ingredient is dexamfetamine or amphetamine. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. In another embodiment, the other active ingredient is sibutramine. In one embodiment, the other active ingredient is orlistat. In one embodiment, the other active ingredient is mazindol or phentermine. In one embodiment, the compounds of formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob / Caromax® (Zunft HJ; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18 (5), 230-6) Caromax is a product containing carob from Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Hóchst, 65926 Frankfurt / Main)). The combination with Caromax® can be achieved by administration of a preparation or by separate administration of compounds of formula I and Caromax®. In this case, Caromax® can also be administered in the form of food products such as, for example, in bakery products or muesli bars. It will be appreciated that each suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more pharmacologically active substances will be considered within the protection conferred by the present invention.

JTT-501 The preparation of the compounds of the formula I is described in the following schemes: The compounds of the formula II are reacted under Buchwaid conditions with amines of the formula III to give compounds of the formula IV in which R11 has the meaning of an ester. In this case, Y is Br or triflate. With these conditions of Buchwaid it is possible to use catalyst systems with Pd (OAc) 2 or Pd2 (dba) 3 as sources of palladium, BINAP, xanthfos and DPPF as ligands and Cs2CO3, K3PO4 or NatBu as bases. Solvents which can be used are, for example, toluene, DME, dioxane, THF or DMF. The reaction conditions may be selected between conventional heating or heating and reaction in a microwave. (Bibliography: Buchwaid, Acc. Chem. Res. 1998, 31, 805). The subsequent optional hydrolysis of the compounds of the formula IV leads to compounds of the formula I: Scheme X The compounds of the formula II can be prepared by various generally known methods such as, for example, those of WO 2002 048113. On the other hand, the compounds of the general formula II in which X is a carbon atom can be synthesized from of the corresponding anilines of the formula V by the route of Gould Jacobs, as shown in scheme 2. The alkylation on nitrogen can be carried out at any point of the synthesis.

Fsquema 2: A further aspect of this invention is a new preparation process for preparing the quinolones of the formula I as shown in scheme 2, wherein the radical Y is an unsubstituted or substituted aniline residue. On the other hand, compounds of the formula II in which X is a carbon atom can be prepared from carboxylic acids of the general formula VIII by conversion to the acid chloride and reaction with malonic ester and orthoformic ester, reaction with amines and subsequent cyclization (scheme 3).

Scheme 3: Vil sustnuiao. Scheme 3a: In this method of preparation, the compounds of the formula Villa are reacted under Buchwaid conditions (see above) with anilines of the general formula R7R8-NH to give compounds of the general formula Vlllb, where R 'is a hydrogen atom or an easily cleavable ester residue. If required, the Vlllb ester is cleaved to give compounds of the formula VIII with the choice of suitable conditions. The compounds of the general formula VIII. they can be converted as described in Scheme 3 by the compounds of formulas IX and VII into compounds of the general formula I. Or the other compounds of the general formula VIII are converted to the acid chloride and reacted with esters 3- dimethylaminoacrylics or by reaction with silymalmalonic esters and the subsequent reaction with dimethyl acetal-dimethylformamide to give compounds of the general formula IXa. The compounds of the general formula IXa can be converted by reaction with amines H2-N-R3 and the subsequent closure of the basic ring in compounds of the general formula I. The compounds of the formula II in which X is a nitrogen atom can be prepared by analogy with scheme 4: Scheme 4: Xll XI 2-Aminopyridines are converted by heating with EMME to compounds of the structure type of XI. These are cyclized to give the desired nullic acid derivatives Xll at temperatures above the 200 ° C in a suitable solvent such as DOWTHERM A or diphenyl ether.

The cyclization takes place in the manner described above only when the substituent R5 is not a hydrogen atom. (Bibliography: Edmont, Rocher, Plisson, Chenault, Bioorg, Med. Chem. Lett., 2000, 1831). The examples shown below serve to illustrate the invention, but not to restrict it.

Table 1 : The activity of the compounds was tested as indicated below: Assay of glycogen phosphorylase activity a The effect of the compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the reverse direction following the synthesis of glycogen from glucose 1 -phosphate by means of determining the release of inorganic phosphate. All reactions were performed as duplicate determinations in 96-well microtiter plates (Half Area Plates, Costar No. 3696), measuring the change in absorption due to the formation of the reaction product at the wavelength specified below in a Reader Elisa Multiskan Ascent (Lab Systems, Finland). To measure the enzymatic activity of GPa in the reverse direction, the general method of Engers et al. (Engers HD, Shechosky S, Madsen NB, Can J Biochem 1970 Jul; 48 (7): 746-754) to measure the conversion of glucose 1-phosphate to glycogen and inorganic phosphate, with the following modifications: glycogen phosphorylase was diluted to human (for example, with 0.76 mg protein / ml (Aventis Pharma Deutschland GmbH), dissolved in buffer solution E (25 mM β-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiothreitol) with buffer T (50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM EDTA) , 2.5 mM-6H2O MgCl2) and 5 mg / ml glycogen was added at a concentration of 10 μg protein / ml. The test substances were prepared as a 10 mM solution in DMSO and diluted to 50 μM with buffer solution T. To 10 μl of this solution were added 10 μl of 37.5 mM glucose, dissolved in buffer solution T, and mg / ml of glycogen, plus 10 μl of a solution of glycogen phosphorylase to human (10 μg protein / ml) and 20 μl of glucose 1-phosphate, 2.5 mM. The initial activity of glycogen phosphorylase a in the absence of the test substance was determined by adding 10 μl of buffer solution T (0.1% DMSO). The mixture was incubated at room temperature for 40 minutes and the inorganic phosphate released was measured by the general method of Drueckes et al. (Drueckes P, Schinzel R, Palm D, Anal Biochem 1995 Sep 1; 230 (1): 173-177) with the following modifications: 50 μl of a stop solution of ammonium molybdate 7.3 mM, zinc acetate is added 10.9 mM, 3.6% ascorbic acid and 0.9% SDS to 50 μl of the enzyme mixture. After incubation at 45 ° C for 60 minutes, absorption was measured at 820 nm. To determine the background absorption, in a separate mixture the stop solution was added immediately after the addition of the glucose-1-phosphate solution. This assay was performed at a concentration of 10 μM of the test substance to determine the particular inhibition of glycogen phosphorylase in vitro by the test substance.

Table 2: Biological activity 15 20 From the data in the table it is clear that the compounds of the formula I inhibit the activity of glycogen phosphorylase a and, thus, are very suitable for reducing the blood glucose level. The preparation of some examples is described in detail below and the other compounds of formula I were obtained analogously: Experimental part: Example 1 1 - . 1-Ethyl-6- (4-ethylphenollamino) -7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylate (Variant A of palladium-catalyzed amination) 100 mg of ethyl 6-bromo-1-ethyl-7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylate were transferred together with 37 mg of 4-ethylaniline, 20 mg of Pd (OAc) 2, 60 mg of BINAP and 250 mg of cesium carbonate to a suitable reaction vessel, a protective gas atmosphere was generated with argon and 10 ml of dioxane was added. Then, the mixture was heated at 80 ° C for 8 h. The pure product was isolated from the reaction solution by chromatography on an HPLC system. This involved the use of a Merck Purospher RP-18 column and a mixture of acetonitrile: water as eluent; the initial content of acetonitrile was 15% and rose to 90% over the course of 20 minutes. Performance: 45% c Example 167 1-Ethyl-6- (4-methoxy-2-methylphenylamino) -8-methyl-4-oxo-1,4-dihydroquinolone-3-carboxylic acid methyl ester (Variant B of palladium-catalyzed amination) 100 mg of 6-bromo-1-ethyl-8-methyl-4-oxo-1,4-dihydro-quinolone-3-carboxylate was transferred together with 42.3 mg of 4-methoxy-2-methylaniline, 20 mg of Pd (OAc) 2, 60 mg of XANTPHOS and 250 mg of cesium carbonate to a suitable reaction vessel, an atmosphere of protective gas was generated with argon and 10 ml of dioxane was added. Then, the mixture was heated at 80 ° C for 8 h. The pure product was isolated from the reaction solution by chromatography on an HPLC system. This involved the use of a Merck Purospher RP-18 column and a mixture of acetonitrile: water as eluent; the initial acetonitrile content was 15% and was raised to 100% over the course of 20 minutes. Performance: 40%.

Example 199 1-ethyl-6- (4-methoxy-2-methylphenylamino) -8-methyl-4-oxo-1,4-dihydroquinolone-3-carboxylic acid 1-Methyl-6- (4-methoxy-2-methylphenylamino) -8-methyl-4-oxo-1,4-dihydro-quinolone-3-carboxylic acid methyl ester (30 mg) was dissolved in 5 ml of dioxane, they added 2.5 equivalents of 1 N NaOH and the mixture was heated at 60 ° C for 4 h. Removal of the solvent in vacuo was followed by chromatography on an HPLC system to purify the product. This involved the use of a Merck Puroispher-RP 18 column and a mixture of acetonitrile: water as eluent; the initial acetonitrile content was 15% and rose to 95% over the course of 20 minutes. Performance: 75%. All other ester cleavages were performed in a similar manner.

Preparation of Intermediate IXa Variant A: a) Ethyl 2,4-dichloro-5- (2-chloro-4,6-difluorophenylamino) benzoate A solution of 100 mg (0.34 mmol) of ethyl 5-bromo-2,4-dichlorobenzoate, 197 mg (0.6 mmol) of cesium carbonate, 70 mg (0.12 mmol) of Xantphos, 23 mg (0.10 mmol) of palladium acetate and 60 mg (0.37 mmol) of 6-chloro-2,4-difluoroaniline in 3 ml of dimethoxyethane was heated at 100 ° C for 2 hours. After cooling to room temperature, the mixture was filtered with suction through kieselguhr and chromatographed on silica gel (heptane: ethyl acetate = 99: 1 to 90:10 in 90 minutes). 70 mg (55%) of the product were obtained. b) 2,4-Dichloro-5- (2-chloro-4,6-difluorophenylamino) benzoic acid 120 mg (0.31 mmol) of ethyl 2,4-dichloro-5- (2-chloro-2,6-difluorophenylamino) benzoate in 6 ml of a (1: 1) mixture of ethanol / hydroxide solution was suspended. 2 N sodium solution and heated at 90 ° C for 3 hours. After cooling to room temperature, the pH was adjusted to 2 with 2N sulfuric acid and the precipitate was filtered off with suction. 98 mg (88%) of the product were obtained. c) 2- [2,4-Dichloro-5- (2-chloro-4,6-difluorophenylamino) benzoyl] -3-dimethylamino-ethyl acrylate 98 mg (0.27 mmol) of 2,4-dichloro-5- (2-chloro-4,6-difluorophenylamino) benzoic acid were refluxed with 0.98 ml of thionyl chloride for 3 hours. The thionyl chloride was removed by distillation and the residue was mixed with 3 ml of toluene and concentrated in vacuo. The residue was taken up in 2 ml of toluene and added to a solution of 39 mg (0.27 mmol) of ethyl 3-dimethylaminoacrylate, 6 μl of triethylamine and 1 ml of toluene. The mixture was heated at 90 ° C for 3 hours. The mixture was concentrated and chromatographed on silica gel (heptane: ethyl acetate = 75:25 to 0: 100 in 45 minutes). 30 mg (23%) of the desired product were obtained. MS: M + H = 477/479 This intermediate was used, for example, for the synthesis of Example 327.

Variant B: a) Ethyl 3- [2,4-Dichloro-5- (2-chloro-4,6-difluorophenylamino) phenyl] -3-oxopropionate 3.0 g (8.51 mmol) of 2,4-dichloro-5- (2-chloro-4,6-difluorophenylamine) benzoic acid (variant A b)) and 9.3 ml of thionyl chloride were heated to the mixture. 70 ° C for 1, 5 hours. The mixture was diluted with 20 ml of dry toluene and concentrated. The residue was mixed twice with toluene and evaporated again. 1.4 ml of a 1.6 M solution of butyllithium in hexane was added to a solution of 3.47 g (17.0 mmol) of trimethylsilyl malonate in 45 ml of diethyl ether at -75 ° C in such a way that the temperature did not exceed -60 ° C after, the mixture was stirred at -75 ° C for 30 minutes. The 2,4-dichloro-5- (2-cyclo-4,6-difluorophenylamino) benzoyl chloride was dissolved in 45 ml of dimethoxyethane and added dropwise over 40 minutes. The mixture was slowly heated to 10 ° C and stirred at this temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed twice with portions of 250 ml each time of water and a saturated solution of sodium bicarbonate. The organic phase was dried and concentrated. 3.88 g of the crude mixture were obtained and reacted without purification in the next step. b) 2- [2,4-Dichloro-5- (2-chloro-4,6-difluorophenylamino) benzoyl] -3-dimethylamino-ethyl acrylate A solution of 3.88 g (crude) of 3- [2, Ethyl 4-dichloro-5- (2-chloro-4,6-difluorophenylamino) -phenyl] -3-oxopropionate and 1.22 g (0.10 mmol) of dimethylformamide dimethyl acetal in 10 ml of toluene was heated to reflux for 1, 5 hours. The mixture was cooled to room temperature and concentrated in vacuo. Purification on silica gel (petroleum ether (45-70 ° C) / ethyl acetate, 8 minutes isocratic 35% ethyl acetate, then 60% ethyl acetate in 7 minutes, flow rate 400 ml / minute) produced 3.59 g (82% in the two stages) of the desired product. MS: M + H = 477/479.

Example 327: 7-Chloro-6- (2-chloro-4,6-difluorophenylamino) -4-oxo-1-pyridin-3-yl-1,4-dihydroxy-nolone-3-carboxylic acid a) 2- [2,4-Dichloro-5- (2-chloro-4,6-difluorophenylamino) benzoyl] -3- (pyridin-3-yl-amino) ethyl acrylate A solution of 30 mg (0.06 mmol) of ethyl 2- [2,4-dichloro-5- (2-chloro-4,6-difluorophenol-amino) benzoyl] -3-dimethylaminoacrylate and 15 mg ( 0.16 mmol) of 3-aminopyridine in 2 ml of toluene was heated at 150 ° C for 7 hours. The concentration resulted in 33 mg of the desired product, which was used without further purification in the next step. b) 7-Chloro-6- (2-chloro-4,6-difluorophenylamino) -4-oxo-1-pyridin-3-yl-1,4-dihydro-quinolone-3-carboxylate in ethyl A suspension of 33 mg (0.06 mmol) of 2- [2,4-dicyoro-5- (2-chloro-4,6-difluoro-phenylamino) benzoyl] -3- (pyridin-3-ylamino) Ethyl acrylate, 10 mg (0.08 mmol) of potassium carbonate and 1 ml of dimethylformamide was heated at 90 ° C for 5 hours. The mixture was concentrated and purified by reverse phase HPLC (Purospher RP-18, acetonitrile / water). 12 mg (37%) of the desired product were obtained. c) 7-Chloro-6- (2-chloro-4,6-difluorophenylamino) -4-oxo-1-pyridin-3-yl-1,4-dihydro-quinolone-3-carboxylic acid 12 mg (0.02 mmol) of 7-chloro-6- (2-chloro-4,6-difluorophenylamino) -4-oxo-1-pyridin-3-yl-1,4-dihydroquinolone-3 was suspended. ethyl carboxylate in 6 ml of a mixture (1: 1) of ethanol / 2N sodium hydroxide solution and the mixture was heated at 90 ° C for 3 hours. After cooling to room temperature, the pH was adjusted to 2 with 2 N hydrochloric acid and the precipitate was filtered off with suction. 6 mg (53%) of the product were obtained. MS: M + H = 462/464.

Claims (14)

1. - A compound of the formula I wherein the meanings are R 1 OH, O-(C 1 -C 6) alkyl or O-C 1 -C 6 alkyl-OCO-(C 1 -C 6) alkyl; R2 H, (C1-C6) alkyl or phenyl; R3 H, (C1-C8) alkyl, (C3-C7) cycloalkyl, pyridyl or phenyl, wherein the alkyl may be substituted with R9 and wherein the phenyl or pyridyl may be substituted with R10; R9 NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2; COOH, COO-alkyl (C1-C6), (C3-C7) cycloalkyl, heteroalkyl, heteroaryl, O-phenyl or phenyl, wherein phenyl and heteroaryl may be substituted with R11; R10 F, Cl, Br, (C1-C6 alkyl), O-(C1-C6) alkyl, COOH, COO- (C1-6) alkyl, NH2, NH- (C1-C6) alkyl or N- (alkyl) C1-C6)) 2; R11 F, Cl, (C1-C6 alkyl), O-(C1-C6) alkyl, NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2, COOH or COO-alkyl ( C1-C4); X C-R4 or N; < J R 4 H, F, Cl, Br, OH, NO 2, CN, (C 1 -C 6) alkyl or O-C 1 -C 6 alkyl, where the alkyl may be substituted more than once with F, Cl or Br; R 5 H, F, Cl, Br, OH, NO 2, CN, (C 1 -C 6) alkyl or O-C 1 -C 6 alkyl, wherein the alkyl may be substituted more than once with F, Cl or Br; R6 H, F, Cl, Br, NO2, CN or (C1-C6) alkyl, wherein the alkyl may be substituted more than once with F, Cl or Br; R7 H or (C1-C6) alkyl; R8 phenyl, wherein the phenyl may be substituted up to five times with F, Cl, Br, CN, NO2, (C1-C8) alkyl, O-(C1-C8) alkyl, S- (C1-C8) alkyl, alkenyl (C2-C8), (C3-C7) cycloalkyl, (C1-C4) -CO-alkyl, phenyl, benzyl, benzoyl, NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2 , P (O) - (O-C 1 -C 4) 2 or heteroalkyl, where alkyl and alkenyl may be substituted more than once with F, Cl, Br, COOH or COO- (C 1 -C 4) alkyl; Heteroalkyl a 4 to 7 membered heterocyclic, saturated or unsaturated ring which may comprise up to 3 heteroatoms N, O or S as ring members, where the ring may be substituted with F, Cl, Br, CN, NO2, alkyl (C1 -C4), OH, COOH, COO-(C1-C4) alkyl; with the exception of the compounds of the formula I in which the radicals 20 have simultaneously the following meanings: X is equal to N, R1 is equal to OH, R2, R3, R4, R5 and R7 are equal to H and R8 is equal to unsubstituted phenyl; and the physiologically acceptable salts thereof.

2. - A compound of the formula I according to claim 1, wherein the meanings are R 1 OH, O-C 1 -C 6 alkyl or O-C 1 -C 6 alkyl-OCO-C 1 -C 6 alkyl; R2 H, (C1-C6) alkyl or phenyl; R3 (C1-C8) alkyl, (C3-C7) cycloalkyl, pyridyl or phenyl, wherein the alkyl may be substituted with R9 and wherein the phenyl or pyridyl may be substituted with R10; R9 NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2; COOH, COO- (C1-C6) alkyl, (C3-C7) cycloalkyl, heteroalkyl, heteroaryl, O-phenyl or phenyl, wherein phenyl and heteroaryl may be substituted with R11; R10 F, Cl, Br, (C1-C6 alkyl), O-(C1-C6) alkyl, COOH, COO- (C1-6) alkyl, NH2, NH- (C1-C6) alkyl or N- (alkyl) C1-C6)) 2; R11 F, Cl, (C1-C6 alkyl), O-(C1-C6) alkyl, NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2, COOH or COO-alkyl ( C1-C4); X C-R4 or N; R 4 H, F, Cl, Br, OH, NO 2, CN, (C 1 -C 6) alkyl or O (C 1 -C 6) alkyl, wherein the alkyl may be substituted more than once with F, Cl or Br; R 5 H, F, Cl, Br, OH, NO 2, CN, (C 1 -C 6) alkyl or O-C 1 -C 6 alkyl, wherein the alkyl may be substituted more than once with F, Cl or Br; R6 H, F, Cl, Br, NO2, CN or (C1-C6) alkyl, where the alkyl may be substituted more than once with F, Cl or Br; R7 H or (C1-C6) alkyl; R8 phenyl, wherein the phenyl may be substituted up to five times with F, Cl, Br, CN, NO2, (C1-C8) alkyl, O-(C1-C8) alkyl, S- (C1-C8) alkyl, alkenyl ( C2-C8), (C3-C7) cycloalkyl, (C1-C4) alkyl, phenyl, benzyl, benzoyl, NH2, NH- (C1-C6) alkyl, N- (C1-C6) alkyl) 2, P (O) - (O- (C 1 -C 4) alkyl) 2 or heteroalkyl, wherein alkyl and alkenyl may be substituted more than once with F, Cl, Br, COOH or COO- (C 1 -C 4) alkyl; heteroalkyl a 4 to 7 membered heterocyclic, saturated or unsaturated ring which may comprise up to 3 N, O or S heteroatoms as ring members, wherein the ring may be substituted with F, Cl, Br, CN, NO2, alkyl (C1-) C4), OH, COOH, COO-(C1-C4) alkyl; and the physiologically acceptable salts thereof.

3. - A compound of the formula I according to claim 1 or 2, wherein the meanings are: R 1 OH, O-C 1 -C 6 alkyl or O-C 1 -C 6 alkyl-OCO-(C 1 -C 6) alkyl; R2 H; R3 phenyl, wherein the phenyl may be substituted with R10; R10 F, Cl, Br, (C1-C6 alkyl), O-(C1-C6) alkyl, COOH, COO- (C1-6) alkyl, NH2, NH- (C1-C6) alkyl or N- (alkyl) C1-C6)) 2; X C-R4; R 4 H, (C 1 -C 6) alkyl; R 5 H, F, Cl, (C 1 -C 6) alkyl; R6 H; R7 H; R8 phenyl, wherein the phenyl may be substituted up to five times with F, Cl; and the physiologically acceptable salts thereof.

4. - A compound of formula I according to one or more of claims 1 to 3, wherein the meanings are: R 1 OH, O-(C 1 -C 6) alkyl; R2 H; R3 phenyl, wherein the phenyl is substituted with R10; R10 COOH, COO-C1-6alkyl; X C-R4; R 4 H, (C 1 -C 6) alkyl; R5 F, Cl, (C1-C6) alkyl; R6 H; R7 H; R8 phenyl, wherein the phenyl is substituted one to five times with F, Cl; and the physiologically tolerable salts thereof.

5. - A compound according to one or more of claims 1 to 4 for use as a medicament.

6. - A medicament comprising one or more of the compounds according to one or more of claims 1 to 4.

7. - A medicament comprising one or more of the compounds according to one or more of claims 1 to 4 and at least one other active ingredient.

8. The medicament according to claim 7, wherein the other active ingredient comprises one or more antidiabetics, active hypoglycaemic ingredients, inhibitors of HMGCoA reductase, inhibitors of cholesterol absorption, PPAR gamma agonists, PPAR alpha agonists, agonists of PPAR alpha / gamma, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, inhibitors of the ATP-citrate lyase, squalene synthetase inhibitors, lipoprotein (a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, a-glucosidase inhibitors, active ingredients that act on the potassium channel dependent on Β-cell ATP, CART agonists, NPY agonists, MC4 agonists, orexin agonists, agonists of H3, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone releasing compounds, HRT agonists, decoupling protein modulators 2 or 3, leptin agonists, DA agonists (bromocriptine, Doprexin) , lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists or amphetamines.

9. The use of the compounds according to one or more of claims 1 to 4 to produce a medicament for reducing blood glucose.

10. The use of the compounds according to one or more of claims 1 to 4, to produce a medicament for the treatment of type II diabetes.

11. The use of the compounds according to one or more of claims 1 to 4 to produce a medicament for the treatment of alterations of lipid and carbohydrate metabolism.

12. The use of the compounds according to one or more of claims 1 to 4 to produce a medicament for the treatment of arteriosclerotic manifestations.

13. The use of the compounds according to one or more of claims 1 to 4 to produce a medicament for the treatment of insulin resistance.

14. - A process for producing a medicament comprising one or more of the compounds according to one or more of claims 1 to 4, which comprises mixing the active ingredient with a pharmaceutically acceptable carrier and converting this mixture into a form suitable for administration .