Title of Invention	CYCLOALKYL-SUBSTITUTED ALKANOIC ACID DERIVATIVES
Abstract	The present invention relates to a compound of the formula I in which Ring A is (C<sub>3</sub>-C<sub>8</sub>)-cycloalkanediyl or (C<sub>3</sub>-C<sub>8</sub>)-cycloalkenediyl, where in the cycloalkane- or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms; R<sup>1</sup>, R<sup>2</sup> independently of one another are H, (C<sub>1</sub>-C<sub>6</sub>)-alkyl, (C<sub>3</sub>-C<sub>8</sub>-cycloalkyl or (C<sub>6</sub>-C<sub>10</sub>)-aryl; R<sup>3</sup> is (C<sub>3</sub>-C<sub>6</sub>)-cycloalkyl or (C<sub>1</sub>-C<sub>2</sub>)-alkyl which are optionally substituted by (C<sub>6</sub>-C<sub>10</sub>)-aryl, (C<sub>5</sub>-C<sub>6</sub>)-heteroaryl or (C<sub>3</sub>-C<sub>6</sub>)-cycloalkyl, where aryl, heteroaryl or cycloalkyl for their part may be substituted by (C<sub>1</sub>-C<sub>6</sub>)-alkyl, (C<sub>1</sub>-C<sub>6</sub>)-alkoxy, CI, Br, I, CO-(C<sub>1</sub>-C<sub>6</sub>)-alkyl, CO-O(C<sub>1</sub>-C<sub>6</sub>)-alkyl, CO-NH(C<sub>1</sub>-C<sub>6</sub>)-alkyl or CO-N((C<sub>1</sub>-C<sub>6</sub>)-alkyl)z; X is (C<sub>1</sub>-C<sub>6</sub>)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; Y<sup>1</sup> is CO or a bond; Y<sup>2</sup> is NH, (C<sub>1</sub>-C<sub>12</sub>)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; R<sup>4</sup> is (C<sub>1</sub>-C<sub>8</sub>)-alkyl; R<sup>5</sup> is H, (C<sub>1</sub>-C<sub>8</sub>)-alkyl; R<sup>6</sup> is H; and its physiologically acceptable salts

Title of Invention

CYCLOALKYL-SUBSTITUTED ALKANOIC ACID DERIVATIVES

Abstract

The present invention relates to a compound of the formula I in which Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, where in the cycloalkane- or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms; R1, R2 independently of one another are H, (C1-C6)-alkyl, (C3-C8-cycloalkyl or (C6-C10)-aryl; R3 is (C3-C6)-cycloalkyl or (C1-C2)-alkyl which are optionally substituted by (C6-C10)-aryl, (C5-C6)-heteroaryl or (C3-C6)-cycloalkyl, where aryl, heteroaryl or cycloalkyl for their part may be substituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, CI, Br, I, CO-(C1-C6)-alkyl, CO-O(C1-C6)-alkyl, CO-NH(C1-C6)-alkyl or CO-N((C1-C6)-alkyl)z; X is (C1-C6)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; Y1 is CO or a bond; Y2 is NH, (C1-C12)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; R4 is (C1-C8)-alkyl; R5 is H, (C1-C8)-alkyl; R6 is H; and its physiologically acceptable salts

Full Text	Description Cycloalkyl-substituted alkanoic acid derivatives, methods for the production thereof, and use thereof as a medicament The invention relates to arylcycloalkyl-substituted alkanoic acid derivatives and to their physiologically acceptable salts and physiologically functional derivatives. Compounds of a similar structure have already been described in the prior art for the treatment of hyperlipidemia and diabetes (WO 2000/64876). It was an object of the invention to provide compounds which allow a therapeutically exploitable modulation of the lipid and/or carbohydrate metabolism and are thus suitable for the prevention and/or treatment of diseases such as type 2 diabetes and atherosclerosis and the various sequelae thereof. Surprisingly, a series of compounds which modulate the activity of PPAR receptors has been found. In particular, the compounds are suitable for the activation of PPARalpha and PPARgamma, and the extent of the relative activation can be different depending on the compounds. Accordingly, the invention relates to compounds of the formula I in which Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, where in the cycloalkane- or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms; R1, R2 independently of one another are H, C1-6-a!kyI, (C3-C8)-cycloalkyl or(C6-C10)-aryi; R3 is (C3-C6)-cycloalkyl or (C1-C12)-alkyl which are optionally substituted by (C6-C10)-aryl, (C1-C6)-heteroaryl or (C3-C6)-cycloalkyl, where aryl, heteroaryl or cycloalkyl for their part may be substituted by (C1-C6)-alkyl, C1-6-alkoxy, CI, Br, I, CO-(C1-C6)kyl, CO-0C1-6-alkyl, CO-NH(1-6)alkyl or CO-N(C1-6-alkyl)2; X is C1-6-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; Y1 is CO or a bond; Y2 is NH, (C1-C12)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; R4 is (C1 -C8)-alkyl; R5 is H, C1-6-alkyl; R6 is H; and their physiologically acceptable salts. Preference is given to compounds of the formula I whose substituents X and Y1 are bonded to the ring A in positions 1 and 3. (X - Ring A - Y1). Preference is also given to compounds of the formula I in which Ring A is (C3-C8)-cycloalkane-1,3-diyl; R1, R2 independently of one another are H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or(C6-Cio)-aryl; R3 is (C1-C12)-cycloalkyl which is optionally substituted by phenyl, where phenyl for its part may be substituted by C1-6-alkyI; X is (C1-C6)-alkanediyl, where in the alkanediyl group one carbon atom may be replaced by an oxygen atom; Y1 is CO or a bond; Y2 is NH, C1-6-alkanediyl, where in the alkanediyl group one carbon atom may be replaced by an oxygen atom; R4 is(C1-C8)-alkyl; R5 is H, C1-6-alkyl; R6 is H. Particular preference is given to compounds of the formula I in which Ring A is cyclohexane-1,3-diyl; R1, R2 independently of one another are H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or phenyl; R3 is (C1-C12)-alkyl which is optionally substituted by phenyl, where phenyl for its part may be substituted by methyl; X is (C1-6)-alkanediyl, where in the alkanediyl group the carbon atom adjacent to ring A may be replaced by an oxygen atom; Y1 is CO or a bond; Y2 is NH, (C1-C6)-alkanediyl, where in the alkanediyl group one carbon atom may be replaced by an oxygen atom; R4 is (C1-C8)-alkyl; R5 isH or(Ci-C4)-alkyl; R6 is H. Very particular preference is given to compounds of the formula I in which Ring A is cyclohexane-1,3-diyl; R1 is H; R2 is C1-6-alkyl, (C3-C8)-cycloalkyl or phenyl; R3 is (C1-C8)-alkyl which is optionally substituted by phenyl, where phenyl for its part may be substituted by methyl; X is ((CH2)2)0; Y1 is CO or a bond; Y2 is NH, (C1-C4)-alkanediyl; R4 is C1-6-alkyl; R5 is H, (C1-C4)-alkyl; R6 is H. The bond to ring A may be either cis or trans, preference is given to the cis-bond. The present invention also encompasses all combinations of the "preferred embodiments" of the invention described herein. The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5 and R6 can be straight-chain or branched. Aryl refers to an aromatic, carbocyclic, mono- or bicyclic ring system which contains from 6 to 10 atoms in the ring or in the rings. Heteroaryl is a mono- or bicyclic aromatic ring system having from 4 to 11 ring members, in which at least one atom in the ring system is a heteroatom from the group of N, O and S. The compounds of the formula I contain at least two centers of asymmetry and may contain more. The compounds of the formula I may therefore be present in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and diastereomer mixtures. The present invention encompasses all of these isomeric forms of the compounds of the formula I. These isomeric forms may, even when some of them are not described expresses verbis, be obtained by known methods. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater solubility in water compared with the starting or base compounds. 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 acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts) and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine. Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutical^ acceptable salts and/or for use in nontherapeutic, for example in vitro, applications. The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester which is able, on administration to a mammal such as, for example, to a human, to form (directly or indirectly) a compound of the formula I or an active metabolite thereof. Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves have activity or not. The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the scope of the invention and are a further aspect of the invention. All references hereinafter to "compound(s) of formula I" refer to compound(s) of the formula I as described above, and to the salts, solvates and physiologically functional derivatives thereof as described herein. Use This invention relates further to the use of compounds of the formula I and their pharmaceutical compositions as PPAR receptor ligands. The PPAR receptor ligands of the invention are suitable as modulators of the activity of the PPAR receptors. Peroxisome proliferator-activated receptors (PPAR) are transcription factors which can be activated by ligands and belong to the class of nuclear hormone receptors. There are three PPAR isoforms, PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes (Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Motojima K, Cell Struct Fund, 1993 Oct, 18(5), 267-77). There exist two variants of PPARgamma, PPARgammai and -gamma2, which are the result of alternative use of promoters and differential mRNA splicing (Vidal-Puig et al.f J. Clin. Invest., 97:2553-2561, 1996). The various PPAR receptors have a different tissue distribution and modulate different physiological functions. The PPAR receptors play a key role in different aspects of the regulation of a multitude of genes, whose gene products are crucially involved directly or indirectly in lipid and carbohydrate metabolism. Thus, for example, PPARalpha receptors play an important role in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARgamma is crucially involved, for example, in the regulation of adipose cell differentiation. In addition, PPAR receptors are also involved in the regulation of many further physiological processes, including those which are not directly connected with carbohydrate or lipid metabolism. The activity of the different PPAR receptors can be modulated to varying extents by various fatty acids, fatty acid derivatives and synthetic compounds. For relevant reviews concerning functions, physiological effect and pathophysiology, see: Joel Berger et al., Annu. Rev. Med., 2002, 53, 409 - 435; Timothy Wilson et alM J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al., Recent Prog Horm Res., 2001, 56, 239-63. The present invention relates to compounds of the formula I which are suitable for modulating the activity of PPAR receptors, especially the activity of PPARalpha and PPARgamma. Depending on the profile of the modulation, the compounds of the formula I are suitable for the treatment, control and prophylaxis of the indications described hereinafter, and for a series of other, connected pharmaceutical applications (see, for example, Joel Berger et al., Annu. Rev. Med., 2002, 53, 409 - 435; Timothy Wilson et al., J. Med. Chem., 2000, Vol. 43(4), 527-550; Steven Kliewer et al., Recent Prog Horm Res., 2001, 56, 239-63; Jean-Charles Fruchart, Bart Staeis and Patrick Duriez: PPARS, Metabolic Disease and Arteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARs in health and disease, NATURE, VOL. 405, 25 MAY 2000, 421-4; Ines Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staeis: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12:2001, 245-254). Compounds of this type are particularly suitable for the treatment and/or prevention of 1. - disorders of fatty acid metabolism and glucose utilization disorders - disorders in which insulin resistance plays a role 2. Diabetes mellitus, in particular type 2 diabetes, including the prevention of the associated sequelae. Particular aspects in this connection are - hyperglycemia - improvement in insulin resistance - improvement in glucose tolerance - protection of the p-cells of the pancreas - prevention of macro- and microvascular disorders 3. Dyslipidemias and their sequelae, such as, for example, atherosclerosis, coronary heart disease, cerebrovascular disorders, etc, especially those (but not restricted to those) which are characterized by one or more of the following factors: - high plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations - low HDL cholesterol concentrations - low ApoA lipoprotein concentrations - high LDL cholesterol concentrations - small dense LDL cholesterol particles - high ApoB lipoprotein concentrations 4. Various other conditions which may be associated with metabolic syndrome are such as: - obesity (excess weight), including central obesity - thromboses, stages of hypercoagulability and prethrombosis (arterial and venous) - high blood pressure - heart failure, such as, for example, (but not restricted to that) in the state after myocardial infarction, hypertensive heart disease or cardiomyopathy 5. Further disorders or conditions in which, for example, inflammatory reactions or cell differentiation play a role: - atherosclerosis, such as, for example, (but not restricted to) coronary sclerosis including angina pectoris or myocardial infarction, stroke - vascular restenosis or reocclusion - chronic inflammatory bowel diseases, such as, for example, Crohn's disease and ulcerative colitis - pancreatitis - other inflammatory states - retinopathy - adipose cell tumors - lipomatous carcinomas such as, for example, liposarcomas - solid tumors and neoplasms, such as, for example, (but not restricted to) carcinomas of the gastrointestinal tract, of the liver, of the biliary tract and of the pancreas, endocrine tumors, carcinomas of the lungs, of the kidneys and the urinary tract, of the genital tract, prostate carcinomas, etc. - acute and chronic myeloproliferative disorders and lymphomas - angiogenesis - neurodegenerative diseases - Alzheimer's disease - multiple sclerosis - Parkinson's disease - erythemato-squamous dermatoses such as, for example, psoriasis - acne vulgaris - other skin disorders and dermatological conditions which are modulated by PPAR - eczemas and neurodermatitis - dermatitis, such as, for example, seborrheic dermatitis or photodermatitis - keratitis and keratoses, such as, for example, seborrheic keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or keratosis follicularis - keloids and keloid prophylaxis - warts, including condylomata or condylomata acuminata - human papilloma virus (HPV) infections, such as, for example, venereal papillomata, viral warts, such as, for example, molluscum contagiosum, leukoplakia - papular dermatoses, such as, for example, lichen planus - skin cancer, such as, for example, basal-cell carcinomas, melanomas or cutaneous T-cell lymphomas - localized benign epidermal tumors, such as, for example, keratoderma, epidermal naevi - chilblains - high blood pressure - syndrome X - polycystic ovary syndrome (PCOS) - asthma - osteoarthritis - lupus erythematosus (LE) or inflammatory rheumatic disorders, such as, for example, rheumatoid arthritis - vasculitis - wasting (cachexia) - gout - ischemia/reperfusion syndrome - acute respiratory distress syndrome (ARDS) ("shock lung") Formulation The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg) per day and per kilogram of body weight, for example 0.1-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.001 mg to LOmg/kg, which can suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active compound. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients. Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated slow-release formulations also belong within the scope of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. Suitable pharmaceutical preparations for oral administration may be in the form of separate units such as, for example, capsules, wafers, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine. Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. The pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place 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 blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound. Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture. Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active compound is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active compound in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active compound concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active compound to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986). The compounds of the formula I act favorably on metabolic disorders. They have a positive effect on lipid and sugar metabolism and, in particular, reduce the concentration of triglycerides, and they are suitable for preventing and treating type II diabetes and arteriosclerosis and their various sequelae. Combinations with other medicaments The compounds of the invention can be administered alone or in combination with one or more further pharmacologically active substances which, for example, act favorably on metabolic disorders or diseases frequently associated therewith. Such medicaments are, for example, 1. medicaments which lower blood glucose, antidiabetics, 2. active compounds for the treatment of dyslipidemias, 3. antiatherosclerotic medicaments, 4. antiobesity agents, 5. antiinflammatory active compounds 6. active compounds for the treatment of malignant tumors 7. antithrombotic active compounds 8. active compounds for the treatment of high blood pressure 9. active compounds for the treatment of heart failure and 10. active compounds for the treatment and/or prevention of complications caused by diabetes or associated with diabetes. They may be combined with the compounds of the formula I according to the invention in particular for synergistic improvement of the effect. Administration of the active compound combination may take place either by separate administration of the active compounds to the patients or in the form of combination products in which a plurality of active compounds are present in one pharmaceutical preparation. Mention may be made by way of example of: Antidiabetics Suitable antidiabetics are disclosed, for example, in the Rote Liste 2001, chapter 12 or in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2003. Antidiabetics include all insulins and insulin derivatives, such as, for example, Lantus® (see www.lantus.com) or Apidra®, and other fast-acting insulins (see US 6,221,633), GLP-1 receptor modulators as described in WO 01/04146 or else, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S. The orally active hypoglycemic active compounds include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, oral GLP-1 agonists, DPP-IV inhibitors, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenosis, modulators of glucose uptake, compounds which alter lipid metabolism and lead to alteration of the lipid compostion of the blood, compounds which reduce food intake or food uptake, PPAR and PXR modulators and active compounds which act on the ATP-dependent potassium channel of the beta cells. In one embodiment of the invention, the compounds of the formula I are administered administered in combination with insulin. In one embodiment of the invention, the compounds of the formula I are in combination with substances which influence hepatic glucose production such as, for example, glycogen phosphorylase inhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188). 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 an active compound which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide. 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, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2- quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione. In one embodiment, the compounds of the formula I are administered in combination with a DPPIV inhibitor as described, for example, in W098/19998, W099/61431, W099/67278, W099/67279, WO01/72290, WO 02/38541, WO03/040174, in particular P 93/01 (1-cyclopentyl-3-methyl-1-oxo-2- pentaneammonium chloride), P-31/98, LAF237 (1-[2-[3-hydroxyadamant-1- yIamino)acetyl]pyrrolidine-2-(S)-carbonitrile), TS021 ((2S, 4S)-4-fluoro-1-[[(2- hydroxy-1,1-dimethylethyl)amino]acetyl]pyrrolidine-2-carbonitrile monobenzenesulfonate). In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARgamma agonist such as, for example, rosiglitazone, pioglitazone. In one embodiment, the compounds of the formula I are administered in combination with compounds with an inhibitory effect on SGLT-1 and/or 2, as disclosed directly or indirectly for example in PCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455. In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor such as, for example, miglitol or acarbose. In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. Lipid modulators In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin. In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor (see, for example, US 6,245,744, US 6,221,897, US 6,277,831, EP 0683 773, EP 0683 774). In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent, such as, for example, cholestyramine, colesevelam. In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, as described, for example, in WO 0250027, or ezetimibe, tiqueside, pamaqueside. In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see, for example, US 6,342,512). In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6); Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt/Main). Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars. In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARalpha agonist. 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, AZ 242 (Tesaglitazar, (S)-3-(4-[2-(4-methane- sulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionic acid), BMS 298585 (N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]phenyl]methyl]glycine) or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, W096/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876. In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrate. In one embodiment of the invention, the compounds of the formula I are administered in combination with nicotinic acid or niacin. In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example CP-529, 414 (torcetrapib). In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor. 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. In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor. In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor. In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist. Antiobesity agents In one 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, the other active compound is fenfluramine or dexfenfluramine. In another embodiment, the other active compound is sibutramine. In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.:Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists (for example N-{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}-naphthalene-1-sulfonamide, hydrochloride (CGP 71683A)), MC4 agonists (for example N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexa- hydropyrazolo[4,3-c]pyridin-5-yl)-1-(4«chlorophenyl)-2-oxoethyl]-l-amino- 1,2,3,4-tetrahydronaphthalene-2-carboxamide (WO 01/91752)), orexin antagonists (for example 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride (SB-334867-A)), H3 agonists (for example 3-cyclohexyl- 1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (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 (for example urocortin), urocortin agonists, (33 agonists (for example 1-(4-chloro-3-methanesulfonylmethylphenyl)- 2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol, hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (for example {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)- thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)); serotonin reuptake inhibitors (for example dexfenfluramine), mixed serotoninergic and noradrenergic compounds (for example WO 00/71549), 5HT agonists (for example 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111)), bombesin agonists, galanin antagonists, growth hormone (for example human growth hormone), growth-hormone-releasing compounds tert-butyl (6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro- 1H-isoquinoline-2-carboxylate (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), decoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors (for example WO 00/40569), PPAR modulators (for example WO 00/78312), RXR modulators or TR-/3 agonists. In one embodiment of the invention, the other active compound is leptin. In one embodiment, the other active compound is dexamphetamine, amphetamine, mazindol or phentermine. In one embodiment, the compounds of the formula I are administered in combination with medicaments having effects on the coronary circulation and the vascular system, such as, for example, ACE inhibitors (e.g. ramipril), medicaments which act on the angiotensin-renin system, calcium antagonists, beta blockers, etc. In one embodiment, the compounds of the formula I are administered in combination with medicaments having an antiinflammatory effect. In one embodiment, the compounds of the formula I are administered in combination with medicaments which are employed for cancer therapy and cancer prevention. It is self-evident that any suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is regarded as falling within the scope of protection conferred by the present invention. The activity of the compounds was tested as follows: Determination of EC50 values of PPAR agonists in the cellular PPARalpha test Principle The potency of substances which bind to human PPARalpha and activate it in an agonistic manner is analyzed using a stably transfected HEK cell line (HEK= human embryo kidney) which is referred to here as PPARalpha reporter cell line. It contains two genetic elements, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) which mediates expression of the luciferase reporter element depending on a PPARalpha ligand. The stably and constitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD binds in the cell nucleus of the PPARalpha reporter cell line via the GAL4 protein portion to the GAL4 DNA binding motif 5'-upstream of the luciferase reporter element which is integrated in the genome of the cell line. There is only little expression of the luciferase reporter gene without addition of a PPARalpha ligand if fatty acid-depleted fetal calf serum (cs-FCS) is used in the test. PPARalpha ligands bind and activate the PPARalpha fusion protein and thereby bring about expression of the luciferase reporter gene. The luciferase which is formed can be detected by means of chemiluminescence via an appropriate substrate. Construction of the cell line The PPARalpha reporter cell line was prepared in 2 stages. Firstly, the luciferase reporter element was constructed and stably transfected into HEK cells. For this purpose, five binding sites of the yeast transcription factor GAL4 (in each case 5'-CGGAGTACTGTCCTCCGAG-3') were cloned in 5'-upstream of a 68 bp-long minimal MMTV promoter (Accession #V01175), The minimal MMTV promoter section contains a CCAAT box and a TATA element in order to enable efficient transcription by RNA polymerase II. The cloning and sequencing of the GAL4-MMTV construct took place in analogy to the description of Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Then the complete Photinus pyralis luciferase gene (Accession # M15077) was cloned in 3'-downstream of the GAL4-MMTV element. After sequencing, the luciferase reporter element consisting of five GAL4 binding sites, MMTV promoter and luciferase gene was recloned into a plasmid which confers zeozin resistance in order to obtain the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfected into HEK cells in accordance with the statements in Ausubel, F.M. et al. (Current protocols in molecular biology, Vol. 1-3, John Wiley & Sons, Inc., 1995). Then zeozin-containing medium (0.5 mg/ml) was used to select a suitable stable cell clone which showed very low basal expression of the luciferase gene. In a second step, the PPARalpha fusion protein (GR-GAL4»humanPPARalpha-LBD) was introduced into the stable cell clone described. For this purpose, initially the cDNA coding for the N-terminal 76 amino acids of the glucocorticoid receptor (Accession # P04150) was linked to the cDNA section coding for amino acids 1-147 of the yeast transcription factor GAL4 (Accession # P04386). The cDNA of the ligand-binding domain of the human PPARalpha receptor (amino acids S167-Y468; Accession #S74349) was cloned in at the 3' end of this GR-GAL4 construct. The fusion construct prepared in this way (GR-GAL4-humanPPARalpha-LBD) was recloned into the plasmid pcDNA3 (from Invitrogen) in order to enable constitutive expression therein by the cytomegalovirus promoter. This plasmid was linearized with a restriction endonuclease and stably transfected into the previously described cell clone containing the luciferase reporter element. The finished PPARalpha reporter cell line which contains a luciferase reporter element and constitutively expresses the PPARalpha fusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by selection with zeozin (0.5 mg/ml) and G418 (0.5 mg/ml). Test procedure The activity of PPARalpha agonists is determined in a 3-day test, described below: Day 1 The PPARalpha reporter cell line is cultivated up to 80% confluence in DMEM (#41965-039, Invitrogen) with the following additives: 10% cs-FCS (fetal calf serum, #SH-30068.03, Hyclone), 0.5 mg/ml of zeozin (#R250-01, Invitrogen), 0.5 mg/ml of G418 (#10131-027, Invitrogen), 1% penicillin streptomycin solution (#15140-122, Invitrogen) and 2mM of L-glutamine (#25030-024, Invitrogen). Cultivation is carried out in standard cell culture bottles (# 353112, Becton Dickinson) in a cell culture incubator at 37°C in the presence of 5% C02. The 80% confluent cells are washed once with 15 ml of PBS (#14190-094, Invitrogen), treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C for 2 min, taken up in 5 ml of the DMEM medium described and counted in a cell counter. After dilution to 500 000 cells/ml, in each case 35 000 cells are sown into each well of a 96-well microtiter plate having a clear plastic bottom (#3610, Corning Costar). The plates are incubated in a cell incubator at 37°C and 5% CO2 for 24 h. Day 2 The PPARalpha agonists to be tested are dissolved in DMSO at a concentration of 10 mM. This stock solution is diluted in DMEM (#41965-039, Invitrogen) to which 5% of cs-FCS (#SH-30068.03, Hyclone), 2 mM of L-glutamine (#25030-024, Invitrogen) and the antibiotics already described (zeozin, G418, penicillin and streptomycin) are added. Test substances are tested at 11 different concentrations in the range of from 10 nM to 100 pM. More potent compounds are tested in concentration ranges of from 1 pM to 10 pM or between 100 nM and 1 pM. The medium of the PPARalpha reporter cell line sown on day 1 is completely removed by aspiration, and, immediately, the test substances diluted in medium are added to the cells. Dilution and addition of the substances are carried out using a robot (Beckman FX). The end volume of the test substances diluted in medium is 100 pi per well of a 96-well microtiter plate. The DMSO concentration in the test is below 0.1 % v/v to prevent cytotoxic effects of the solvent. To demonstrate that the test is working in each individual plate, a standard PPARalpha agonist, which is also diluted to 11 different concentrations, was To demonstrate that the test is working in each individual plate, a standard PPARalpha agonist, which is also diluted to 11 different concentrations, was added to each plate. The test plates are incubated in an incubator at 37°C and 5% C02for24h. Day 3 The PPARalpha receptor cells treated with the test substances are removed from the incubator and the medium is aspirated off. The cells are lyzed by pipetting 50 IJ\ of Bright Glo reagent (from Promega) into each well of a 96-well microtiter plate. After incubation at room temperature in the dark for 10 minutes, the microtiter plates are measured in the luminometer (Trilux from Wallac). The measuring time for each well of a microtiter plate is 1 sec. Evaluation The crude data of the luminometer are exported into a Microsoft Excel file. Dose-activity curves and EC50 values of PPAR agonists are calculated using the program XL.Fit according to the instructions of the manufacturer (IDBS). The PPARalpha EC50 values for the compounds of examples 1 to 15 in this assay are in the range from 0.04 nM to > 10 jaM. The results for the activity of some compounds of the formula I according to the invention are listed in table I below: It is evident from table I that the compounds of the formula i according to the invention activate the PPARalpha receptor, thus effecting, for example, analogously to clinically used fibrates, a lowering of the triglyceride concentration in the organism (see, for example, J.-Ch. Fruchard et al.: PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001; S. Kersten et al.: Roles of PPARs in health and disease, NATURE, VOL 405, 25 MAY 2000, 421-4; I. Pineda et al.: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001,245-254). Determination of EC50 values of PPAR agonists in the cellular PPARgamma test Principle A transient transfection system is employed to determine the cellular PPARgamma activity of PPAR agonists. It is based on the use of a luciferase reporter plasmid (pGL3basic-5xGAL4-TK) and of a PPARgamma expression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids are transiently transfected into human embryonic kidney cells (HEK cells). There is then expression in these cells of the fusion protein GAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of the reporter plasmid. In the presence of a PPARgamma-active ligand, the activated fusion protein GAL4-humanPPARgammaLBD induces expression of the luciferase reporter gene, which can be detected in the form of a chemiluminescence signal after addition of a luciferase substrate. As a difference from the stably transfected PPARalpha reporter cell line, in the cellular PPARgamma test the two components (luciferase reporter plasmid and PPARgamma expression plasmid) are transiently transfected into HEK cells because stable and permanent expression of the PPARgamma fusion protein is cytotoxic. Construction of the plasmids The luciferase reporter plasmid pGL3basic-5xGAL4-TK is based on the vector pGL3basic from Promega. The reporter piasmid is prepared by cloning five binding sites of the yeast transcription factor GAL4 (each binding site with the sequence 5'-CTCGGAGGACAGTACTCCG-3'), together with a 160 bp-long thymidine kinase promoter section (Accession # AF027128) 5'-upstream into pGL3basic. 3'-downstream of the thymidine kinase promoter is the complete luciferase gene from Photinus pyralis (Accession # M15077) which is already a constituent of the plasmid pGL3basic used. The cloning and sequencing of the reporter plasmid pGL3basic-5xGAL4-TK took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). The PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD was prepared by first cloning the cDNA coding for amino acids 1-147 of the yeast transcription factor GAL4 (Accession # P04386) into the plasmid pcDNA3 (from Invitrogen) 3'-downstream of the cytomegalovirus promoter. Subsequently, the cDNA of the ligand-binding domain (LBD) of the human PPARgamma receptor (amino acids I152-Y475; Accession # g1480099) was cloned 3'-downstream of the GAL4 DNA binding domain. Cloning and sequencing of the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD again took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Besides the luciferase reporter plasmid pGL3basic-5xGAL4-TK and the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD, also used for the cellular PPARgamma test are the reference plasmid pRL-CMV (from Promega) and the plasmid pBluescript-SK(+) from Stratagene. All four plasmids were prepared using a plasmid preparation kit from Qiagen, which ensures a plasmid quality with a minimal endotoxin content, before transfection into HEK cells. Test procedure The activity of PPARgamma agonists is determined in a 4-day test which is described below. Before the transfection, HEK cells are cultivated in DMEM (#41965-039, Invitrogen) which is mixed with the following additions: 10% FCS (#16000-044, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Day 1 Firstly, solution A, a transfection mixture which contains all four plasmids previously described in addition to DMEM, is prepared. The following amounts are used to make up 3 ml of solution A for each 96-well microtiter plate for one test: 2622 \|jl of antibiotic- and serum-free DMEM (# 41965-039, Invitrogen), 100 pi of reference plasmid pRL-CMV (1 ng/pl), 100 pi of luciferase reporter plasmid pGL3basic-5xGAL4-TK (10 ng/pl), 100 pi of PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD (100 ng/pl) and 78 pi of plasmid pBluescript-SK(+) (500 ng/pl). Then 2 ml of solution B are prepared by mixing 1.9 ml of DMEM-(# 41965-039, Invitrogen) with 100 pi of PolyFect transfection reagent (from Qiagen) for each 96-well microtiter plate. Subsequently, 3 ml of solution A are mixed with 2 ml of solution B to give 5 ml of solution C, which is thoroughly mixed by multiple pipetting and incubated at room temperature for 10 min. 80%-confluent HEK cells from a cell culture bottle with a capacity of 175 cm2 are washed once with 15 ml of PBS (#14190-094, Invitrogen) and treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C for 2 min. The cells are then taken up in 15 ml of DMEM (#41965-039, Invitrogen) which is mixed with 10% FCS (# 16000-044, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). After the cell suspension has been counted in a cell counter, the suspension is diluted to 250 000 cells/ml. 15 ml of this cell suspension are mixed with 5 ml of solution C for one microtiter plate. 200 pi of the suspension are seeded in each well of a 96-well microtiter plate with a clear plastic base (#3610, Corning Costar). The plates are incubated in a cell culture incubator at 37°C and 5% C02 for 24 h. Day 2 PPAR agonists to be tested are dissolved in DMSO in a concentration of 10 mM. This stock solution is diluted in DMEM (# 41965-039, Invitrogen) which is mixed with 2% Ultroser (#12039-012, Biosepra), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Test substances are tested in a total of 11 different concentrations in the range from 10 \|JM to 100 pM. More potent compounds are tested in concentration ranges from 1 ptol0pM. The medium of the HEK cells transfected and seeded on day 1 is completely removed by aspiration, and the test substances diluted in medium are immediately added to the cells. The dilution and addition of the substances is carried out by a robot (Beckman FX). The final volume of the test substances diluted in medium is 100 pi per well of a 96-well microtiter plate. Each plate is charged with a standard PPARgamma agonist, which is likewise diluted in 11 different concentrations, in order to demonstrate the functioning of the test in each individual plate. The test plates are incubated in an incubator at 37°C and 5% C02for 48 h. Day 4 After removal of the medium by aspiration, 50 \i\ of Dual-Glo™ reagent (Dual- Glo™ Luciferase Assay System; Promega) are added to each well in accordance with the manufacturer's instructions in order to lyze the cells and provide the substrate for the firefly luciferase (Photinus pyralis) formed in the cells. After incubation at room temperature in the dark for 10 minutes, the firefly luciferase-mediated chemiluminescence is measured in a measuring instrument (measuring time/well 1 sec; Trilux from Wallac). Then 50 pi of the Dual-Glo™ Stop & Glo reagent (Dual-Glo™ Luciferase Assay System; Promega) is added to each well in order to stop the activity of the firefly luciferase and provide the substrate for the Renilla luciferase expressed by the reference plasmid pRL-CMV. After incubation at room temperature in the dark for a further 10 minutes, the chemiluminescence mediated by the Renilla luciferase is again measured for 1 sec/well in the measuring instrument. Evaluation The crude data from the luminometer are transferred into a Microsoft Excel file. The firefly/Renilla luciferase activity ratio is determined for each measurement derived from one well of the microtiter plate. The dose-activity curves and EC50 values of PPAR agonists are calculated from the ratios by the XL.Fit program as specified by the manufacturer (IDBS). PPARgamma EC50 values in the range from 160 nM to >10 //M were measured using the PPAR agonists described in this application. The compounds of the formula I of the invention may be obtained according to the following reaction schemes: configured. The broken line indicates the point of attachment to the substituent. The invention furthermore provides processes for preparing the compounds of the formula I which are obtained in accordance with the reaction schemes A, B and C below: The compound of the general formula A in which R4 is as defined above is deprotonated with n-butyllithium in tetrahydrofuran at -78°C, and compound B is then added at this temperature, giving a compound of the general formula C. The compound C is then reacted with tetrabutylammonium fluoride solution in tetrahydrofuran to give compound D. The latter is hydrogenated with hydrogen over pailadium-on-carbon, giving compound E. Compound E is deprotonated with sodium hydride in dimethylformamide, allyl bromide is added and the mixture is stirred at room temperature for a number of hours, giving compound F. The latter is reacted with osmium tetroxide and sodium periodate in diethyl ether, giving aldehyde G. Compound G is then stirred with a primary amine R3-NH2, where R3 is as defined above, and sodium borohydride in methanol at 0°C, worked up and then reacted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, to give the compound of the general formula H. To cleave the tert-butyl ester, compound H is stirred at room temperature in trifluoroacetic acid for a number of hours, giving the compound of the general formula J. Using this process, it is possible to synthesize the compounds of Examples 1 to 8. Compound B (see process A) is reacted with the compound of the general formula K to give compound C where R4 = H. The latter compound is hydrogenated with hydrogen over palladium-on-carbon, giving compound L. Compound L is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0°C and then reacted with an alkyl iodide of the general formula R4-I, where R4 may have the meaning described above. After work-up, this compound is then again deprotonated with lithium diisopropylamide in tetrahydrofuran at 0°C and subsequently reacted with an alkyl iodide of the general formula R5-I, where R5 may have the meaning described above, giving the compound of the general formula M. Compound M is reacted with tetrabutylammonium fluoride in tetrahydrofuran to give compound N which is deprotonated with sodium hydride in dimethylformamide and reacted with allyl bromide to give compound O. The latter is converted with osmium tetroxide and sodium periodate in diethyl ether to give compound P. Compound P is then stirred with a primary amine of the general formula R3-NH2, where R3 is as defined above, and sodium borohydride in methanol at 0°C, worked up and then reacted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, giving the compound of the general formula Q. To cleave the tert-butyl ester, compound Q is stirred in trifluoroacetic acid at room temperature for a number of hours, giving the compound of the general formula R. Using this process, it is possible to synthesize the compounds of Examples 9 to 12. Compound S is stirred at room temperature in methanol with sodium methoxide. After work-up, the product is converted with tert-butyldiphenylsilyl chloride and imidazole in dimethylformamide at room temperature into compound T. Compound T is stirred in isopropanol with sodium hydroxide at 60°C for 1 hour. After work-up, the product is reacted in dimethylformamide with a tert-butyl ester of an a-amino acid, hydroxybenzotriazole, diisopropylethylamine and 0-[cyano(ethoxycarbonyl)methyieneamino]-1,1,3,3,-tetramethyluronium tetrafluoroborate (TOTU), giving the product of the general formula U in which R4 and R5 are as defined above. Compound U is reacted with tetrabutylammonium fluoride in tetrahydrofuran, giving compound V. The latter is deprotonated with sodium hydride in dimethylformamide and alkylated with ally! bromide, giving compound W. The terminal double bond is then cleaved with osmium tetroxide and sodium periodate in diethyl ether, giving aldehyde X. Compound X is reacted with a primary amine of the general formula R3-NH2, where R2 is as defined above, in methanol with sodium borohydride, worked up and then converted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, into compound Y. The latter is converted by stirring in trifluoroacetic acid into product Z. Using this process, it is possible to synthesize Examples 13 to 15. Other compounds of the formula I can be prepared analogously or by known processes. The examples adduced below serve to illustrate the invention, but without limiting it. The syntheses of the example compounds are described below. Example 1 4-[cis-3-{2-[3-Cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyric acid 9.3 ml of tert-butyl diethylphosphonoacetate are dissolved in 80 ml of dimethylformamide, and 1.38 g of sodium hydride (60% strength in paraffin oil) are added a little at a time at 0°C. The suspension is stirred at 0°C for 15 minutes, and 4.02 ml of ethyl iodide are then added. The mixture is stirred at room temperature for 12 hours. 250 ml of ethyl acetate are then added, and the reaction mixture is washed three times with in each case 150 ml of water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1. This gives 6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate as an oil. C13H27O5P (294.33), 1H-NMR (CDCI3, 8 = ppm): 4.15 (q, 4H), 2.73 (ddd, 1H), 2.0-1.8 (m, 2H), 1.49 (s, 9H), 1.35 (q, 6H), 1.00 (t, 3H). cis-3-Allylcyclohexanol cis/racemate cis/racemate 87 ml of a 1 molar solution of lithium diisobutylaluminum hydride in n-hexane are dissolved in 100 ml of diethyl ether, and 7 ml of isopropanol are added at 0°C. After the evolution of gas has ended, 12.4 g of 3-allylcylohexanone, dissolved in 50 ml of diethyl ether, are added. The mixture is stirred at room temperature for 48 hours. The reaction mixture is quenched by addition of 1M hydrochloric acid and the aqueous phase is saturated with sodium chloride and extracted five times with in each case 200 ml of ethyl acetate. The combined organic phases are washed with 2N sodium hydroxide solution and dried over magnesium sulfate, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 15:1=> 5:1. This gives 6.8 g of cis-3-allylcyclohexanol as an oil. C9H16O (140.23), MS(ESI): 141 (M+H+), Rf(n- heptane:ethyl acetate = 2:1) = 0.22. (cis-3-Allylcyclohexyloxy)-tert-butyl-diphenylsilane 6.8 g of cis-3-aIlylcyclohexanol and 15 ml of tert-butyldiphenylsilyl chloride, 5 g of imidazole and 200 mg of dimethylaminopyridine are dissolved in 100 ml of dimethylformamide and stirred at room temperature for 12 hours. 400 ml of methyl tert-buthyl ether are added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 20.5 g of (cis-3- allylcyclohexyloxy)tert-butyl-diphenylsilane as an oil. C2sH340Si (378.64), MS(ESI): 379 (M+H+), Rf(n-heptane:ethyl acetate = 2:1) = 0.93. cis/racemate cis/racemate 5.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenylsilane are dissolved in 100 ml of diethyl ether, and 9.4 g of sodium periodate, dissolved in 100 ml of water, are added. At 0°C, 15 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 5 hours, a further 5g of sodium periodate are added, and the mixture is stirred at room temperature for another 3 hours. The reaction mixture is then diluted by addition of 300 ml of methyl tert-buthyl ether and washed with saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 6 g of [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde as a yellow-brown oil. C24H3202Si (380.61), MS(ESI): 381 (M+H+), Rf(n-heptane:ethyl acetate = 5:1) = 0.44. 6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate are dissolved in 90 ml of tetrahydrofuran, and 7.32 ml of a 2.7 M solution of n-butyllithium in n-hexane are added at -20°C. After 1 hour of stirring at -20°C, 4.36 g of [cis-3-(tert-butyl-diphenylsi!anoxy)cyclohexyl]acetaldehyde, dissolved in 40 ml of tetrahydrofuran, are added dropwise. The reaction mixture is slowly warmed to room temperature. 50 ml of water are then added, and the mixture is extracted three times with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n«heptane:ethyl acetate = 30:1. This gives 3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenyl- silanyloxy)cyclohexyl]-2-ethylbut-2-enoate as an oil. C32H4603Si (506.81), Rf(n- heptane:ethyl acetate = 5:1) = 0.73. tert-Butyl 2-ethyl-4~(cis-3-hydroxycyclohexyl)but-2-enoate 1.3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2-ethylbut-2-enoate are dissolved in 20 ml of tetrahydrofuran, and 15.7 ml of a 1M solution of • tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 30:1 => ethyl acetate. This gives 1.65 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl]but- 2-enoate as an oil. C16H28O3 (268.40), Rf(n-heptane:ethyl acetate = 5:1) = 0.07. tert-Butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate 1.65 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)but-2-enoate are dissolved in 50 ml of methanol, and 100 mg of Perlmans catalyst are added. The mixture is stirred under an atmosphere of hydrogen for 24 hours. The catalyst is filtered off through Ceiite, and the filtrate is then concentrated under reduced pressure. This gives 1.49 g of tert-butyl 2~ethyl-4-(cis-3-hydroxycyclohexyl)butyrate as a colorless oil. C16H30O3 (270.40), Rf(n-heptane:ethyl acetate = 5:1) = 0.10. tert-Butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate 1.19 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate are dissolved in 50 ml of dimethylformamide, and 210 mg g of sodium hydride (60% strength in paraffin oil) are added. The suspension is stirred at room temperature for 15 minutes, and 1.6 ml of allyl bromide are then added. After one hour, a further 320 mg of sodium hydride are added. After 12 hours of stirring at room temperature, another 320 mg of sodium hydride and then 1.6 ml of allyl bromide are metered in. Stirring at room temperature is continued for a further 12 hours. After addition of 200 ml of methyl tert-butyl ether, the mixture is washed three times with in each case 100 ml of water and the organic phase is separated off and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 60:1 => 30:1. This gives 770 mg of tert-butyl 4-(cis-3- allyloxycyclohexyl)-2-ethylbutyrate as an oil. C19H34O3 (310.48), Rf(n- heptane:ethyl acetate = 5:1) = 0.48. 770 mg of tert-butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate are dissolved in 50 ml of diethyl ether, and 1.59 g of sodium periodate, dissolved in 50 ml of water, are added. At 0°C, 2.56 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 9 hours, a further 12.8 ml of the osmium tetroxide solution are added, and stirring at room temperature is continued for a further 3 hours. 200 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 710 mg of tert-butyl 2- ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate as a yellow-brown oil. C18H32O4 (312.45), Rf(n-heptane:ethyl acetate = 5:1) = 0.15. tert-Butyl 4-(cis-3-{2-[3-cyclohexyl»1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyrate 380 mg of the aldehyde tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate and 0.14 ml of 4-methylbenzylamine are dissolved in 5 ml of methanol. 400 mg of 4 A molecular sieve, which had been dried by heating, is added, and the mixture is stirred at room temperature for two hours. 55 mg of sodium borohydride are then added to the reaction mixture. After 30 minutes, the molecular sieve is removed by filtration of the mixture through Celite. The filtrate is concentrated under reduced pressure. The residue is dissolved in 8 ml of dimethylformamide, and 0.11 ml of cyclohexyl isocyanate is added. After 12 hours, the dimethylformamide is removed under reduced pressure and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 9:1 => 7:1. This gives 160 mg of the urea tert- butyl 4-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2- ethylbutyrate as an oil. C33H54N2O4 (542.81), MS(ESI): 543 (M + H+). 4-(cis-3-{2-[3-cycIohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyric acid 160 mg of tert-butyl 4-(cis-3-{2-[3-cyciohexyl-1-(4-methylbenzyl)ureido]-ethoxy}cyclohexyl)-2-ethylbutyrate are dissolved in 16 ml of dichloromethane, and 4 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 12 hours. 50 ml of toluene are then added, and the solvents are removed under reduced pressure. The residue is purified by RP-HPLC. Freeze drying gives 123 mg of 4-(cis«3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2- ethylbutyric acid as a colorless oil. C29H46N2O4 (486.70), MS(ESI): 487 (M + H+). Example 2 Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, heptylamine and butyl isocyanate gave 4-{cis-3-[2-(3-butyl-1-heptylureido)ethoxy]cyclohexyl}-2-ethylbutyricacid. Example 3 Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, heptylamine and cyclohexyl isocyanate gave 4-{cis-3-[2-(3-cyclohexyl-1-heptylureido)ethoxy]cyclohexyl}-2-ethylbutyricacid. C28H52N2O4 (480.74), MS(ESI): 481 (M + H+). Example 4 Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, p-methylbenzylamine and butyl isocyanate gave 4-(cis-3-{2-[3-butyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)»2-ethylbutyricacid. Example 5 Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cycIohexyl]acetaldehyde, heptylamine and butyl isocyanate gave 2-(2-{cis-3-[2-(3-butyl-1- heptylureido)ethoxy]cyclohexyl}ethyl)-3-methylbutyricacid. C27H52N2O4 (468.73), MS(ESI): 469 (M + H+). Example 6 Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, heptylamine and cyclohexyl isocyanate gave 2-(2-{cis-3-[2-(3-cyclohexyl-1 - heptylureido)ethoxy]cyclohexyl}ethyl)-3-methylbutyricacid. C29H54N2O4 (494.76), MS(ESI): 495 (M + H+). Example 7 Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, p-benzylamine and butyl isocyanate gave 2-[2-(cis-3-{2-[3-butyl-1-(4- methylbenzyl)ureido]ethoxy}cyclohexyl)ethyl]-3-methylbutyricacid. C28H46N2O4 (474.69), MS(ESI): 475 (M + H+). Example 8 Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, p-methylbenzylamine and cyclohexyl isocyanate gave 2-[2-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)ethyl)-3-methylbutyric acid. C30H48N2O4 (500.73), MS(ESI): 501 (M + H+). Example 9 tert-Butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]but-2-enoate butyl-diphenylsilanyloxy)cyclohexyl]butanoate as an oil. C3oH4403Si (480.75), MS(ESI): 481 (M+H+). tert-Butyl4-[cis-3-(tert-butyl-diphenylsilany^ 2 g of tert-butyl 4«[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyI]butanoate are dissolved in 20 ml of tetrahydrofuran, and 3.1 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to -30°C, and 1.6 ml of methyl iodide are added. The mixture is allowed to warm to room temperature over a period of 12 hours. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 2.1 g of the monomethylated product. This product is dissolved in 20 ml of tetrahydrofuran, and 6 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to 0°C, and, after 10 minutes at 0°C, 2.5 ml of methyl iodide are added. The mixture is allowed to warm to room temperature over a period of 12 hours. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 1.8 g of tert-butyl 4-[cis«3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate as an oil. C32H4803Si (508.82), Rf(n-heptane:ethyl acetate = 5:1) = 0.49. tert-Butyl4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate 2 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate are dissolved in 10 ml of tetrahydrofuran, and 8 ml of a 1 M solution of tetrabutylammonium fluoride and tetrahydrofuran are added. The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 20:1 => 1:1. This gives 730 mg of tert-butyl 4-[cis-3-hydroxycyclohexyl)- 2,2-dimethylbutyrate as an oil. C16H30O3 (270.42), Rf(n-heptane:ethyl acetate = 5:1) = 0.22. Analogously to Example 1, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-heptylamine and butyl isocyanate gave 4-{cis-3-[2-(3-butyl-1-heptylureido)ethoxy]cyclohexyl)-2,2-dimethylbutyricacid. Example 10 Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-methylbenzylamine and butyl isocyanate gave 4-(cis-3-{2-[3-butyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2,2-dimethylbutyric acid. C27H44N2O4 (460.66), MS(ESI): 461 (M + H+). Example 11 Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-heptylamine and cyclohexyl isocyanate gave 4-{cis-3-[2-(3-cyclohexyl-1«heptylureido)ethoxy]cyclohexyl}-2,2-dimethylbutyrate. C28H52N2O4 (480.74), MS(ESI): 481 (M + H+). Example 12 Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-methylbenzylamine and cyclohexyl isocyanate gave 4-(cis-3- {2-[3-cyclohexyl-1-(4-methyibenzyl)ureido]ethoxy}cyciohexyl)-2,2-dim acid. C29H46N2O4 (486.70), MS(ESI): 487 (M + H+). Example 13 Methyl cis-3-(tert-butyl-diphenylsi!anyloxy)cyclohexanecarboxylate 22 g of 6-oxabicycio[3.2.1]octan-7-one are dissolved in 200 ml of methanol, and 10% strength sodium methoxide solution is added until a pH of 10 is reached. The mixture is stirred at room temperature for 30 minutes and then neutralized by addition of dilute acetic acid, and the mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, dried over magnesium sulfate and then concentrated under reduced pressure. This gives 21 g of the methyl ether as a colorless oil. This is dissolved in 200 ml of dimethylformamide, 43 g of tert-butyldiphenylsilyi chloride, 13 g of imidazole and 1 g of dimethylaminopyridine are added and the mixture is stirred at room temperature for 12 hours. The solvent is removed under reduced pressure and the residue is taken up in methyl tert-butyl ether and washed with water. The organic phase is dried over magnesium sulfate and the solvent is then removed. This gives 56.8 g of methyl cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarboxylate as a yellow oil. C24H3203Si (396.61), MS(ESI): 397 (M+H+). tert-Butyl cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarbonyl]amino}-(3S)-methylbutyrate 36.8 g of cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarboxyIic acid are dissolved in 150 ml of isopropanol, and 8g of sodium hydroxide, dissolved in 50 ml of water, are added. The mixture is heated at 60°C for 1 hour. The reaction mixture is cooled and neutralized by addition of 2N hydrochloric acid. The reaction mixture is concentrated under reduced pressure and extracted with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 34 g of the free acid as a colorless oil (Rf(ethyl acetate) = 0.63). This is dissolved in 250 ml of dimethylformamide, and 18.6 g of ferf-butyl L-valinate hydrochloride are added. At 0°C, 29.1 g of 0-[cyano(ethoxycarbonyl)methyleneamino]-1,1,3,3,-tetramethyluronium tetrafluoroborate are added. After 10 minutes, the ice bath is removed and 23.9 g of hydroxybenzotriazole and 61.8 ml of Hunig base are added. The mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the resulting residue is dissolved in ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate 2:1. This gives 43.0 g of tert-butyl 2-{[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarbonyl]-amino}-(3S)-methylbutyrate as a yellow oil. C32H47N04Si (537.82), MS(ESI): 538. tert-Butyl2-[(cis-3-hydroxycyclohexanecarbonyl)aminoH3S)-methyl-butyrate 43.0 g of tert-butyl 2-{[cis«3-(tert-butyl-diphenylsilanyloxy)cyclohexane-carbonyl]amino}-(3S)-methylbutyrate are dissolved in 80 ml of tetrahydrofuran, and 80 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60°C for 3 h and then concentrated under reduced pressure, and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1 => 1:1. This gives 18 g of a white solid. Since this is still slightly impure, 8 g are subjected to another purification on silica gel. This gives 6.8 g of tert-butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)- methylbutyrate as a white solid. C16H29NO4 (299.41), MS(ESI): 300 (M+H+). tert-Butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methyl-butyrate can be separated by chiral HPLC. This gives tert-butyl 2-[((1R,3S)-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate (Rt = 4.9 min) and tert-butyl 2-[((1S,3R)-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate (Rt = 5.7 min) as colorless lyophilisates. (Chiralpak AD/34 250 x 4.6; mobile phase n-heptane:ethanol:methanol = 20:1:1 + 0.1% trifluoroacetic acid). tert-Butyl 2-[(cis-3-allyloxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate 2.8 g of tert-butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methyl butyrate are dissolved in 20 ml of dimethylformamide, and 450 mg of sodium hydride (60% strength suspension in mineral oil) are added. After 10 minutes, 3.4 ml of allyl bromide are added dropwise. After 3 hours of stirring at room temperature, another 700 mg of sodium hydride are added. After 2 hours of stirring at room temperature, another 3.4 ml of allyl bromide are metered in. The mixture is stirred at room temperature for 12 hours, 200 ml of methyl tert-butyl ether are then added to the reaction mixture and the mixture is washed three times with in each case 100 ml of water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 40:1 => 10:1. This gives 900 mg of tert-butyl 2-[(cis-3-allyloxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate as a colorless oil. C19H33NO4 (339.48), MS(ESI): 340 (M+H+), Rf(n-heptane:ethyl acetate = 1:1) = 0.58. tert-Butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecarbonyl]amino}butyrate 900 mg of tert-butyl 2-[(cis-3-allyioxy)cyclohexanecarbonyl)amino]-(3S)-methylbutyrate are dissolved in 20 ml of diethyl ether, and 1.7 g of sodium, periodate, dissolved in 20 ml of water, are added. At 0°C, 1.6 ml of a solution of osmium tetroxide (2.5% by weight) in tert-butanol are added. The reaction mixture is stirred vigorously at room temperature for 3 hours. At 0°C, 50 ml of saturated sodium thiosulfate solution are then added. The organic phase is separated off. The aqueous phase is extracted three times with in each case 50 ml of methyl tert-butyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 1.0 g of tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecarbonyl]amino}butyrate as a colorless oil which is reacted further without purification. C18H31NO5 (341.45), Rf(n-heptane:ethyl acetate = 1:1) = 0.19. tert-Butyl 2-[(cis-3^2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclo-hexanecarbo hexanecarbonyl)amino]-(3S)-methylbutyrate 330 mg of tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecar- bonyI]amino}butyrate are dissolved in 3 ml of methanol, and 0.12 ml of 4- methylbenzylamine, dissolved in 5 ml of methanol, is added. 300 mg of molecular sieve (4 A), which had been dried by heating, are added, and the mixture is stirred at room temperature for 2 hours. 50 mg of sodium borohydride are then added, and stirring at room temperature is continued for another 30 minutes. The molecular sieve is filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in 20 ml of dimethylformamide, and 80 l are added. The mixture is stirred at room temperature for 12 hours. The dimethylformamide is removed under reduced pressure and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 9:1 => 2:1. This gives 320 mg of tert-butyl 2-[cis-3-{2-[3-ethyl-1 -(4- methylbenzyl)ureido]ethoxy}cyclohexanecarbonyl)amino]-(3S)-methylbutyrate as a light-yellow oil. C29H47N3O5 (517.72), MS(ESI): 518. 2-[(cis-3-{2-[3-Ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexane-carbonyl)amino]-(3S)-methylbutyricacid 320 mg of tert-butyl 2-[(cis-3-{2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}-cydohexanecarbonyl)amino]-(3S)-methylbutyrate are dissolved in 20 ml of dichloromethane, and 10 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 3 hours. The solvents are removed under reduced pressure and the residue is purified by RP-HPLC. This gives 115 mg of 2-[(cis-3-{2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexanecarbonyl)amino]-(3S)- methylbutyric acid as a white lyophilisate. C25H39N3O5 (461.61), MS(ESI): 462. Example 14 Analogously to Example 13, tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)-cyclohexanecarbonyl]amino}butyrate, n-heptylamine and phenyl isocyanate gave 2-({cis-3-[2-(1-heptyl-3-phenylureido)ethoxy]cyclohexanecarbonyl}amino)-(3S)-methylbutyric acid. cis/diastereomer mixture C28H45N3O5 (503.69), MS(ESI): 504. Example 15 Analogously to Example 13, tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)- cyclohexanecarbonyl]amino}butyrate, 2,2-dimethyIpropylamine and phenyl isocyanate gave 2-[(cis-3-{2-[1-(2,2-dimethylpropyl)-3-phenylureido]- ethoxy}cyclohexanecarbonyl)aminoH3S)-methylbutyricacid. cis/diastereomer mixture C26H41N3O5 (475.63), MS(ESI): 476. V We claim: 1. A compound of the formula l Ring A is (C3-C8)-cycloalkanediyi or (C3-C8)-cycloaIkenediyI, where in the cycloalkane- or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms; R1.R2 independently of one another are H, (C1-6alkyl, (C3-C8)-cycloalkyl or (C6-C10)-aryl; R3 is (C3-C6)-cycloalkyl or (C1\|-C12)-alkyl which are optionally substituted by (C6-C10o)-aryl, (C5-C6)-heteroaryl or (C3-C6)-cycloalkyl, where aryl, heteroaryl or cycloalkyl for their part may be substituted by (C1-C6)J-alkyI, (C1-6)J-alkoxy, CI, Br, I, CO- (C1-6)-alkyl, CO-0(Ci-Ce)-alkyl, CO-NH(C1-6)-alkyl or CO- N((C1-6)-alkyl)2; X is (C1-6)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; Y1 is CO or a bond; Y2 is NH, (C1-6)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; R4 is(C1-C8)-alkyi; R5 isHf(C1-6-alkyl; R6 is H; and its physiologically acceptable salts. 2. A compound of the formula I as claimed in claim 1 in which Ring A is (C3-C8)-cycloalkane-1,3-diyl; R1,R2 independently of one another are H, (C1-6)-alkyl, (C3-C8)-cycloalkyl or (C6-C10)-aryl; R3 is (C1-6)-cycloalkyl which is optionally substituted by phenyl, where phenyl for its part may be substituted by (C1-6)-alkyl; X is (C1-6)-alkanediyl, where in the alkanediyl group one carbon atom may be replaced by an oxygen atom; Y1 is CO or a bond; Y2 is NH, (C1-6)-alkanediyl, where in the alkanediyl group one carbon atom may be replaced by an oxygen atom; R4 is (Ci-C8)-alkyl; R5 is H, (C1-6)-alkyl; R6 is H. 3. A compound of the formula I as claimed in claim 1 or 2, in which Ring A is cyclohexane-1,3-diyl; R1.R2 independently of one another are H, (C1-6)-alkyl, (C3-C8)-cycloalkyl or phenyl; R3 is (C1-C12)-alkyl which is optionally substituted by phenyl, where phenyl for its part may be substituted by methyl; X is (C1-6)-alkanediyl, where in the alkanediyl group the carbon atom adjacent to ring A may be replaced by an oxygen atom; Y1 is CO or a bond; Y2 is NH, (C1-C6)-alkanediyl, where in the alkanediyl group one carbon atom may be replaced by an oxygen atom; R4 is (C1-6-alkyl; R5 isHor(C1-6)-alkyl; R6 isH. 4. A compound of the formula I as claimed in any of claims 1 to 3, in which Ring A is cyclohexane-1,3-diyl; R1 is H; R2 is (C1-6-alkyl, (C3-C8)-cyc!oalkyl or phenyl; R3 is (C1-C8)-alkyl which is optionally substituted by phenyl, where phenyl for its part may be substituted by methyl; X is ((CH2)2)0; Y1 is CO or a bond; Y2 isNH, (C1-6-alkanediyl; R4 is (C1-6-alkyl; R5 is H, (C1-6-alkyl; R6 is H. 5. A compound of the formula I as claimed in claims 1 to 4, wherein the bond X-ring A-Yi is cis-configured. 6. A pharmaceutical, comprising one or more of the compounds of the formula I as claimed in one or more of claims 1 to 5. 7. A pharmaceutical, comprising one or more of the compounds of the formula I as claimed in one or more of claims 1 to 5 and one or more active compounds which have a favorable effect on metabolic disorders or associated diseases. 8. A pharmaceutical comprising one or more of the compounds of the formula I as claimed in one or more of claims 1 to 5 and one or more antidiabetics. 9. A pharmaceutical comprising one or more of the compounds of the formula I as claimed in one or more of claims 1 to 5 and one or more lipid modulators. 10. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders. 11. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of disorders in which insulin resistance plays a role. 12. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of diabetes mellitus and the associated sequelae. 13. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of dyslipidemias and their sequelae. 14. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of conditions associated with the metabolic syndrome. 15. The use of the compounds as claimed in one or more of claims 1 to 5 in combination with at least one further active compound for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders. 16. The use of the compounds as claimed in one or more of claims 1 to 5 in combination with at least one further active compound for the treatment and/or prevention of disorders in which insulin resistance plays a role. 17. A process for preparing a pharmaceutical comprising one or more compounds as claimed in one or more of claims 1 to 5, which comprises mixing the active compound with a pharmaceutically suitable carrier and bringing this mixture into a form suitable for administration. Description Cycloalkyl-substituted alkanoic acid derivatives, methods for the production thereof, and use thereof as a medicament The invention relates to arylcycloalkyl-substituted alkanoic acid derivatives and to their physiologically acceptable salts and physiologically functional derivatives. Compounds of a similar structure have already been described in the prior art for the treatment of hyperlipidemia and diabetes (WO 2000/64876). It was an object of the invention to provide compounds which allow a therapeutically exploitable modulation of the lipid and/or carbohydrate metabolism and are thus suitable for the prevention and/or treatment of diseases such as type 2 diabetes and atherosclerosis and the various sequelae thereof. Surprisingly, a series of compounds which modulate the activity of PPAR receptors has been found. In particular, the compounds are suitable for the activation of PPARalpha and PPARgamma, and the extent of the relative activation can be different depending on the compounds. Accordingly, the invention relates to compounds of the formula I in which Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, where in the cycloalkane- or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms; R1, R2 independently of one another are H, C1-6-a!kyI, (C3-C8)-cycloalkyl or(C6-C10)-aryi; R3 is (C3-C6)-cycloalkyl or (C1-C12)-alkyl which are optionally substituted by (C6-C10)-aryl, (C1-C6)-heteroaryl or (C3-C6)-cycloalkyl, where aryl, heteroaryl or cycloalkyl for their part may be substituted by (C1-C6)-alkyl, C1-6-alkoxy, CI, Br, I, CO-(C1-C6)kyl, CO-0C1-6-alkyl, CO-NH(1-6)alkyl or CO-N(C1-6-alkyl)2; X is C1-6-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; Y1 is CO or a bond; Y2 is NH, (C1-C12)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms; R4 is (C1 -C8)-alkyl; R5 is H, C1-6-alkyl; R6 is H; and their physiologically acceptable salts. Preference is given to compounds of the formula I whose substituents X and Y1 are bonded to the ring A in positions 1 and 3. (X - Ring A - Y1). Preference is also given to compounds of the formula I in which Ring A is (C3-C8)-cycloalkane-1,3-diyl; R1, R2 independently of one another are H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or(C6-Cio)-aryl; R3 is (C1-C12)-cycloalkyl which is optionally substituted by phenyl, where phenyl for its part may be substituted by C1-6-alkyI; X is (C1-C6)-alkanediyl, where in the alkanediyl group one carbon atom may be replaced by an oxygen atom; Y1 is CO or a bond; Y2 is NH, C1-6-alkanediyl, where in the alkanediyl group one carbon atom may be replaced by an oxygen atom; R4 is(C1-C8)-alkyl; R5 is H, C1-6-alkyl; R6 is H. Particular preference is given to compounds of the formula I in which Ring A is cyclohexane-1,3-diyl; R1, R2 independently of one another are H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or phenyl; R3 is (C1-C12)-alkyl which is optionally substituted by phenyl, where phenyl for its part may be substituted by methyl; X is (C1-6)-alkanediyl, where in the alkanediyl group the carbon atom adjacent to ring A may be replaced by an oxygen atom; Y1 is CO or a bond; Y2 is NH, (C1-C6)-alkanediyl, where in the alkanediyl group one carbon atom may be replaced by an oxygen atom; R4 is (C1-C8)-alkyl; R5 isH or(Ci-C4)-alkyl; R6 is H. Very particular preference is given to compounds of the formula I in which Ring A is cyclohexane-1,3-diyl; R1 is H; R2 is C1-6-alkyl, (C3-C8)-cycloalkyl or phenyl; R3 is (C1-C8)-alkyl which is optionally substituted by phenyl, where phenyl for its part may be substituted by methyl; X is ((CH2)2)0; Y1 is CO or a bond; Y2 is NH, (C1-C4)-alkanediyl; R4 is C1-6-alkyl; R5 is H, (C1-C4)-alkyl; R6 is H. The bond to ring A may be either cis or trans, preference is given to the cis-bond. The present invention also encompasses all combinations of the "preferred embodiments" of the invention described herein. The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5 and R6 can be straight-chain or branched. Aryl refers to an aromatic, carbocyclic, mono- or bicyclic ring system which contains from 6 to 10 atoms in the ring or in the rings. Heteroaryl is a mono- or bicyclic aromatic ring system having from 4 to 11 ring members, in which at least one atom in the ring system is a heteroatom from the group of N, O and S. The compounds of the formula I contain at least two centers of asymmetry and may contain more. The compounds of the formula I may therefore be present in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and diastereomer mixtures. The present invention encompasses all of these isomeric forms of the compounds of the formula I. These isomeric forms may, even when some of them are not described expresses verbis, be obtained by known methods. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater solubility in water compared with the starting or base compounds. 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 acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts) and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine. Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutical^ acceptable salts and/or for use in nontherapeutic, for example in vitro, applications. The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester which is able, on administration to a mammal such as, for example, to a human, to form (directly or indirectly) a compound of the formula I or an active metabolite thereof. Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves have activity or not. The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the scope of the invention and are a further aspect of the invention. All references hereinafter to "compound(s) of formula I" refer to compound(s) of the formula I as described above, and to the salts, solvates and physiologically functional derivatives thereof as described herein. Use This invention relates further to the use of compounds of the formula I and their pharmaceutical compositions as PPAR receptor ligands. The PPAR receptor ligands of the invention are suitable as modulators of the activity of the PPAR receptors. Peroxisome proliferator-activated receptors (PPAR) are transcription factors which can be activated by ligands and belong to the class of nuclear hormone receptors. There are three PPAR isoforms, PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes (Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Motojima K, Cell Struct Fund, 1993 Oct, 18(5), 267-77). There exist two variants of PPARgamma, PPARgammai and -gamma2, which are the result of alternative use of promoters and differential mRNA splicing (Vidal-Puig et al.f J. Clin. Invest., 97:2553-2561, 1996). The various PPAR receptors have a different tissue distribution and modulate different physiological functions. The PPAR receptors play a key role in different aspects of the regulation of a multitude of genes, whose gene products are crucially involved directly or indirectly in lipid and carbohydrate metabolism. Thus, for example, PPARalpha receptors play an important role in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARgamma is crucially involved, for example, in the regulation of adipose cell differentiation. In addition, PPAR receptors are also involved in the regulation of many further physiological processes, including those which are not directly connected with carbohydrate or lipid metabolism. The activity of the different PPAR receptors can be modulated to varying extents by various fatty acids, fatty acid derivatives and synthetic compounds. For relevant reviews concerning functions, physiological effect and pathophysiology, see: Joel Berger et al., Annu. Rev. Med., 2002, 53, 409 - 435; Timothy Wilson et alM J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al., Recent Prog Horm Res., 2001, 56, 239-63. The present invention relates to compounds of the formula I which are suitable for modulating the activity of PPAR receptors, especially the activity of PPARalpha and PPARgamma. Depending on the profile of the modulation, the compounds of the formula I are suitable for the treatment, control and prophylaxis of the indications described hereinafter, and for a series of other, connected pharmaceutical applications (see, for example, Joel Berger et al., Annu. Rev. Med., 2002, 53, 409 - 435; Timothy Wilson et al., J. Med. Chem., 2000, Vol. 43(4), 527-550; Steven Kliewer et al., Recent Prog Horm Res., 2001, 56, 239-63; Jean-Charles Fruchart, Bart Staeis and Patrick Duriez: PPARS, Metabolic Disease and Arteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARs in health and disease, NATURE, VOL. 405, 25 MAY 2000, 421-4; Ines Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staeis: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12:2001, 245-254). Compounds of this type are particularly suitable for the treatment and/or prevention of 1. - disorders of fatty acid metabolism and glucose utilization disorders - disorders in which insulin resistance plays a role 2. Diabetes mellitus, in particular type 2 diabetes, including the prevention of the associated sequelae. Particular aspects in this connection are - hyperglycemia - improvement in insulin resistance - improvement in glucose tolerance - protection of the p-cells of the pancreas - prevention of macro- and microvascular disorders 3. Dyslipidemias and their sequelae, such as, for example, atherosclerosis, coronary heart disease, cerebrovascular disorders, etc, especially those (but not restricted to those) which are characterized by one or more of the following factors: - high plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations - low HDL cholesterol concentrations - low ApoA lipoprotein concentrations - high LDL cholesterol concentrations - small dense LDL cholesterol particles - high ApoB lipoprotein concentrations 4. Various other conditions which may be associated with metabolic syndrome are such as: - obesity (excess weight), including central obesity - thromboses, stages of hypercoagulability and prethrombosis (arterial and venous) - high blood pressure - heart failure, such as, for example, (but not restricted to that) in the state after myocardial infarction, hypertensive heart disease or cardiomyopathy 5. Further disorders or conditions in which, for example, inflammatory reactions or cell differentiation play a role: - atherosclerosis, such as, for example, (but not restricted to) coronary sclerosis including angina pectoris or myocardial infarction, stroke - vascular restenosis or reocclusion - chronic inflammatory bowel diseases, such as, for example, Crohn's disease and ulcerative colitis - pancreatitis - other inflammatory states - retinopathy - adipose cell tumors - lipomatous carcinomas such as, for example, liposarcomas - solid tumors and neoplasms, such as, for example, (but not restricted to) carcinomas of the gastrointestinal tract, of the liver, of the biliary tract and of the pancreas, endocrine tumors, carcinomas of the lungs, of the kidneys and the urinary tract, of the genital tract, prostate carcinomas, etc. - acute and chronic myeloproliferative disorders and lymphomas - angiogenesis - neurodegenerative diseases - Alzheimer's disease - multiple sclerosis - Parkinson's disease - erythemato-squamous dermatoses such as, for example, psoriasis - acne vulgaris - other skin disorders and dermatological conditions which are modulated by PPAR - eczemas and neurodermatitis - dermatitis, such as, for example, seborrheic dermatitis or photodermatitis - keratitis and keratoses, such as, for example, seborrheic keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or keratosis follicularis - keloids and keloid prophylaxis - warts, including condylomata or condylomata acuminata - human papilloma virus (HPV) infections, such as, for example, venereal papillomata, viral warts, such as, for example, molluscum contagiosum, leukoplakia - papular dermatoses, such as, for example, lichen planus - skin cancer, such as, for example, basal-cell carcinomas, melanomas or cutaneous T-cell lymphomas - localized benign epidermal tumors, such as, for example, keratoderma, epidermal naevi - chilblains - high blood pressure - syndrome X - polycystic ovary syndrome (PCOS) - asthma - osteoarthritis - lupus erythematosus (LE) or inflammatory rheumatic disorders, such as, for example, rheumatoid arthritis - vasculitis - wasting (cachexia) - gout - ischemia/reperfusion syndrome - acute respiratory distress syndrome (ARDS) ("shock lung") Formulation The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg) per day and per kilogram of body weight, for example 0.1-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.001 mg to LOmg/kg, which can suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active compound. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients. Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated slow-release formulations also belong within the scope of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. Suitable pharmaceutical preparations for oral administration may be in the form of separate units such as, for example, capsules, wafers, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine. Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. The pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place 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 blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound. Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture. Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active compound is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active compound in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active compound concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active compound to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986). The compounds of the formula I act favorably on metabolic disorders. They have a positive effect on lipid and sugar metabolism and, in particular, reduce the concentration of triglycerides, and they are suitable for preventing and treating type II diabetes and arteriosclerosis and their various sequelae. Combinations with other medicaments The compounds of the invention can be administered alone or in combination with one or more further pharmacologically active substances which, for example, act favorably on metabolic disorders or diseases frequently associated therewith. Such medicaments are, for example, 1. medicaments which lower blood glucose, antidiabetics, 2. active compounds for the treatment of dyslipidemias, 3. antiatherosclerotic medicaments, 4. antiobesity agents, 5. antiinflammatory active compounds 6. active compounds for the treatment of malignant tumors 7. antithrombotic active compounds 8. active compounds for the treatment of high blood pressure 9. active compounds for the treatment of heart failure and 10. active compounds for the treatment and/or prevention of complications caused by diabetes or associated with diabetes. They may be combined with the compounds of the formula I according to the invention in particular for synergistic improvement of the effect. Administration of the active compound combination may take place either by separate administration of the active compounds to the patients or in the form of combination products in which a plurality of active compounds are present in one pharmaceutical preparation. Mention may be made by way of example of: Antidiabetics Suitable antidiabetics are disclosed, for example, in the Rote Liste 2001, chapter 12 or in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2003. Antidiabetics include all insulins and insulin derivatives, such as, for example, Lantus® (see www.lantus.com) or Apidra®, and other fast-acting insulins (see US 6,221,633), GLP-1 receptor modulators as described in WO 01/04146 or else, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S. The orally active hypoglycemic active compounds include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, oral GLP-1 agonists, DPP-IV inhibitors, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenosis, modulators of glucose uptake, compounds which alter lipid metabolism and lead to alteration of the lipid compostion of the blood, compounds which reduce food intake or food uptake, PPAR and PXR modulators and active compounds which act on the ATP-dependent potassium channel of the beta cells. In one embodiment of the invention, the compounds of the formula I are administered administered in combination with insulin. In one embodiment of the invention, the compounds of the formula I are in combination with substances which influence hepatic glucose production such as, for example, glycogen phosphorylase inhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188). 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 an active compound which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide. 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, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2- quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione. In one embodiment, the compounds of the formula I are administered in combination with a DPPIV inhibitor as described, for example, in W098/19998, W099/61431, W099/67278, W099/67279, WO01/72290, WO 02/38541, WO03/040174, in particular P 93/01 (1-cyclopentyl-3-methyl-1-oxo-2- pentaneammonium chloride), P-31/98, LAF237 (1-[2-[3-hydroxyadamant-1- yIamino)acetyl]pyrrolidine-2-(S)-carbonitrile), TS021 ((2S, 4S)-4-fluoro-1-[[(2- hydroxy-1,1-dimethylethyl)amino]acetyl]pyrrolidine-2-carbonitrile monobenzenesulfonate). In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARgamma agonist such as, for example, rosiglitazone, pioglitazone. In one embodiment, the compounds of the formula I are administered in combination with compounds with an inhibitory effect on SGLT-1 and/or 2, as disclosed directly or indirectly for example in PCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455. In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor such as, for example, miglitol or acarbose. In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. Lipid modulators In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin. In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor (see, for example, US 6,245,744, US 6,221,897, US 6,277,831, EP 0683 773, EP 0683 774). In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent, such as, for example, cholestyramine, colesevelam. In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, as described, for example, in WO 0250027, or ezetimibe, tiqueside, pamaqueside. In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see, for example, US 6,342,512). In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6); Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt/Main). Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars. In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARalpha agonist. 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, AZ 242 (Tesaglitazar, (S)-3-(4-[2-(4-methane- sulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionic acid), BMS 298585 (N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]phenyl]methyl]glycine) or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, W096/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876. In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrate. In one embodiment of the invention, the compounds of the formula I are administered in combination with nicotinic acid or niacin. In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example CP-529, 414 (torcetrapib). In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor. 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. In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor. In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor. In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist. Antiobesity agents In one 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, the other active compound is fenfluramine or dexfenfluramine. In another embodiment, the other active compound is sibutramine. In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.:Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists (for example N-{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}-naphthalene-1-sulfonamide, hydrochloride (CGP 71683A)), MC4 agonists (for example N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexa- hydropyrazolo[4,3-c]pyridin-5-yl)-1-(4«chlorophenyl)-2-oxoethyl]-l-amino- 1,2,3,4-tetrahydronaphthalene-2-carboxamide (WO 01/91752)), orexin antagonists (for example 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride (SB-334867-A)), H3 agonists (for example 3-cyclohexyl- 1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (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 (for example urocortin), urocortin agonists, (33 agonists (for example 1-(4-chloro-3-methanesulfonylmethylphenyl)- 2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol, hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (for example {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)- thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)); serotonin reuptake inhibitors (for example dexfenfluramine), mixed serotoninergic and noradrenergic compounds (for example WO 00/71549), 5HT agonists (for example 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111)), bombesin agonists, galanin antagonists, growth hormone (for example human growth hormone), growth-hormone-releasing compounds tert-butyl (6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro- 1H-isoquinoline-2-carboxylate (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), decoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors (for example WO 00/40569), PPAR modulators (for example WO 00/78312), RXR modulators or TR-/3 agonists. In one embodiment of the invention, the other active compound is leptin. In one embodiment, the other active compound is dexamphetamine, amphetamine, mazindol or phentermine. In one embodiment, the compounds of the formula I are administered in combination with medicaments having effects on the coronary circulation and the vascular system, such as, for example, ACE inhibitors (e.g. ramipril), medicaments which act on the angiotensin-renin system, calcium antagonists, beta blockers, etc. In one embodiment, the compounds of the formula I are administered in combination with medicaments having an antiinflammatory effect. In one embodiment, the compounds of the formula I are administered in combination with medicaments which are employed for cancer therapy and cancer prevention. It is self-evident that any suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is regarded as falling within the scope of protection conferred by the present invention. The activity of the compounds was tested as follows: Determination of EC50 values of PPAR agonists in the cellular PPARalpha test Principle The potency of substances which bind to human PPARalpha and activate it in an agonistic manner is analyzed using a stably transfected HEK cell line (HEK= human embryo kidney) which is referred to here as PPARalpha reporter cell line. It contains two genetic elements, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) which mediates expression of the luciferase reporter element depending on a PPARalpha ligand. The stably and constitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD binds in the cell nucleus of the PPARalpha reporter cell line via the GAL4 protein portion to the GAL4 DNA binding motif 5'-upstream of the luciferase reporter element which is integrated in the genome of the cell line. There is only little expression of the luciferase reporter gene without addition of a PPARalpha ligand if fatty acid-depleted fetal calf serum (cs-FCS) is used in the test. PPARalpha ligands bind and activate the PPARalpha fusion protein and thereby bring about expression of the luciferase reporter gene. The luciferase which is formed can be detected by means of chemiluminescence via an appropriate substrate. Construction of the cell line The PPARalpha reporter cell line was prepared in 2 stages. Firstly, the luciferase reporter element was constructed and stably transfected into HEK cells. For this purpose, five binding sites of the yeast transcription factor GAL4 (in each case 5'-CGGAGTACTGTCCTCCGAG-3') were cloned in 5'-upstream of a 68 bp-long minimal MMTV promoter (Accession #V01175), The minimal MMTV promoter section contains a CCAAT box and a TATA element in order to enable efficient transcription by RNA polymerase II. The cloning and sequencing of the GAL4-MMTV construct took place in analogy to the description of Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Then the complete Photinus pyralis luciferase gene (Accession # M15077) was cloned in 3'-downstream of the GAL4-MMTV element. After sequencing, the luciferase reporter element consisting of five GAL4 binding sites, MMTV promoter and luciferase gene was recloned into a plasmid which confers zeozin resistance in order to obtain the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfected into HEK cells in accordance with the statements in Ausubel, F.M. et al. (Current protocols in molecular biology, Vol. 1-3, John Wiley & Sons, Inc., 1995). Then zeozin-containing medium (0.5 mg/ml) was used to select a suitable stable cell clone which showed very low basal expression of the luciferase gene. In a second step, the PPARalpha fusion protein (GR-GAL4»humanPPARalpha-LBD) was introduced into the stable cell clone described. For this purpose, initially the cDNA coding for the N-terminal 76 amino acids of the glucocorticoid receptor (Accession # P04150) was linked to the cDNA section coding for amino acids 1-147 of the yeast transcription factor GAL4 (Accession # P04386). The cDNA of the ligand-binding domain of the human PPARalpha receptor (amino acids S167-Y468; Accession #S74349) was cloned in at the 3' end of this GR-GAL4 construct. The fusion construct prepared in this way (GR-GAL4-humanPPARalpha-LBD) was recloned into the plasmid pcDNA3 (from Invitrogen) in order to enable constitutive expression therein by the cytomegalovirus promoter. This plasmid was linearized with a restriction endonuclease and stably transfected into the previously described cell clone containing the luciferase reporter element. The finished PPARalpha reporter cell line which contains a luciferase reporter element and constitutively expresses the PPARalpha fusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by selection with zeozin (0.5 mg/ml) and G418 (0.5 mg/ml). Test procedure The activity of PPARalpha agonists is determined in a 3-day test, described below: Day 1 The PPARalpha reporter cell line is cultivated up to 80% confluence in DMEM (#41965-039, Invitrogen) with the following additives: 10% cs-FCS (fetal calf serum, #SH-30068.03, Hyclone), 0.5 mg/ml of zeozin (#R250-01, Invitrogen), 0.5 mg/ml of G418 (#10131-027, Invitrogen), 1% penicillin streptomycin solution (#15140-122, Invitrogen) and 2mM of L-glutamine (#25030-024, Invitrogen). Cultivation is carried out in standard cell culture bottles (# 353112, Becton Dickinson) in a cell culture incubator at 37°C in the presence of 5% C02. The 80% confluent cells are washed once with 15 ml of PBS (#14190-094, Invitrogen), treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C for 2 min, taken up in 5 ml of the DMEM medium described and counted in a cell counter. After dilution to 500 000 cells/ml, in each case 35 000 cells are sown into each well of a 96-well microtiter plate having a clear plastic bottom (#3610, Corning Costar). The plates are incubated in a cell incubator at 37°C and 5% CO2 for 24 h. Day 2 The PPARalpha agonists to be tested are dissolved in DMSO at a concentration of 10 mM. This stock solution is diluted in DMEM (#41965-039, Invitrogen) to which 5% of cs-FCS (#SH-30068.03, Hyclone), 2 mM of L-glutamine (#25030-024, Invitrogen) and the antibiotics already described (zeozin, G418, penicillin and streptomycin) are added. Test substances are tested at 11 different concentrations in the range of from 10 nM to 100 pM. More potent compounds are tested in concentration ranges of from 1 pM to 10 pM or between 100 nM and 1 pM. The medium of the PPARalpha reporter cell line sown on day 1 is completely removed by aspiration, and, immediately, the test substances diluted in medium are added to the cells. Dilution and addition of the substances are carried out using a robot (Beckman FX). The end volume of the test substances diluted in medium is 100 pi per well of a 96-well microtiter plate. The DMSO concentration in the test is below 0.1 % v/v to prevent cytotoxic effects of the solvent. To demonstrate that the test is working in each individual plate, a standard PPARalpha agonist, which is also diluted to 11 different concentrations, was To demonstrate that the test is working in each individual plate, a standard PPARalpha agonist, which is also diluted to 11 different concentrations, was added to each plate. The test plates are incubated in an incubator at 37°C and 5% C02for24h. Day 3 The PPARalpha receptor cells treated with the test substances are removed from the incubator and the medium is aspirated off. The cells are lyzed by pipetting 50 IJ\ of Bright Glo reagent (from Promega) into each well of a 96-well microtiter plate. After incubation at room temperature in the dark for 10 minutes, the microtiter plates are measured in the luminometer (Trilux from Wallac). The measuring time for each well of a microtiter plate is 1 sec. Evaluation The crude data of the luminometer are exported into a Microsoft Excel file. Dose-activity curves and EC50 values of PPAR agonists are calculated using the program XL.Fit according to the instructions of the manufacturer (IDBS). The PPARalpha EC50 values for the compounds of examples 1 to 15 in this assay are in the range from 0.04 nM to > 10 jaM. The results for the activity of some compounds of the formula I according to the invention are listed in table I below: It is evident from table I that the compounds of the formula i according to the invention activate the PPARalpha receptor, thus effecting, for example, analogously to clinically used fibrates, a lowering of the triglyceride concentration in the organism (see, for example, J.-Ch. Fruchard et al.: PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001; S. Kersten et al.: Roles of PPARs in health and disease, NATURE, VOL 405, 25 MAY 2000, 421-4; I. Pineda et al.: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001,245-254). Determination of EC50 values of PPAR agonists in the cellular PPARgamma test Principle A transient transfection system is employed to determine the cellular PPARgamma activity of PPAR agonists. It is based on the use of a luciferase reporter plasmid (pGL3basic-5xGAL4-TK) and of a PPARgamma expression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids are transiently transfected into human embryonic kidney cells (HEK cells). There is then expression in these cells of the fusion protein GAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of the reporter plasmid. In the presence of a PPARgamma-active ligand, the activated fusion protein GAL4-humanPPARgammaLBD induces expression of the luciferase reporter gene, which can be detected in the form of a chemiluminescence signal after addition of a luciferase substrate. As a difference from the stably transfected PPARalpha reporter cell line, in the cellular PPARgamma test the two components (luciferase reporter plasmid and PPARgamma expression plasmid) are transiently transfected into HEK cells because stable and permanent expression of the PPARgamma fusion protein is cytotoxic. Construction of the plasmids The luciferase reporter plasmid pGL3basic-5xGAL4-TK is based on the vector pGL3basic from Promega. The reporter piasmid is prepared by cloning five binding sites of the yeast transcription factor GAL4 (each binding site with the sequence 5'-CTCGGAGGACAGTACTCCG-3'), together with a 160 bp-long thymidine kinase promoter section (Accession # AF027128) 5'-upstream into pGL3basic. 3'-downstream of the thymidine kinase promoter is the complete luciferase gene from Photinus pyralis (Accession # M15077) which is already a constituent of the plasmid pGL3basic used. The cloning and sequencing of the reporter plasmid pGL3basic-5xGAL4-TK took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). The PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD was prepared by first cloning the cDNA coding for amino acids 1-147 of the yeast transcription factor GAL4 (Accession # P04386) into the plasmid pcDNA3 (from Invitrogen) 3'-downstream of the cytomegalovirus promoter. Subsequently, the cDNA of the ligand-binding domain (LBD) of the human PPARgamma receptor (amino acids I152-Y475; Accession # g1480099) was cloned 3'-downstream of the GAL4 DNA binding domain. Cloning and sequencing of the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD again took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Besides the luciferase reporter plasmid pGL3basic-5xGAL4-TK and the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD, also used for the cellular PPARgamma test are the reference plasmid pRL-CMV (from Promega) and the plasmid pBluescript-SK(+) from Stratagene. All four plasmids were prepared using a plasmid preparation kit from Qiagen, which ensures a plasmid quality with a minimal endotoxin content, before transfection into HEK cells. Test procedure The activity of PPARgamma agonists is determined in a 4-day test which is described below. Before the transfection, HEK cells are cultivated in DMEM (#41965-039, Invitrogen) which is mixed with the following additions: 10% FCS (#16000-044, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Day 1 Firstly, solution A, a transfection mixture which contains all four plasmids previously described in addition to DMEM, is prepared. The following amounts are used to make up 3 ml of solution A for each 96-well microtiter plate for one test: 2622 \|jl of antibiotic- and serum-free DMEM (# 41965-039, Invitrogen), 100 pi of reference plasmid pRL-CMV (1 ng/pl), 100 pi of luciferase reporter plasmid pGL3basic-5xGAL4-TK (10 ng/pl), 100 pi of PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD (100 ng/pl) and 78 pi of plasmid pBluescript-SK(+) (500 ng/pl). Then 2 ml of solution B are prepared by mixing 1.9 ml of DMEM-(# 41965-039, Invitrogen) with 100 pi of PolyFect transfection reagent (from Qiagen) for each 96-well microtiter plate. Subsequently, 3 ml of solution A are mixed with 2 ml of solution B to give 5 ml of solution C, which is thoroughly mixed by multiple pipetting and incubated at room temperature for 10 min. 80%-confluent HEK cells from a cell culture bottle with a capacity of 175 cm2 are washed once with 15 ml of PBS (#14190-094, Invitrogen) and treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C for 2 min. The cells are then taken up in 15 ml of DMEM (#41965-039, Invitrogen) which is mixed with 10% FCS (# 16000-044, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). After the cell suspension has been counted in a cell counter, the suspension is diluted to 250 000 cells/ml. 15 ml of this cell suspension are mixed with 5 ml of solution C for one microtiter plate. 200 pi of the suspension are seeded in each well of a 96-well microtiter plate with a clear plastic base (#3610, Corning Costar). The plates are incubated in a cell culture incubator at 37°C and 5% C02 for 24 h. Day 2 PPAR agonists to be tested are dissolved in DMSO in a concentration of 10 mM. This stock solution is diluted in DMEM (# 41965-039, Invitrogen) which is mixed with 2% Ultroser (#12039-012, Biosepra), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Test substances are tested in a total of 11 different concentrations in the range from 10 \|JM to 100 pM. More potent compounds are tested in concentration ranges from 1 ptol0pM. The medium of the HEK cells transfected and seeded on day 1 is completely removed by aspiration, and the test substances diluted in medium are immediately added to the cells. The dilution and addition of the substances is carried out by a robot (Beckman FX). The final volume of the test substances diluted in medium is 100 pi per well of a 96-well microtiter plate. Each plate is charged with a standard PPARgamma agonist, which is likewise diluted in 11 different concentrations, in order to demonstrate the functioning of the test in each individual plate. The test plates are incubated in an incubator at 37°C and 5% C02for 48 h. Day 4 After removal of the medium by aspiration, 50 \i\ of Dual-Glo™ reagent (Dual- Glo™ Luciferase Assay System; Promega) are added to each well in accordance with the manufacturer's instructions in order to lyze the cells and provide the substrate for the firefly luciferase (Photinus pyralis) formed in the cells. After incubation at room temperature in the dark for 10 minutes, the firefly luciferase-mediated chemiluminescence is measured in a measuring instrument (measuring time/well 1 sec; Trilux from Wallac). Then 50 pi of the Dual-Glo™ Stop & Glo reagent (Dual-Glo™ Luciferase Assay System; Promega) is added to each well in order to stop the activity of the firefly luciferase and provide the substrate for the Renilla luciferase expressed by the reference plasmid pRL-CMV. After incubation at room temperature in the dark for a further 10 minutes, the chemiluminescence mediated by the Renilla luciferase is again measured for 1 sec/well in the measuring instrument. Evaluation The crude data from the luminometer are transferred into a Microsoft Excel file. The firefly/Renilla luciferase activity ratio is determined for each measurement derived from one well of the microtiter plate. The dose-activity curves and EC50 values of PPAR agonists are calculated from the ratios by the XL.Fit program as specified by the manufacturer (IDBS). PPARgamma EC50 values in the range from 160 nM to >10 //M were measured using the PPAR agonists described in this application. The compounds of the formula I of the invention may be obtained according to the following reaction schemes: configured. The broken line indicates the point of attachment to the substituent. The invention furthermore provides processes for preparing the compounds of the formula I which are obtained in accordance with the reaction schemes A, B and C below: The compound of the general formula A in which R4 is as defined above is deprotonated with n-butyllithium in tetrahydrofuran at -78°C, and compound B is then added at this temperature, giving a compound of the general formula C. The compound C is then reacted with tetrabutylammonium fluoride solution in tetrahydrofuran to give compound D. The latter is hydrogenated with hydrogen over pailadium-on-carbon, giving compound E. Compound E is deprotonated with sodium hydride in dimethylformamide, allyl bromide is added and the mixture is stirred at room temperature for a number of hours, giving compound F. The latter is reacted with osmium tetroxide and sodium periodate in diethyl ether, giving aldehyde G. Compound G is then stirred with a primary amine R3-NH2, where R3 is as defined above, and sodium borohydride in methanol at 0°C, worked up and then reacted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, to give the compound of the general formula H. To cleave the tert-butyl ester, compound H is stirred at room temperature in trifluoroacetic acid for a number of hours, giving the compound of the general formula J. Using this process, it is possible to synthesize the compounds of Examples 1 to 8. Compound B (see process A) is reacted with the compound of the general formula K to give compound C where R4 = H. The latter compound is hydrogenated with hydrogen over palladium-on-carbon, giving compound L. Compound L is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0°C and then reacted with an alkyl iodide of the general formula R4-I, where R4 may have the meaning described above. After work-up, this compound is then again deprotonated with lithium diisopropylamide in tetrahydrofuran at 0°C and subsequently reacted with an alkyl iodide of the general formula R5-I, where R5 may have the meaning described above, giving the compound of the general formula M. Compound M is reacted with tetrabutylammonium fluoride in tetrahydrofuran to give compound N which is deprotonated with sodium hydride in dimethylformamide and reacted with allyl bromide to give compound O. The latter is converted with osmium tetroxide and sodium periodate in diethyl ether to give compound P. Compound P is then stirred with a primary amine of the general formula R3-NH2, where R3 is as defined above, and sodium borohydride in methanol at 0°C, worked up and then reacted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, giving the compound of the general formula Q. To cleave the tert-butyl ester, compound Q is stirred in trifluoroacetic acid at room temperature for a number of hours, giving the compound of the general formula R. Using this process, it is possible to synthesize the compounds of Examples 9 to 12. Compound S is stirred at room temperature in methanol with sodium methoxide. After work-up, the product is converted with tert-butyldiphenylsilyl chloride and imidazole in dimethylformamide at room temperature into compound T. Compound T is stirred in isopropanol with sodium hydroxide at 60°C for 1 hour. After work-up, the product is reacted in dimethylformamide with a tert-butyl ester of an a-amino acid, hydroxybenzotriazole, diisopropylethylamine and 0-[cyano(ethoxycarbonyl)methyieneamino]-1,1,3,3,-tetramethyluronium tetrafluoroborate (TOTU), giving the product of the general formula U in which R4 and R5 are as defined above. Compound U is reacted with tetrabutylammonium fluoride in tetrahydrofuran, giving compound V. The latter is deprotonated with sodium hydride in dimethylformamide and alkylated with ally! bromide, giving compound W. The terminal double bond is then cleaved with osmium tetroxide and sodium periodate in diethyl ether, giving aldehyde X. Compound X is reacted with a primary amine of the general formula R3-NH2, where R2 is as defined above, in methanol with sodium borohydride, worked up and then converted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, into compound Y. The latter is converted by stirring in trifluoroacetic acid into product Z. Using this process, it is possible to synthesize Examples 13 to 15. Other compounds of the formula I can be prepared analogously or by known processes. The examples adduced below serve to illustrate the invention, but without limiting it. The syntheses of the example compounds are described below. Example 1 4-[cis-3-{2-[3-Cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyric acid 9.3 ml of tert-butyl diethylphosphonoacetate are dissolved in 80 ml of dimethylformamide, and 1.38 g of sodium hydride (60% strength in paraffin oil) are added a little at a time at 0°C. The suspension is stirred at 0°C for 15 minutes, and 4.02 ml of ethyl iodide are then added. The mixture is stirred at room temperature for 12 hours. 250 ml of ethyl acetate are then added, and the reaction mixture is washed three times with in each case 150 ml of water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1. This gives 6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate as an oil. C13H27O5P (294.33), 1H-NMR (CDCI3, 8 = ppm): 4.15 (q, 4H), 2.73 (ddd, 1H), 2.0-1.8 (m, 2H), 1.49 (s, 9H), 1.35 (q, 6H), 1.00 (t, 3H). cis-3-Allylcyclohexanol cis/racemate cis/racemate 87 ml of a 1 molar solution of lithium diisobutylaluminum hydride in n-hexane are dissolved in 100 ml of diethyl ether, and 7 ml of isopropanol are added at 0°C. After the evolution of gas has ended, 12.4 g of 3-allylcylohexanone, dissolved in 50 ml of diethyl ether, are added. The mixture is stirred at room temperature for 48 hours. The reaction mixture is quenched by addition of 1M hydrochloric acid and the aqueous phase is saturated with sodium chloride and extracted five times with in each case 200 ml of ethyl acetate. The combined organic phases are washed with 2N sodium hydroxide solution and dried over magnesium sulfate, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 15:1=> 5:1. This gives 6.8 g of cis-3-allylcyclohexanol as an oil. C9H16O (140.23), MS(ESI): 141 (M+H+), Rf(n- heptane:ethyl acetate = 2:1) = 0.22. (cis-3-Allylcyclohexyloxy)-tert-butyl-diphenylsilane 6.8 g of cis-3-aIlylcyclohexanol and 15 ml of tert-butyldiphenylsilyl chloride, 5 g of imidazole and 200 mg of dimethylaminopyridine are dissolved in 100 ml of dimethylformamide and stirred at room temperature for 12 hours. 400 ml of methyl tert-buthyl ether are added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 20.5 g of (cis-3- allylcyclohexyloxy)tert-butyl-diphenylsilane as an oil. C2sH340Si (378.64), MS(ESI): 379 (M+H+), Rf(n-heptane:ethyl acetate = 2:1) = 0.93. cis/racemate cis/racemate 5.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenylsilane are dissolved in 100 ml of diethyl ether, and 9.4 g of sodium periodate, dissolved in 100 ml of water, are added. At 0°C, 15 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 5 hours, a further 5g of sodium periodate are added, and the mixture is stirred at room temperature for another 3 hours. The reaction mixture is then diluted by addition of 300 ml of methyl tert-buthyl ether and washed with saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 6 g of [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde as a yellow-brown oil. C24H3202Si (380.61), MS(ESI): 381 (M+H+), Rf(n-heptane:ethyl acetate = 5:1) = 0.44. 6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate are dissolved in 90 ml of tetrahydrofuran, and 7.32 ml of a 2.7 M solution of n-butyllithium in n-hexane are added at -20°C. After 1 hour of stirring at -20°C, 4.36 g of [cis-3-(tert-butyl-diphenylsi!anoxy)cyclohexyl]acetaldehyde, dissolved in 40 ml of tetrahydrofuran, are added dropwise. The reaction mixture is slowly warmed to room temperature. 50 ml of water are then added, and the mixture is extracted three times with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n«heptane:ethyl acetate = 30:1. This gives 3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenyl- silanyloxy)cyclohexyl]-2-ethylbut-2-enoate as an oil. C32H4603Si (506.81), Rf(n- heptane:ethyl acetate = 5:1) = 0.73. tert-Butyl 2-ethyl-4~(cis-3-hydroxycyclohexyl)but-2-enoate 1.3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2-ethylbut-2-enoate are dissolved in 20 ml of tetrahydrofuran, and 15.7 ml of a 1M solution of • tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 30:1 => ethyl acetate. This gives 1.65 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl]but- 2-enoate as an oil. C16H28O3 (268.40), Rf(n-heptane:ethyl acetate = 5:1) = 0.07. tert-Butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate 1.65 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)but-2-enoate are dissolved in 50 ml of methanol, and 100 mg of Perlmans catalyst are added. The mixture is stirred under an atmosphere of hydrogen for 24 hours. The catalyst is filtered off through Ceiite, and the filtrate is then concentrated under reduced pressure. This gives 1.49 g of tert-butyl 2~ethyl-4-(cis-3-hydroxycyclohexyl)butyrate as a colorless oil. C16H30O3 (270.40), Rf(n-heptane:ethyl acetate = 5:1) = 0.10. tert-Butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate 1.19 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate are dissolved in 50 ml of dimethylformamide, and 210 mg g of sodium hydride (60% strength in paraffin oil) are added. The suspension is stirred at room temperature for 15 minutes, and 1.6 ml of allyl bromide are then added. After one hour, a further 320 mg of sodium hydride are added. After 12 hours of stirring at room temperature, another 320 mg of sodium hydride and then 1.6 ml of allyl bromide are metered in. Stirring at room temperature is continued for a further 12 hours. After addition of 200 ml of methyl tert-butyl ether, the mixture is washed three times with in each case 100 ml of water and the organic phase is separated off and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 60:1 => 30:1. This gives 770 mg of tert-butyl 4-(cis-3- allyloxycyclohexyl)-2-ethylbutyrate as an oil. C19H34O3 (310.48), Rf(n- heptane:ethyl acetate = 5:1) = 0.48. 770 mg of tert-butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate are dissolved in 50 ml of diethyl ether, and 1.59 g of sodium periodate, dissolved in 50 ml of water, are added. At 0°C, 2.56 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 9 hours, a further 12.8 ml of the osmium tetroxide solution are added, and stirring at room temperature is continued for a further 3 hours. 200 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 710 mg of tert-butyl 2- ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate as a yellow-brown oil. C18H32O4 (312.45), Rf(n-heptane:ethyl acetate = 5:1) = 0.15. tert-Butyl 4-(cis-3-{2-[3-cyclohexyl»1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyrate 380 mg of the aldehyde tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate and 0.14 ml of 4-methylbenzylamine are dissolved in 5 ml of methanol. 400 mg of 4 A molecular sieve, which had been dried by heating, is added, and the mixture is stirred at room temperature for two hours. 55 mg of sodium borohydride are then added to the reaction mixture. After 30 minutes, the molecular sieve is removed by filtration of the mixture through Celite. The filtrate is concentrated under reduced pressure. The residue is dissolved in 8 ml of dimethylformamide, and 0.11 ml of cyclohexyl isocyanate is added. After 12 hours, the dimethylformamide is removed under reduced pressure and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 9:1 => 7:1. This gives 160 mg of the urea tert- butyl 4-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2- ethylbutyrate as an oil. C33H54N2O4 (542.81), MS(ESI): 543 (M + H+). 4-(cis-3-{2-[3-cycIohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyric acid 160 mg of tert-butyl 4-(cis-3-{2-[3-cyciohexyl-1-(4-methylbenzyl)ureido]-ethoxy}cyclohexyl)-2-ethylbutyrate are dissolved in 16 ml of dichloromethane, and 4 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 12 hours. 50 ml of toluene are then added, and the solvents are removed under reduced pressure. The residue is purified by RP-HPLC. Freeze drying gives 123 mg of 4-(cis«3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2- ethylbutyric acid as a colorless oil. C29H46N2O4 (486.70), MS(ESI): 487 (M + H+). Example 2 Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, heptylamine and butyl isocyanate gave 4-{cis-3-[2-(3-butyl-1-heptylureido)ethoxy]cyclohexyl}-2-ethylbutyricacid. Example 3 Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, heptylamine and cyclohexyl isocyanate gave 4-{cis-3-[2-(3-cyclohexyl-1-heptylureido)ethoxy]cyclohexyl}-2-ethylbutyricacid. C28H52N2O4 (480.74), MS(ESI): 481 (M + H+). Example 4 Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, p-methylbenzylamine and butyl isocyanate gave 4-(cis-3-{2-[3-butyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)»2-ethylbutyricacid. Example 5 Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cycIohexyl]acetaldehyde, heptylamine and butyl isocyanate gave 2-(2-{cis-3-[2-(3-butyl-1- heptylureido)ethoxy]cyclohexyl}ethyl)-3-methylbutyricacid. C27H52N2O4 (468.73), MS(ESI): 469 (M + H+). Example 6 Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, heptylamine and cyclohexyl isocyanate gave 2-(2-{cis-3-[2-(3-cyclohexyl-1 - heptylureido)ethoxy]cyclohexyl}ethyl)-3-methylbutyricacid. C29H54N2O4 (494.76), MS(ESI): 495 (M + H+). Example 7 Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, p-benzylamine and butyl isocyanate gave 2-[2-(cis-3-{2-[3-butyl-1-(4- methylbenzyl)ureido]ethoxy}cyclohexyl)ethyl]-3-methylbutyricacid. C28H46N2O4 (474.69), MS(ESI): 475 (M + H+). Example 8 Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, p-methylbenzylamine and cyclohexyl isocyanate gave 2-[2-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)ethyl)-3-methylbutyric acid. C30H48N2O4 (500.73), MS(ESI): 501 (M + H+). Example 9 tert-Butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]but-2-enoate butyl-diphenylsilanyloxy)cyclohexyl]butanoate as an oil. C3oH4403Si (480.75), MS(ESI): 481 (M+H+). tert-Butyl4-[cis-3-(tert-butyl-diphenylsilany^ 2 g of tert-butyl 4«[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyI]butanoate are dissolved in 20 ml of tetrahydrofuran, and 3.1 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to -30°C, and 1.6 ml of methyl iodide are added. The mixture is allowed to warm to room temperature over a period of 12 hours. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 2.1 g of the monomethylated product. This product is dissolved in 20 ml of tetrahydrofuran, and 6 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to 0°C, and, after 10 minutes at 0°C, 2.5 ml of methyl iodide are added. The mixture is allowed to warm to room temperature over a period of 12 hours. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 1.8 g of tert-butyl 4-[cis«3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate as an oil. C32H4803Si (508.82), Rf(n-heptane:ethyl acetate = 5:1) = 0.49. tert-Butyl4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate 2 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate are dissolved in 10 ml of tetrahydrofuran, and 8 ml of a 1 M solution of tetrabutylammonium fluoride and tetrahydrofuran are added. The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 20:1 => 1:1. This gives 730 mg of tert-butyl 4-[cis-3-hydroxycyclohexyl)- 2,2-dimethylbutyrate as an oil. C16H30O3 (270.42), Rf(n-heptane:ethyl acetate = 5:1) = 0.22. Analogously to Example 1, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-heptylamine and butyl isocyanate gave 4-{cis-3-[2-(3-butyl-1-heptylureido)ethoxy]cyclohexyl)-2,2-dimethylbutyricacid. Example 10 Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-methylbenzylamine and butyl isocyanate gave 4-(cis-3-{2-[3-butyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2,2-dimethylbutyric acid. C27H44N2O4 (460.66), MS(ESI): 461 (M + H+). Example 11 Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-heptylamine and cyclohexyl isocyanate gave 4-{cis-3-[2-(3-cyclohexyl-1«heptylureido)ethoxy]cyclohexyl}-2,2-dimethylbutyrate. C28H52N2O4 (480.74), MS(ESI): 481 (M + H+). Example 12 Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-methylbenzylamine and cyclohexyl isocyanate gave 4-(cis-3- {2-[3-cyclohexyl-1-(4-methyibenzyl)ureido]ethoxy}cyciohexyl)-2,2-dim acid. C29H46N2O4 (486.70), MS(ESI): 487 (M + H+). Example 13 Methyl cis-3-(tert-butyl-diphenylsi!anyloxy)cyclohexanecarboxylate 22 g of 6-oxabicycio[3.2.1]octan-7-one are dissolved in 200 ml of methanol, and 10% strength sodium methoxide solution is added until a pH of 10 is reached. The mixture is stirred at room temperature for 30 minutes and then neutralized by addition of dilute acetic acid, and the mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, dried over magnesium sulfate and then concentrated under reduced pressure. This gives 21 g of the methyl ether as a colorless oil. This is dissolved in 200 ml of dimethylformamide, 43 g of tert-butyldiphenylsilyi chloride, 13 g of imidazole and 1 g of dimethylaminopyridine are added and the mixture is stirred at room temperature for 12 hours. The solvent is removed under reduced pressure and the residue is taken up in methyl tert-butyl ether and washed with water. The organic phase is dried over magnesium sulfate and the solvent is then removed. This gives 56.8 g of methyl cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarboxylate as a yellow oil. C24H3203Si (396.61), MS(ESI): 397 (M+H+). tert-Butyl cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarbonyl]amino}-(3S)-methylbutyrate 36.8 g of cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarboxyIic acid are dissolved in 150 ml of isopropanol, and 8g of sodium hydroxide, dissolved in 50 ml of water, are added. The mixture is heated at 60°C for 1 hour. The reaction mixture is cooled and neutralized by addition of 2N hydrochloric acid. The reaction mixture is concentrated under reduced pressure and extracted with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 34 g of the free acid as a colorless oil (Rf(ethyl acetate) = 0.63). This is dissolved in 250 ml of dimethylformamide, and 18.6 g of ferf-butyl L-valinate hydrochloride are added. At 0°C, 29.1 g of 0-[cyano(ethoxycarbonyl)methyleneamino]-1,1,3,3,-tetramethyluronium tetrafluoroborate are added. After 10 minutes, the ice bath is removed and 23.9 g of hydroxybenzotriazole and 61.8 ml of Hunig base are added. The mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the resulting residue is dissolved in ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate 2:1. This gives 43.0 g of tert-butyl 2-{[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarbonyl]-amino}-(3S)-methylbutyrate as a yellow oil. C32H47N04Si (537.82), MS(ESI): 538. tert-Butyl2-[(cis-3-hydroxycyclohexanecarbonyl)aminoH3S)-methyl-butyrate 43.0 g of tert-butyl 2-{[cis«3-(tert-butyl-diphenylsilanyloxy)cyclohexane-carbonyl]amino}-(3S)-methylbutyrate are dissolved in 80 ml of tetrahydrofuran, and 80 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60°C for 3 h and then concentrated under reduced pressure, and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1 => 1:1. This gives 18 g of a white solid. Since this is still slightly impure, 8 g are subjected to another purification on silica gel. This gives 6.8 g of tert-butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)- methylbutyrate as a white solid. C16H29NO4 (299.41), MS(ESI): 300 (M+H+). tert-Butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methyl-butyrate can be separated by chiral HPLC. This gives tert-butyl 2-[((1R,3S)-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate (Rt = 4.9 min) and tert-butyl 2-[((1S,3R)-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate (Rt = 5.7 min) as colorless lyophilisates. (Chiralpak AD/34 250 x 4.6; mobile phase n-heptane:ethanol:methanol = 20:1:1 + 0.1% trifluoroacetic acid). tert-Butyl 2-[(cis-3-allyloxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate 2.8 g of tert-butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methyl butyrate are dissolved in 20 ml of dimethylformamide, and 450 mg of sodium hydride (60% strength suspension in mineral oil) are added. After 10 minutes, 3.4 ml of allyl bromide are added dropwise. After 3 hours of stirring at room temperature, another 700 mg of sodium hydride are added. After 2 hours of stirring at room temperature, another 3.4 ml of allyl bromide are metered in. The mixture is stirred at room temperature for 12 hours, 200 ml of methyl tert-butyl ether are then added to the reaction mixture and the mixture is washed three times with in each case 100 ml of water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 40:1 => 10:1. This gives 900 mg of tert-butyl 2-[(cis-3-allyloxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate as a colorless oil. C19H33NO4 (339.48), MS(ESI): 340 (M+H+), Rf(n-heptane:ethyl acetate = 1:1) = 0.58. tert-Butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecarbonyl]amino}butyrate 900 mg of tert-butyl 2-[(cis-3-allyioxy)cyclohexanecarbonyl)amino]-(3S)-methylbutyrate are dissolved in 20 ml of diethyl ether, and 1.7 g of sodium, periodate, dissolved in 20 ml of water, are added. At 0°C, 1.6 ml of a solution of osmium tetroxide (2.5% by weight) in tert-butanol are added. The reaction mixture is stirred vigorously at room temperature for 3 hours. At 0°C, 50 ml of saturated sodium thiosulfate solution are then added. The organic phase is separated off. The aqueous phase is extracted three times with in each case 50 ml of methyl tert-butyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 1.0 g of tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecarbonyl]amino}butyrate as a colorless oil which is reacted further without purification. C18H31NO5 (341.45), Rf(n-heptane:ethyl acetate = 1:1) = 0.19. tert-Butyl 2-[(cis-3^2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclo-hexanecarbo hexanecarbonyl)amino]-(3S)-methylbutyrate 330 mg of tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecar- bonyI]amino}butyrate are dissolved in 3 ml of methanol, and 0.12 ml of 4- methylbenzylamine, dissolved in 5 ml of methanol, is added. 300 mg of molecular sieve (4 A), which had been dried by heating, are added, and the mixture is stirred at room temperature for 2 hours. 50 mg of sodium borohydride are then added, and stirring at room temperature is continued for another 30 minutes. The molecular sieve is filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in 20 ml of dimethylformamide, and 80 l are added. The mixture is stirred at room temperature for 12 hours. The dimethylformamide is removed under reduced pressure and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 9:1 => 2:1. This gives 320 mg of tert-butyl 2-[cis-3-{2-[3-ethyl-1 -(4- methylbenzyl)ureido]ethoxy}cyclohexanecarbonyl)amino]-(3S)-methylbutyrate as a light-yellow oil. C29H47N3O5 (517.72), MS(ESI): 518. 2-[(cis-3-{2-[3-Ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexane-carbonyl)amino]-(3S)-methylbutyricacid 320 mg of tert-butyl 2-[(cis-3-{2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}-cydohexanecarbonyl)amino]-(3S)-methylbutyrate are dissolved in 20 ml of dichloromethane, and 10 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 3 hours. The solvents are removed under reduced pressure and the residue is purified by RP-HPLC. This gives 115 mg of 2-[(cis-3-{2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexanecarbonyl)amino]-(3S)- methylbutyric acid as a white lyophilisate. C25H39N3O5 (461.61), MS(ESI): 462. Example 14 Analogously to Example 13, tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)-cyclohexanecarbonyl]amino}butyrate, n-heptylamine and phenyl isocyanate gave 2-({cis-3-[2-(1-heptyl-3-phenylureido)ethoxy]cyclohexanecarbonyl}amino)-(3S)-methylbutyric acid. cis/diastereomer mixture C28H45N3O5 (503.69), MS(ESI): 504. Example 15 Analogously to Example 13, tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)- cyclohexanecarbonyl]amino}butyrate, 2,2-dimethyIpropylamine and phenyl isocyanate gave 2-[(cis-3-{2-[1-(2,2-dimethylpropyl)-3-phenylureido]- ethoxy}cyclohexanecarbonyl)aminoH3S)-methylbutyricacid. cis/diastereomer mixture C26H41N3O5 (475.63), MS(ESI): 476.

Full Text

Description
Cycloalkyl-substituted alkanoic acid derivatives, methods for the production thereof, and use thereof as a medicament
The invention relates to arylcycloalkyl-substituted alkanoic acid derivatives and to their physiologically acceptable salts and physiologically functional derivatives.
Compounds of a similar structure have already been described in the prior art for the treatment of hyperlipidemia and diabetes (WO 2000/64876).
It was an object of the invention to provide compounds which allow a therapeutically exploitable modulation of the lipid and/or carbohydrate metabolism and are thus suitable for the prevention and/or treatment of diseases such as type 2 diabetes and atherosclerosis and the various sequelae thereof.
Surprisingly, a series of compounds which modulate the activity of PPAR receptors has been found. In particular, the compounds are suitable for the activation of PPARalpha and PPARgamma, and the extent of the relative activation can be different depending on the compounds.
Accordingly, the invention relates to compounds of the formula I

in which
Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, where in the
cycloalkane- or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms;

R1, R2 independently of one another are H, C1-6-a!kyI, (C3-C8)-cycloalkyl or(C6-C10)-aryi;
R3 is (C3-C6)-cycloalkyl or (C1-C12)-alkyl which are optionally substituted
by (C6-C10)-aryl, (C1-C6)-heteroaryl or (C3-C6)-cycloalkyl, where aryl, heteroaryl or cycloalkyl for their part may be substituted by (C1-C6)-alkyl, C1-6-alkoxy, CI, Br, I, CO-(C1-C6)kyl, CO-0C1-6-alkyl, CO-NH(1-6)alkyl or CO-N(C1-6-alkyl)2;
X is C1-6-alkanediyl, where in the alkanediyl group one or more
carbon atoms may be replaced by oxygen atoms;
Y1 is CO or a bond;
Y2 is NH, (C1-C12)-alkanediyl, where in the alkanediyl group one or more
carbon atoms may be replaced by oxygen atoms;
R4 is (C1
-C8)-alkyl;
R5 is H, C1-6-alkyl;
R6 is H;
and their physiologically acceptable salts.
Preference is given to compounds of the formula I whose substituents X and Y1 are bonded to the ring A in positions 1 and 3. (X - Ring A - Y1).

Preference is also given to compounds of the formula I in which Ring A is (C3-C8)-cycloalkane-1,3-diyl;
R1, R2 independently of one another are H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or(C6-Cio)-aryl;
R3 is (C1-C12)-cycloalkyl which is optionally substituted by phenyl, where
phenyl for its part may be substituted by C1-6-alkyI;
X is (C1-C6)-alkanediyl, where in the alkanediyl group one carbon atom
may be replaced by an oxygen atom;
Y1 is CO or a bond;
Y2 is NH, C1-6-alkanediyl, where in the alkanediyl group one carbon
atom may be replaced by an oxygen atom;
R4 is(C1-C8)-alkyl;
R5 is H, C1-6-alkyl;
R6 is H.
Particular preference is given to compounds of the formula I in which
Ring A is cyclohexane-1,3-diyl;
R1, R2 independently of one another are H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or phenyl;

R3 is (C1-C12)-alkyl which is optionally substituted by phenyl, where
phenyl for its part may be substituted by methyl;
X is (C1-6)-alkanediyl, where in the alkanediyl group the carbon atom
adjacent to ring A may be replaced by an oxygen atom;
Y1 is CO or a bond;
Y2 is NH, (C1-C6)-alkanediyl, where in the alkanediyl group one carbon
atom may be replaced by an oxygen atom;
R4 is (C1-C8)-alkyl;
R5 isH or(Ci-C4)-alkyl;
R6 is H.
Very particular preference is given to compounds of the formula I
in which
Ring A is cyclohexane-1,3-diyl;
R1 is H;
R2 is C1-6-alkyl, (C3-C8)-cycloalkyl or phenyl;
R3 is (C1-C8)-alkyl which is optionally substituted by phenyl, where phenyl
for its part may be substituted by methyl;

X is ((CH2)2)0;
Y1 is CO or a bond;
Y2 is NH, (C1-C4)-alkanediyl;
R4 is C1-6-alkyl;
R5 is H, (C1-C4)-alkyl;
R6 is H.
The bond to ring A may be either cis or trans, preference is given to the cis-bond.
The present invention also encompasses all combinations of the "preferred embodiments" of the invention described herein.
The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5 and R6 can be straight-chain or branched.
Aryl refers to an aromatic, carbocyclic, mono- or bicyclic ring system which contains from 6 to 10 atoms in the ring or in the rings.
Heteroaryl is a mono- or bicyclic aromatic ring system having from 4 to 11 ring members, in which at least one atom in the ring system is a heteroatom from the group of N, O and S.
The compounds of the formula I contain at least two centers of asymmetry and may contain more. The compounds of the formula I may therefore be present in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and diastereomer mixtures. The present invention encompasses all of these isomeric forms of the compounds of the formula I. These isomeric forms may,

even when some of them are not described expresses verbis, be obtained by known methods.
Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater solubility in water compared with the starting or base compounds. 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 acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts) and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutical^ acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester which is able, on administration to a mammal such as, for example, to a human, to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.
Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves have activity or not.

The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the scope of the invention and are a further aspect of the invention.
All references hereinafter to "compound(s) of formula I" refer to compound(s) of the formula I as described above, and to the salts, solvates and physiologically functional derivatives thereof as described herein.
Use
This invention relates further to the use of compounds of the formula I and their pharmaceutical compositions as PPAR receptor ligands. The PPAR receptor ligands of the invention are suitable as modulators of the activity of the PPAR receptors.
Peroxisome proliferator-activated receptors (PPAR) are transcription factors which can be activated by ligands and belong to the class of nuclear hormone receptors. There are three PPAR isoforms, PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes (Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Motojima K, Cell Struct Fund, 1993 Oct, 18(5), 267-77).
There exist two variants of PPARgamma, PPARgammai and -gamma2, which are the result of alternative use of promoters and differential mRNA splicing (Vidal-Puig et al.f J. Clin. Invest., 97:2553-2561, 1996). The various PPAR receptors have a different tissue distribution and modulate different physiological functions. The PPAR receptors play a key role in different aspects of the regulation of a multitude of genes, whose gene products are crucially involved directly or indirectly in lipid and carbohydrate metabolism. Thus, for example, PPARalpha receptors play an important role in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARgamma is crucially involved, for example, in the regulation of adipose cell differentiation.
In addition, PPAR receptors are also involved in the regulation of many further physiological processes, including those which are not directly connected with carbohydrate or lipid metabolism. The activity of the different PPAR receptors can be modulated to varying extents by various fatty acids, fatty acid derivatives and synthetic compounds. For relevant reviews concerning functions, physiological effect and pathophysiology, see: Joel Berger et al., Annu. Rev. Med., 2002, 53,

409 - 435; Timothy Wilson et alM J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al., Recent Prog Horm Res., 2001, 56, 239-63. The present invention relates to compounds of the formula I which are suitable for modulating the activity of PPAR receptors, especially the activity of PPARalpha and PPARgamma. Depending on the profile of the modulation, the compounds of the formula I are suitable for the treatment, control and prophylaxis of the indications described hereinafter, and for a series of other, connected pharmaceutical applications (see, for example, Joel Berger et al., Annu. Rev. Med., 2002, 53, 409 - 435; Timothy Wilson et al., J. Med. Chem., 2000, Vol. 43(4), 527-550; Steven Kliewer et al., Recent Prog Horm Res., 2001, 56, 239-63; Jean-Charles Fruchart, Bart Staeis and Patrick Duriez: PPARS, Metabolic Disease and Arteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARs in health and disease, NATURE, VOL. 405, 25 MAY 2000, 421-4; Ines Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staeis: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12:2001, 245-254).
Compounds of this type are particularly suitable for the treatment and/or prevention of
1. - disorders of fatty acid metabolism and glucose utilization disorders
- disorders in which insulin resistance plays a role
2. Diabetes mellitus, in particular type 2 diabetes, including the prevention of the
associated sequelae.
Particular aspects in this connection are
- hyperglycemia
- improvement in insulin resistance
- improvement in glucose tolerance
- protection of the p-cells of the pancreas
- prevention of macro- and microvascular disorders
3. Dyslipidemias and their sequelae, such as, for example, atherosclerosis,
coronary heart disease, cerebrovascular disorders, etc, especially those (but
not restricted to those) which are characterized by one or more of the following
factors:
- high plasma triglyceride concentrations, high postprandial plasma
triglyceride concentrations

- low HDL cholesterol concentrations
- low ApoA lipoprotein concentrations
- high LDL cholesterol concentrations
- small dense LDL cholesterol particles
- high ApoB lipoprotein concentrations
4. Various other conditions which may be associated with metabolic syndrome
are such as:
- obesity (excess weight), including central obesity
- thromboses, stages of hypercoagulability and prethrombosis (arterial and venous)
- high blood pressure
- heart failure, such as, for example, (but not restricted to that) in the state after myocardial infarction, hypertensive heart disease or cardiomyopathy
5. Further disorders or conditions in which, for example, inflammatory reactions or
cell differentiation play a role:
- atherosclerosis, such as, for example, (but not restricted to) coronary sclerosis including angina pectoris or myocardial infarction, stroke
- vascular restenosis or reocclusion
- chronic inflammatory bowel diseases, such as, for example, Crohn's disease and ulcerative colitis
- pancreatitis
- other inflammatory states
- retinopathy
- adipose cell tumors
- lipomatous carcinomas such as, for example, liposarcomas
- solid tumors and neoplasms, such as, for example, (but not restricted to) carcinomas of the gastrointestinal tract, of the liver, of the biliary tract and of the pancreas, endocrine tumors, carcinomas of the lungs, of the kidneys and the urinary tract, of the genital tract, prostate carcinomas, etc.
- acute and chronic myeloproliferative disorders and lymphomas
- angiogenesis
- neurodegenerative diseases
- Alzheimer's disease
- multiple sclerosis
- Parkinson's disease
- erythemato-squamous dermatoses such as, for example, psoriasis
- acne vulgaris

- other skin disorders and dermatological conditions which are modulated by PPAR
- eczemas and neurodermatitis
- dermatitis, such as, for example, seborrheic dermatitis or photodermatitis
- keratitis and keratoses, such as, for example, seborrheic keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or keratosis follicularis
- keloids and keloid prophylaxis
- warts, including condylomata or condylomata acuminata
- human papilloma virus (HPV) infections, such as, for example, venereal papillomata, viral warts, such as, for example, molluscum contagiosum, leukoplakia
- papular dermatoses, such as, for example, lichen planus
- skin cancer, such as, for example, basal-cell carcinomas, melanomas or cutaneous T-cell lymphomas
- localized benign epidermal tumors, such as, for example, keratoderma, epidermal naevi
- chilblains
- high blood pressure
- syndrome X
- polycystic ovary syndrome (PCOS)
- asthma
- osteoarthritis
- lupus erythematosus (LE) or inflammatory rheumatic disorders, such as, for example, rheumatoid arthritis
- vasculitis
- wasting (cachexia)
- gout
- ischemia/reperfusion syndrome
- acute respiratory distress syndrome (ARDS) ("shock lung")
Formulation
The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.001 mg to

100 mg (typically from 0.01 mg to 50 mg) per day and per kilogram of body weight, for example 0.1-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.001 mg to LOmg/kg, which can suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active compound. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated slow-release formulations also belong within the scope of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical preparations for oral administration may be in the form of separate units such as, for example, capsules, wafers, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
The pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place 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 blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active compound is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active compound in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active compound concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active compound to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).
The compounds of the formula I act favorably on metabolic disorders. They have a positive effect on lipid and sugar metabolism and, in particular, reduce the concentration of triglycerides, and they are suitable for preventing and treating type II diabetes and arteriosclerosis and their various sequelae.
Combinations with other medicaments
The compounds of the invention can be administered alone or in combination with one or more further pharmacologically active substances which, for example, act favorably on metabolic disorders or diseases frequently associated therewith. Such medicaments are, for example,

1. medicaments which lower blood glucose, antidiabetics,
2. active compounds for the treatment of dyslipidemias,
3. antiatherosclerotic medicaments,
4. antiobesity agents,
5. antiinflammatory active compounds
6. active compounds for the treatment of malignant tumors
7. antithrombotic active compounds
8. active compounds for the treatment of high blood pressure
9. active compounds for the treatment of heart failure and
10. active compounds for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.
They may be combined with the compounds of the formula I according to the invention in particular for synergistic improvement of the effect. Administration of the active compound combination may take place either by separate administration of the active compounds to the patients or in the form of combination products in which a plurality of active compounds are present in one pharmaceutical preparation.
Mention may be made by way of example of:
Antidiabetics
Suitable antidiabetics are disclosed, for example, in the Rote Liste 2001, chapter 12 or in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2003. Antidiabetics include all insulins and insulin derivatives, such as, for example, Lantus® (see www.lantus.com) or Apidra®, and other fast-acting insulins (see US 6,221,633), GLP-1 receptor modulators as described in WO 01/04146 or else, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S. The orally active hypoglycemic active compounds include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, oral GLP-1 agonists, DPP-IV inhibitors, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenosis, modulators of glucose uptake, compounds which alter lipid metabolism and lead to alteration of the lipid compostion of the blood, compounds

which reduce food intake or food uptake, PPAR and PXR modulators and active compounds which act on the ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the compounds of the formula I are
administered administered in combination with insulin.
In one embodiment of the invention, the compounds of the formula I are in
combination with substances which influence hepatic glucose production such as,
for example, glycogen phosphorylase inhibitors (see: WO 01/94300,
WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188).
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 an active compound which acts on the ATP-dependent
potassium channel of the beta cells, such as, for example, tolbutamide,
glibenclamide, glipizide, glimepiride or repaglinide.
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, ciglitazone,
pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr.
Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-
quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in
combination with a DPPIV inhibitor as described, for example, in W098/19998,
W099/61431, W099/67278, W099/67279, WO01/72290, WO 02/38541,
WO03/040174, in particular P 93/01 (1-cyclopentyl-3-methyl-1-oxo-2-
pentaneammonium chloride), P-31/98, LAF237 (1-[2-[3-hydroxyadamant-1-
yIamino)acetyl]pyrrolidine-2-(S)-carbonitrile), TS021 ((2S, 4S)-4-fluoro-1-[[(2-
hydroxy-1,1-dimethylethyl)amino]acetyl]pyrrolidine-2-carbonitrile
monobenzenesulfonate).
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARgamma agonist such as, for example, rosiglitazone, pioglitazone.

In one embodiment, the compounds of the formula I are administered in combination with compounds with an inhibitory effect on SGLT-1 and/or 2, as disclosed directly or indirectly for example in PCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455.
In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor such as, for example, miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
Lipid modulators
In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor (see, for example, US 6,245,744, US 6,221,897, US 6,277,831, EP 0683 773, EP 0683 774).
In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent, such as, for example, cholestyramine, colesevelam.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, as described, for example, in WO 0250027, or ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see, for example, US 6,342,512).

In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6); Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt/Main). Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARalpha agonist.
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, AZ 242 (Tesaglitazar, (S)-3-(4-[2-(4-methane-
sulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionic acid), BMS 298585 (N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]phenyl]methyl]glycine) or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, W096/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I are administered in combination with nicotinic acid or niacin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example CP-529, 414 (torcetrapib).
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor.

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.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist.
Antiobesity agents
In one 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, the other active compound is fenfluramine or dexfenfluramine. In another embodiment, the other active compound is sibutramine.
In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.:Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists (for example N-{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}-naphthalene-1-sulfonamide, hydrochloride (CGP 71683A)), MC4 agonists (for example N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexa-

hydropyrazolo[4,3-c]pyridin-5-yl)-1-(4«chlorophenyl)-2-oxoethyl]-l-amino-
1,2,3,4-tetrahydronaphthalene-2-carboxamide (WO 01/91752)), orexin antagonists
(for example 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea
hydrochloride (SB-334867-A)), H3 agonists (for example 3-cyclohexyl-
1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic
acid salt (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 (for example urocortin), urocortin agonists,
(33 agonists (for example 1-(4-chloro-3-methanesulfonylmethylphenyl)-
2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol, hydrochloride
(WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A
agonists (for example {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-
thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt
(WO 99/15525)); serotonin reuptake inhibitors (for example dexfenfluramine),
mixed serotoninergic and noradrenergic compounds (for example WO 00/71549),
5HT agonists (for example 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt
(WO 01/09111)), bombesin agonists, galanin antagonists, growth hormone (for
example human growth hormone), growth-hormone-releasing compounds
tert-butyl (6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-
1H-isoquinoline-2-carboxylate (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), decoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors (for example WO 00/40569), PPAR modulators (for example WO 00/78312), RXR modulators or TR-/3 agonists.
In one embodiment of the invention, the other active compound is leptin.
In one embodiment, the other active compound is dexamphetamine, amphetamine, mazindol or phentermine.
In one embodiment, the compounds of the formula I are administered in combination with medicaments having effects on the coronary circulation and the vascular system, such as, for example, ACE inhibitors (e.g. ramipril), medicaments

which act on the angiotensin-renin system, calcium antagonists, beta blockers, etc.
In one embodiment, the compounds of the formula I are administered in combination with medicaments having an antiinflammatory effect.
In one embodiment, the compounds of the formula I are administered in combination with medicaments which are employed for cancer therapy and cancer prevention.
It is self-evident that any suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is regarded as falling within the scope of protection conferred by the present invention.
The activity of the compounds was tested as follows:
Determination of EC50 values of PPAR agonists in the cellular PPARalpha test
Principle
The potency of substances which bind to human PPARalpha and activate it in an agonistic manner is analyzed using a stably transfected HEK cell line (HEK= human embryo kidney) which is referred to here as PPARalpha reporter cell line. It contains two genetic elements, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) which mediates expression of the luciferase reporter element depending on a PPARalpha ligand. The stably and constitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD binds in the cell nucleus of the PPARalpha reporter cell line via the GAL4 protein portion to the GAL4 DNA binding motif 5'-upstream of the luciferase reporter element which is integrated in the genome of the cell line. There is only little expression of the luciferase reporter gene without addition of a PPARalpha ligand if fatty acid-depleted fetal calf serum (cs-FCS) is used in the test. PPARalpha ligands bind and activate the PPARalpha fusion protein and thereby bring about expression of the luciferase reporter gene. The luciferase which is formed can be detected by means of chemiluminescence via an appropriate substrate.

Construction of the cell line
The PPARalpha reporter cell line was prepared in 2 stages. Firstly, the luciferase reporter element was constructed and stably transfected into HEK cells. For this purpose, five binding sites of the yeast transcription factor GAL4 (in each case 5'-CGGAGTACTGTCCTCCGAG-3') were cloned in 5'-upstream of a 68 bp-long minimal MMTV promoter (Accession #V01175), The minimal MMTV promoter section contains a CCAAT box and a TATA element in order to enable efficient transcription by RNA polymerase II. The cloning and sequencing of the GAL4-MMTV construct took place in analogy to the description of Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Then the complete Photinus pyralis luciferase gene (Accession # M15077) was cloned in 3'-downstream of the GAL4-MMTV element. After sequencing, the luciferase reporter element consisting of five GAL4 binding sites, MMTV promoter and luciferase gene was recloned into a plasmid which confers zeozin resistance in order to obtain the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfected into HEK cells in accordance with the statements in Ausubel, F.M. et al. (Current protocols in molecular biology, Vol. 1-3, John Wiley & Sons, Inc., 1995). Then zeozin-containing medium (0.5 mg/ml) was used to select a suitable stable cell clone which showed very low basal expression of the luciferase gene. In a second step, the PPARalpha fusion protein (GR-GAL4»humanPPARalpha-LBD) was introduced into the stable cell clone described. For this purpose, initially the cDNA coding for the N-terminal 76 amino acids of the glucocorticoid receptor (Accession # P04150) was linked to the cDNA section coding for amino acids 1-147 of the yeast transcription factor GAL4 (Accession # P04386). The cDNA of the ligand-binding domain of the human PPARalpha receptor (amino acids S167-Y468; Accession #S74349) was cloned in at the 3' end of this GR-GAL4 construct. The fusion construct prepared in this way (GR-GAL4-humanPPARalpha-LBD) was recloned into the plasmid pcDNA3 (from Invitrogen) in order to enable constitutive expression therein by the cytomegalovirus promoter. This plasmid was linearized with a restriction endonuclease and stably transfected into the previously described cell clone containing the luciferase reporter element. The finished PPARalpha reporter cell line which contains a luciferase reporter element and constitutively expresses the PPARalpha fusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by selection with zeozin (0.5 mg/ml) and G418 (0.5 mg/ml).
Test procedure

The activity of PPARalpha agonists is determined in a 3-day test, described below:
Day 1
The PPARalpha reporter cell line is cultivated up to 80% confluence in DMEM (#41965-039, Invitrogen) with the following additives: 10% cs-FCS (fetal calf serum, #SH-30068.03, Hyclone), 0.5 mg/ml of zeozin (#R250-01, Invitrogen), 0.5 mg/ml of G418 (#10131-027, Invitrogen), 1% penicillin streptomycin solution (#15140-122, Invitrogen) and 2mM of L-glutamine (#25030-024, Invitrogen). Cultivation is carried out in standard cell culture bottles (# 353112, Becton Dickinson) in a cell culture incubator at 37°C in the presence of 5% C02. The 80% confluent cells are washed once with 15 ml of PBS (#14190-094, Invitrogen), treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C for 2 min, taken up in 5 ml of the DMEM medium described and counted in a cell counter. After dilution to 500 000 cells/ml, in each case 35 000 cells are sown into each well of a 96-well microtiter plate having a clear plastic bottom (#3610, Corning Costar). The plates are incubated in a cell incubator at 37°C and 5% CO2 for 24 h.
Day 2
The PPARalpha agonists to be tested are dissolved in DMSO at a concentration of 10 mM. This stock solution is diluted in DMEM (#41965-039, Invitrogen) to which 5% of cs-FCS (#SH-30068.03, Hyclone), 2 mM of L-glutamine (#25030-024, Invitrogen) and the antibiotics already described (zeozin, G418, penicillin and streptomycin) are added.
Test substances are tested at 11 different concentrations in the range of from 10 nM to 100 pM. More potent compounds are tested in concentration ranges of from 1 pM to 10 pM or between 100 nM and 1 pM.
The medium of the PPARalpha reporter cell line sown on day 1 is completely removed by aspiration, and, immediately, the test substances diluted in medium are added to the cells. Dilution and addition of the substances are carried out using a robot (Beckman FX). The end volume of the test substances diluted in medium is 100 pi per well of a 96-well microtiter plate. The DMSO concentration in the test is below 0.1 % v/v to prevent cytotoxic effects of the solvent. To demonstrate that the test is working in each individual plate, a standard PPARalpha agonist, which is also diluted to 11 different concentrations, was

To demonstrate that the test is working in each individual plate, a standard PPARalpha agonist, which is also diluted to 11 different concentrations, was added to each plate. The test plates are incubated in an incubator at 37°C and 5% C02for24h.
Day 3
The PPARalpha receptor cells treated with the test substances are removed from the incubator and the medium is aspirated off. The cells are lyzed by pipetting 50 IJ\ of Bright Glo reagent (from Promega) into each well of a 96-well microtiter plate. After incubation at room temperature in the dark for 10 minutes, the microtiter plates are measured in the luminometer (Trilux from Wallac). The measuring time for each well of a microtiter plate is 1 sec.
Evaluation
The crude data of the luminometer are exported into a Microsoft Excel file. Dose-activity curves and EC50 values of PPAR agonists are calculated using the program XL.Fit according to the instructions of the manufacturer (IDBS).
The PPARalpha EC50 values for the compounds of examples 1 to 15 in this assay are in the range from 0.04 nM to > 10 jaM.
The results for the activity of some compounds of the formula I according to the invention are listed in table I below:

It is evident from table I that the compounds of the formula i according to the invention activate the PPARalpha receptor, thus effecting, for example, analogously to clinically used fibrates, a lowering of the triglyceride concentration in the organism (see, for example, J.-Ch. Fruchard et al.: PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001; S. Kersten et al.: Roles of PPARs in health and disease, NATURE, VOL 405, 25 MAY 2000, 421-4; I. Pineda et al.: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001,245-254).
Determination of EC50 values of PPAR agonists in the cellular PPARgamma test
Principle
A transient transfection system is employed to determine the cellular PPARgamma activity of PPAR agonists. It is based on the use of a luciferase reporter plasmid (pGL3basic-5xGAL4-TK) and of a PPARgamma expression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids are transiently transfected into human embryonic kidney cells (HEK cells). There is then expression in these cells of the fusion protein GAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of the reporter plasmid. In the presence of a PPARgamma-active ligand, the activated fusion protein GAL4-humanPPARgammaLBD induces expression of the luciferase reporter gene, which can be detected in the form of a chemiluminescence signal after addition of a luciferase substrate. As a difference

from the stably transfected PPARalpha reporter cell line, in the cellular PPARgamma test the two components (luciferase reporter plasmid and PPARgamma expression plasmid) are transiently transfected into HEK cells because stable and permanent expression of the PPARgamma fusion protein is cytotoxic.
Construction of the plasmids
The luciferase reporter plasmid pGL3basic-5xGAL4-TK is based on the vector pGL3basic from Promega. The reporter piasmid is prepared by cloning five binding sites of the yeast transcription factor GAL4 (each binding site with the sequence 5'-CTCGGAGGACAGTACTCCG-3'), together with a 160 bp-long thymidine kinase promoter section (Accession # AF027128) 5'-upstream into pGL3basic. 3'-downstream of the thymidine kinase promoter is the complete luciferase gene from Photinus pyralis (Accession # M15077) which is already a constituent of the plasmid pGL3basic used. The cloning and sequencing of the reporter plasmid pGL3basic-5xGAL4-TK took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). The PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD was prepared by first cloning the cDNA coding for amino acids 1-147 of the yeast transcription factor GAL4 (Accession # P04386) into the plasmid pcDNA3 (from Invitrogen) 3'-downstream of the cytomegalovirus promoter. Subsequently, the cDNA of the ligand-binding domain (LBD) of the human PPARgamma receptor (amino acids I152-Y475; Accession # g1480099) was cloned 3'-downstream of the GAL4 DNA binding domain. Cloning and sequencing of the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD again took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Besides the luciferase reporter plasmid pGL3basic-5xGAL4-TK and the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD, also used for the cellular PPARgamma test are the reference plasmid pRL-CMV (from Promega) and the plasmid pBluescript-SK(+) from Stratagene. All four plasmids were prepared using a plasmid preparation kit from Qiagen, which ensures a plasmid quality with a minimal endotoxin content, before transfection into HEK cells.

Test procedure
The activity of PPARgamma agonists is determined in a 4-day test which is described below. Before the transfection, HEK cells are cultivated in DMEM (#41965-039, Invitrogen) which is mixed with the following additions: 10% FCS (#16000-044, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen).
Day 1
Firstly, solution A, a transfection mixture which contains all four plasmids previously described in addition to DMEM, is prepared. The following amounts are used to make up 3 ml of solution A for each 96-well microtiter plate for one test: 2622 |jl of antibiotic- and serum-free DMEM (# 41965-039, Invitrogen), 100 pi of reference plasmid pRL-CMV (1 ng/pl), 100 pi of luciferase reporter plasmid pGL3basic-5xGAL4-TK (10 ng/pl), 100 pi of PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD (100 ng/pl) and 78 pi of plasmid pBluescript-SK(+) (500 ng/pl). Then 2 ml of solution B are prepared by mixing 1.9 ml of DMEM-(# 41965-039, Invitrogen) with 100 pi of PolyFect transfection reagent (from Qiagen) for each 96-well microtiter plate. Subsequently, 3 ml of solution A are mixed with 2 ml of solution B to give 5 ml of solution C, which is thoroughly mixed by multiple pipetting and incubated at room temperature for 10 min. 80%-confluent HEK cells from a cell culture bottle with a capacity of 175 cm2 are washed once with 15 ml of PBS (#14190-094, Invitrogen) and treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C for 2 min. The cells are then taken up in 15 ml of DMEM (#41965-039, Invitrogen) which is mixed with 10% FCS (# 16000-044, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). After the cell suspension has been counted in a cell counter, the suspension is diluted to 250 000 cells/ml. 15 ml of this cell suspension are mixed with 5 ml of solution C for one microtiter plate. 200 pi of the suspension are seeded in each well of a 96-well microtiter plate with a clear plastic base (#3610, Corning Costar). The plates are incubated in a cell culture incubator at 37°C and 5% C02 for 24 h.

Day 2
PPAR agonists to be tested are dissolved in DMSO in a concentration of 10 mM.
This stock solution is diluted in DMEM (# 41965-039, Invitrogen) which is mixed with 2% Ultroser (#12039-012, Biosepra), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Test substances are tested in a total of 11 different concentrations in the range from 10 |JM to 100 pM. More potent compounds are tested in concentration ranges from 1 ptol0pM.
The medium of the HEK cells transfected and seeded on day 1 is completely removed by aspiration, and the test substances diluted in medium are immediately added to the cells. The dilution and addition of the substances is carried out by a robot (Beckman FX). The final volume of the test substances diluted in medium is 100 pi per well of a 96-well microtiter plate. Each plate is charged with a standard PPARgamma agonist, which is likewise diluted in 11 different concentrations, in order to demonstrate the functioning of the test in each individual plate. The test plates are incubated in an incubator at 37°C and 5% C02for 48 h.
Day 4
After removal of the medium by aspiration, 50 \i\ of Dual-Glo™ reagent (Dual-
Glo™ Luciferase Assay System; Promega) are added to each well in accordance with the manufacturer's instructions in order to lyze the cells and provide the substrate for the firefly luciferase (Photinus pyralis) formed in the cells. After incubation at room temperature in the dark for 10 minutes, the firefly luciferase-mediated chemiluminescence is measured in a measuring instrument (measuring time/well 1 sec; Trilux from Wallac). Then 50 pi of the Dual-Glo™ Stop & Glo reagent (Dual-Glo™ Luciferase Assay System; Promega) is added to each well in order to stop the activity of the firefly luciferase and provide the substrate for the Renilla luciferase expressed by the reference plasmid pRL-CMV. After incubation at room temperature in the dark for a further 10 minutes, the chemiluminescence mediated by the Renilla luciferase is again measured for 1 sec/well in the measuring instrument.
Evaluation

The crude data from the luminometer are transferred into a Microsoft Excel file.
The firefly/Renilla luciferase activity ratio is determined for each measurement
derived from one well of the microtiter plate. The dose-activity curves and EC50
values of PPAR agonists are calculated from the ratios by the XL.Fit program as
specified by the manufacturer (IDBS).
PPARgamma EC50 values in the range from 160 nM to >10 //M were measured
using the PPAR agonists described in this application.
The compounds of the formula I of the invention may be obtained according to the
following reaction schemes:

configured.
The broken line indicates the point of attachment to the substituent.
The invention furthermore provides processes for preparing the compounds of the formula I which are obtained in accordance with the reaction schemes A, B and C below:

The compound of the general formula A in which R4 is as defined above is deprotonated with n-butyllithium in tetrahydrofuran at -78°C, and compound B is then added at this temperature, giving a compound of the general formula C.
The compound C is then reacted with tetrabutylammonium fluoride solution in tetrahydrofuran to give compound D. The latter is hydrogenated with hydrogen

over pailadium-on-carbon, giving compound E. Compound E is deprotonated with sodium hydride in dimethylformamide, allyl bromide is added and the mixture is stirred at room temperature for a number of hours, giving compound F. The latter is reacted with osmium tetroxide and sodium periodate in diethyl ether, giving aldehyde G.
Compound G is then stirred with a primary amine R3-NH2, where R3 is as defined
above, and sodium borohydride in methanol at 0°C, worked up and then reacted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, to give the compound of the general formula H.
To cleave the tert-butyl ester, compound H is stirred at room temperature in trifluoroacetic acid for a number of hours, giving the compound of the general formula J.
Using this process, it is possible to synthesize the compounds of Examples 1 to 8.

Compound B (see process A) is reacted with the compound of the general formula K to give compound C where R4 = H. The latter compound is hydrogenated with hydrogen over palladium-on-carbon, giving compound L.
Compound L is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0°C and then reacted with an alkyl iodide of the general formula R4-I, where R4 may have the meaning described above. After work-up, this compound is then again deprotonated with lithium diisopropylamide in tetrahydrofuran at 0°C and subsequently reacted with an alkyl iodide of the general formula R5-I, where R5 may have the meaning described above, giving the compound of the general formula M.

Compound M is reacted with tetrabutylammonium fluoride in tetrahydrofuran to give compound N which is deprotonated with sodium hydride in dimethylformamide and reacted with allyl bromide to give compound O. The latter is converted with osmium tetroxide and sodium periodate in diethyl ether to give compound P.
Compound P is then stirred with a primary amine of the general formula R3-NH2,
where R3 is as defined above, and sodium borohydride in methanol at 0°C, worked up and then reacted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, giving the compound of the general formula Q.
To cleave the tert-butyl ester, compound Q is stirred in trifluoroacetic acid at room temperature for a number of hours, giving the compound of the general formula R.
Using this process, it is possible to synthesize the compounds of Examples 9 to 12.

Compound S is stirred at room temperature in methanol with sodium methoxide. After work-up, the product is converted with tert-butyldiphenylsilyl chloride and imidazole in dimethylformamide at room temperature into compound T.
Compound T is stirred in isopropanol with sodium hydroxide at 60°C for 1 hour. After work-up, the product is reacted in dimethylformamide with a tert-butyl ester of an a-amino acid, hydroxybenzotriazole, diisopropylethylamine and 0-[cyano(ethoxycarbonyl)methyieneamino]-1,1,3,3,-tetramethyluronium tetrafluoroborate (TOTU), giving the product of the general formula U in which R4 and R5 are as defined above.
Compound U is reacted with tetrabutylammonium fluoride in tetrahydrofuran, giving compound V. The latter is deprotonated with sodium hydride in dimethylformamide and alkylated with ally! bromide, giving compound W. The

terminal double bond is then cleaved with osmium tetroxide and sodium periodate in diethyl ether, giving aldehyde X.
Compound X is reacted with a primary amine of the general formula R3-NH2,
where R2 is as defined above, in methanol with sodium borohydride, worked up and then converted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, into compound Y. The latter is converted by stirring in trifluoroacetic acid into product Z.
Using this process, it is possible to synthesize Examples 13 to 15.
Other compounds of the formula I can be prepared analogously or by known processes.
The examples adduced below serve to illustrate the invention, but without limiting it.
The syntheses of the example compounds are described below.
Example 1
4-[cis-3-{2-[3-Cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyric acid

9.3 ml of tert-butyl diethylphosphonoacetate are dissolved in 80 ml of dimethylformamide, and 1.38 g of sodium hydride (60% strength in paraffin oil) are

added a little at a time at 0°C. The suspension is stirred at 0°C for 15 minutes, and 4.02 ml of ethyl iodide are then added. The mixture is stirred at room temperature for 12 hours. 250 ml of ethyl acetate are then added, and the reaction mixture is washed three times with in each case 150 ml of water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1. This
gives 6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate as an oil. C13H27O5P
(294.33), 1H-NMR (CDCI3, 8 = ppm): 4.15 (q, 4H), 2.73 (ddd, 1H), 2.0-1.8 (m, 2H), 1.49 (s, 9H), 1.35 (q, 6H), 1.00 (t, 3H).
cis-3-Allylcyclohexanol

cis/racemate cis/racemate
87 ml of a 1 molar solution of lithium diisobutylaluminum hydride in n-hexane are dissolved in 100 ml of diethyl ether, and 7 ml of isopropanol are added at 0°C. After the evolution of gas has ended, 12.4 g of 3-allylcylohexanone, dissolved in 50 ml of diethyl ether, are added. The mixture is stirred at room temperature for 48 hours. The reaction mixture is quenched by addition of 1M hydrochloric acid and the aqueous phase is saturated with sodium chloride and extracted five times with in each case 200 ml of ethyl acetate. The combined organic phases are washed with 2N sodium hydroxide solution and dried over magnesium sulfate, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 15:1=> 5:1. This gives 6.8 g
of cis-3-allylcyclohexanol as an oil. C9H16O (140.23), MS(ESI): 141 (M+H+), Rf(n-
heptane:ethyl acetate = 2:1) = 0.22.
(cis-3-Allylcyclohexyloxy)-tert-butyl-diphenylsilane

6.8 g of cis-3-aIlylcyclohexanol and 15 ml of tert-butyldiphenylsilyl chloride, 5 g of imidazole and 200 mg of dimethylaminopyridine are dissolved in 100 ml of dimethylformamide and stirred at room temperature for 12 hours. 400 ml of methyl tert-buthyl ether are added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 20.5 g of (cis-3-
allylcyclohexyloxy)tert-butyl-diphenylsilane as an oil. C2sH340Si (378.64), MS(ESI): 379 (M+H+), Rf(n-heptane:ethyl acetate = 2:1) = 0.93.

cis/racemate cis/racemate
5.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenylsilane are dissolved in 100 ml of diethyl ether, and 9.4 g of sodium periodate, dissolved in 100 ml of water, are added. At 0°C, 15 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 5 hours, a further 5g of sodium periodate are added, and the mixture is stirred at room temperature for another 3 hours. The reaction mixture is then diluted by addition of 300 ml of methyl tert-buthyl ether and washed with saturated

sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 6 g of [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde as a yellow-brown oil.
C24H3202Si (380.61), MS(ESI): 381 (M+H+), Rf(n-heptane:ethyl acetate = 5:1) =
0.44.

6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate are dissolved in 90 ml of tetrahydrofuran, and 7.32 ml of a 2.7 M solution of n-butyllithium in n-hexane are added at -20°C. After 1 hour of stirring at -20°C, 4.36 g of [cis-3-(tert-butyl-diphenylsi!anoxy)cyclohexyl]acetaldehyde, dissolved in 40 ml of tetrahydrofuran, are added dropwise. The reaction mixture is slowly warmed to room temperature. 50 ml of water are then added, and the mixture is extracted three times with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n«heptane:ethyl acetate = 30:1. This gives 3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenyl-
silanyloxy)cyclohexyl]-2-ethylbut-2-enoate as an oil. C32H4603Si (506.81), Rf(n-
heptane:ethyl acetate = 5:1) = 0.73.
tert-Butyl 2-ethyl-4~(cis-3-hydroxycyclohexyl)but-2-enoate

1.3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2-ethylbut-2-enoate are dissolved in 20 ml of tetrahydrofuran, and 15.7 ml of a 1M solution of • tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 30:1 => ethyl acetate. This gives 1.65 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl]but-
2-enoate as an oil. C16H28O3 (268.40), Rf(n-heptane:ethyl acetate = 5:1) = 0.07. tert-Butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate

1.65 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)but-2-enoate are dissolved in 50 ml of methanol, and 100 mg of Perlmans catalyst are added. The mixture is stirred under an atmosphere of hydrogen for 24 hours. The catalyst is filtered off through Ceiite, and the filtrate is then concentrated under reduced pressure. This gives 1.49 g of tert-butyl 2~ethyl-4-(cis-3-hydroxycyclohexyl)butyrate as a colorless
oil. C16H30O3 (270.40), Rf(n-heptane:ethyl acetate = 5:1) = 0.10. tert-Butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate

1.19 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate are dissolved in 50 ml of dimethylformamide, and 210 mg g of sodium hydride (60% strength in paraffin oil) are added. The suspension is stirred at room temperature for 15 minutes, and 1.6 ml of allyl bromide are then added. After one hour, a further 320 mg of sodium hydride are added. After 12 hours of stirring at room temperature, another 320 mg of sodium hydride and then 1.6 ml of allyl bromide are metered in. Stirring at room temperature is continued for a further 12 hours. After addition of 200 ml of methyl tert-butyl ether, the mixture is washed three times with in each case 100 ml of water and the organic phase is separated off and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 60:1 => 30:1. This gives 770 mg of tert-butyl 4-(cis-3-
allyloxycyclohexyl)-2-ethylbutyrate as an oil. C19H34O3 (310.48), Rf(n-
heptane:ethyl acetate = 5:1) = 0.48.

770 mg of tert-butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate are dissolved in 50 ml of diethyl ether, and 1.59 g of sodium periodate, dissolved in 50 ml of water, are added. At 0°C, 2.56 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 9 hours, a further 12.8 ml of the osmium tetroxide solution are added, and

stirring at room temperature is continued for a further 3 hours. 200 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 710 mg of tert-butyl 2-
ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate as a yellow-brown oil. C18H32O4 (312.45), Rf(n-heptane:ethyl acetate = 5:1) = 0.15.
tert-Butyl 4-(cis-3-{2-[3-cyclohexyl»1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyrate

380 mg of the aldehyde tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate
and 0.14 ml of 4-methylbenzylamine are dissolved in 5 ml of methanol. 400 mg of
4 A molecular sieve, which had been dried by heating, is added, and the mixture is
stirred at room temperature for two hours. 55 mg of sodium borohydride are then
added to the reaction mixture. After 30 minutes, the molecular sieve is removed by
filtration of the mixture through Celite. The filtrate is concentrated under reduced
pressure. The residue is dissolved in 8 ml of dimethylformamide, and 0.11 ml of
cyclohexyl isocyanate is added. After 12 hours, the dimethylformamide is removed
under reduced pressure and the residue is purified on silica gel using the mobile
phase n-heptane:ethyl acetate = 9:1 => 7:1. This gives 160 mg of the urea tert-
butyl 4-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-
ethylbutyrate as an oil. C33H54N2O4 (542.81), MS(ESI): 543 (M + H+).
4-(cis-3-{2-[3-cycIohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyric acid

160 mg of tert-butyl 4-(cis-3-{2-[3-cyciohexyl-1-(4-methylbenzyl)ureido]-ethoxy}cyclohexyl)-2-ethylbutyrate are dissolved in 16 ml of dichloromethane, and 4 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 12 hours. 50 ml of toluene are then added, and the solvents are removed under reduced pressure. The residue is purified by RP-HPLC. Freeze drying gives 123 mg of 4-(cis«3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-
ethylbutyric acid as a colorless oil. C29H46N2O4 (486.70), MS(ESI): 487 (M + H+).
Example 2
Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, heptylamine and butyl isocyanate gave 4-{cis-3-[2-(3-butyl-1-heptylureido)ethoxy]cyclohexyl}-2-ethylbutyricacid.

Example 3
Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, heptylamine and cyclohexyl isocyanate gave 4-{cis-3-[2-(3-cyclohexyl-1-heptylureido)ethoxy]cyclohexyl}-2-ethylbutyricacid.

C28H52N2O4 (480.74), MS(ESI): 481 (M + H+).
Example 4
Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, p-methylbenzylamine and butyl isocyanate gave 4-(cis-3-{2-[3-butyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)»2-ethylbutyricacid.

Example 5
Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide,
[cis-3-(tert-butyl-diphenylsilanyloxy)cycIohexyl]acetaldehyde, heptylamine and
butyl isocyanate gave 2-(2-{cis-3-[2-(3-butyl-1-
heptylureido)ethoxy]cyclohexyl}ethyl)-3-methylbutyricacid.

C27H52N2O4 (468.73), MS(ESI): 469 (M + H+).
Example 6
Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide,
[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, heptylamine and
cyclohexyl isocyanate gave 2-(2-{cis-3-[2-(3-cyclohexyl-1 -
heptylureido)ethoxy]cyclohexyl}ethyl)-3-methylbutyricacid.

C29H54N2O4 (494.76), MS(ESI): 495 (M + H+).

Example 7
Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide,
[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, p-benzylamine and
butyl isocyanate gave 2-[2-(cis-3-{2-[3-butyl-1-(4-
methylbenzyl)ureido]ethoxy}cyclohexyl)ethyl]-3-methylbutyricacid.

C28H46N2O4 (474.69), MS(ESI): 475 (M + H+).
Example 8
Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, p-methylbenzylamine and cyclohexyl isocyanate gave 2-[2-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)ethyl)-3-methylbutyric acid.

C30H48N2O4 (500.73), MS(ESI): 501 (M + H+).
Example 9
tert-Butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]but-2-enoate

butyl-diphenylsilanyloxy)cyclohexyl]butanoate as an oil. C3oH4403Si (480.75), MS(ESI): 481 (M+H+).
tert-Butyl4-[cis-3-(tert-butyl-diphenylsilany^

2 g of tert-butyl 4«[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyI]butanoate are dissolved in 20 ml of tetrahydrofuran, and 3.1 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to -30°C, and 1.6 ml of methyl iodide are added. The mixture is allowed to warm to room temperature over a period of 12 hours. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 2.1 g of the monomethylated product. This product is dissolved in 20 ml of tetrahydrofuran, and 6 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to 0°C, and, after 10 minutes at 0°C, 2.5 ml of methyl iodide are added. The mixture is allowed to warm to room temperature over a period of 12 hours. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 1.8 g of tert-butyl 4-[cis«3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate as an
oil. C32H4803Si (508.82), Rf(n-heptane:ethyl acetate = 5:1) = 0.49.

tert-Butyl4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate

2 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate are dissolved in 10 ml of tetrahydrofuran, and 8 ml of a 1 M solution of tetrabutylammonium fluoride and tetrahydrofuran are added. The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 20:1 => 1:1. This gives 730 mg of tert-butyl 4-[cis-3-hydroxycyclohexyl)-
2,2-dimethylbutyrate as an oil. C16H30O3 (270.42), Rf(n-heptane:ethyl acetate =
5:1) = 0.22.
Analogously to Example 1, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-heptylamine and butyl isocyanate gave 4-{cis-3-[2-(3-butyl-1-heptylureido)ethoxy]cyclohexyl)-2,2-dimethylbutyricacid.

Example 10
Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-methylbenzylamine and butyl isocyanate gave 4-(cis-3-{2-[3-butyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2,2-dimethylbutyric acid.

C27H44N2O4 (460.66), MS(ESI): 461 (M + H+).
Example 11
Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-heptylamine and cyclohexyl isocyanate gave 4-{cis-3-[2-(3-cyclohexyl-1«heptylureido)ethoxy]cyclohexyl}-2,2-dimethylbutyrate.

C28H52N2O4 (480.74), MS(ESI): 481 (M + H+).
Example 12
Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-methylbenzylamine and cyclohexyl isocyanate gave 4-(cis-3-

{2-[3-cyclohexyl-1-(4-methyibenzyl)ureido]ethoxy}cyciohexyl)-2,2-dim acid.

C29H46N2O4 (486.70), MS(ESI): 487 (M + H+).
Example 13
Methyl cis-3-(tert-butyl-diphenylsi!anyloxy)cyclohexanecarboxylate

22 g of 6-oxabicycio[3.2.1]octan-7-one are dissolved in 200 ml of methanol, and 10% strength sodium methoxide solution is added until a pH of 10 is reached. The mixture is stirred at room temperature for 30 minutes and then neutralized by addition of dilute acetic acid, and the mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, dried over magnesium sulfate and then concentrated under reduced pressure. This gives 21 g of the methyl ether as a colorless oil. This is dissolved in 200 ml of dimethylformamide, 43 g of tert-butyldiphenylsilyi chloride, 13 g of imidazole and 1 g of dimethylaminopyridine are added and the mixture is stirred at room temperature for 12 hours. The solvent is removed under reduced pressure and the residue is taken up in methyl tert-butyl ether and washed with water. The organic phase is dried over magnesium sulfate and the solvent is then removed. This gives 56.8 g of methyl cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarboxylate as a yellow oil.

C24H3203Si (396.61), MS(ESI): 397 (M+H+).
tert-Butyl cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarbonyl]amino}-(3S)-methylbutyrate

36.8 g of cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarboxyIic acid are dissolved in 150 ml of isopropanol, and 8g of sodium hydroxide, dissolved in 50 ml of water, are added. The mixture is heated at 60°C for 1 hour. The reaction mixture is cooled and neutralized by addition of 2N hydrochloric acid. The reaction mixture is concentrated under reduced pressure and extracted with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 34 g of the free acid as a colorless oil (Rf(ethyl acetate) = 0.63). This is dissolved in 250 ml of dimethylformamide, and 18.6 g of ferf-butyl L-valinate hydrochloride are added. At 0°C, 29.1 g of 0-[cyano(ethoxycarbonyl)methyleneamino]-1,1,3,3,-tetramethyluronium tetrafluoroborate are added. After 10 minutes, the ice bath is removed and 23.9 g of hydroxybenzotriazole and 61.8 ml of Hunig base are added. The mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the resulting residue is dissolved in ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate 2:1. This gives 43.0 g of tert-butyl 2-{[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarbonyl]-amino}-(3S)-methylbutyrate as a yellow
oil. C32H47N04Si (537.82), MS(ESI): 538.

tert-Butyl2-[(cis-3-hydroxycyclohexanecarbonyl)aminoH3S)-methyl-butyrate

43.0 g of tert-butyl 2-{[cis«3-(tert-butyl-diphenylsilanyloxy)cyclohexane-carbonyl]amino}-(3S)-methylbutyrate are dissolved in 80 ml of tetrahydrofuran, and 80 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60°C for 3 h and then concentrated under reduced pressure, and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1 => 1:1. This gives 18 g of a white solid. Since this is still slightly impure, 8 g are subjected to another purification on silica gel. This gives 6.8 g of tert-butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-
methylbutyrate as a white solid. C16H29NO4 (299.41), MS(ESI): 300 (M+H+).
tert-Butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methyl-butyrate can be separated by chiral HPLC. This gives tert-butyl 2-[((1R,3S)-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate (Rt = 4.9 min) and tert-butyl 2-[((1S,3R)-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate (Rt = 5.7 min) as colorless lyophilisates. (Chiralpak AD/34 250 x 4.6; mobile phase n-heptane:ethanol:methanol = 20:1:1 + 0.1% trifluoroacetic acid).
tert-Butyl 2-[(cis-3-allyloxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate

2.8 g of tert-butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methyl butyrate are dissolved in 20 ml of dimethylformamide, and 450 mg of sodium hydride (60% strength suspension in mineral oil) are added. After 10 minutes, 3.4 ml of allyl bromide are added dropwise. After 3 hours of stirring at room temperature, another 700 mg of sodium hydride are added. After 2 hours of stirring at room temperature, another 3.4 ml of allyl bromide are metered in. The mixture is stirred at room temperature for 12 hours, 200 ml of methyl tert-butyl ether are then added to the reaction mixture and the mixture is washed three times with in each case 100 ml of water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 40:1 => 10:1. This gives 900 mg of tert-butyl 2-[(cis-3-allyloxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate as a
colorless oil. C19H33NO4 (339.48), MS(ESI): 340 (M+H+), Rf(n-heptane:ethyl
acetate = 1:1) = 0.58.
tert-Butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecarbonyl]amino}butyrate

900 mg of tert-butyl 2-[(cis-3-allyioxy)cyclohexanecarbonyl)amino]-(3S)-methylbutyrate are dissolved in 20 ml of diethyl ether, and 1.7 g of sodium, periodate, dissolved in 20 ml of water, are added. At 0°C, 1.6 ml of a solution of osmium tetroxide (2.5% by weight) in tert-butanol are added. The reaction mixture is stirred vigorously at room temperature for 3 hours. At 0°C, 50 ml of saturated sodium thiosulfate solution are then added. The organic phase is separated off. The aqueous phase is extracted three times with in each case 50 ml of methyl tert-butyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 1.0 g of tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecarbonyl]amino}butyrate as a colorless oil which is reacted further without purification.

C18H31NO5 (341.45), Rf(n-heptane:ethyl acetate = 1:1) = 0.19.
tert-Butyl 2-[(cis-3^2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclo-hexanecarbo hexanecarbonyl)amino]-(3S)-methylbutyrate

330 mg of tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecar-
bonyI]amino}butyrate are dissolved in 3 ml of methanol, and 0.12 ml of 4-
methylbenzylamine, dissolved in 5 ml of methanol, is added. 300 mg of molecular
sieve (4 A), which had been dried by heating, are added, and the mixture is stirred
at room temperature for 2 hours. 50 mg of sodium borohydride are then added,
and stirring at room temperature is continued for another 30 minutes. The
molecular sieve is filtered off and the filtrate is concentrated under reduced
pressure. The resulting residue is dissolved in 20 ml of dimethylformamide, and
80 l are added. The mixture is stirred at room temperature for 12 hours. The
dimethylformamide is removed under reduced pressure and the residue is purified
on silica gel using the mobile phase n-heptane:ethyl acetate = 9:1 => 2:1. This
gives 320 mg of tert-butyl 2-[cis-3-{2-[3-ethyl-1 -(4-
methylbenzyl)ureido]ethoxy}cyclohexanecarbonyl)amino]-(3S)-methylbutyrate as a
light-yellow oil. C29H47N3O5 (517.72), MS(ESI): 518.
2-[(cis-3-{2-[3-Ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexane-carbonyl)amino]-(3S)-methylbutyricacid

320 mg of tert-butyl 2-[(cis-3-{2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}-cydohexanecarbonyl)amino]-(3S)-methylbutyrate are dissolved in 20 ml of dichloromethane, and 10 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 3 hours. The solvents are removed under reduced pressure and the residue is purified by RP-HPLC. This gives 115 mg of 2-[(cis-3-{2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexanecarbonyl)amino]-(3S)-
methylbutyric acid as a white lyophilisate. C25H39N3O5 (461.61), MS(ESI): 462.
Example 14
Analogously to Example 13, tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)-cyclohexanecarbonyl]amino}butyrate, n-heptylamine and phenyl isocyanate gave 2-({cis-3-[2-(1-heptyl-3-phenylureido)ethoxy]cyclohexanecarbonyl}amino)-(3S)-methylbutyric acid.

cis/diastereomer mixture C28H45N3O5 (503.69), MS(ESI): 504.

Example 15
Analogously to Example 13, tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)-
cyclohexanecarbonyl]amino}butyrate, 2,2-dimethyIpropylamine and phenyl
isocyanate gave 2-[(cis-3-{2-[1-(2,2-dimethylpropyl)-3-phenylureido]-
ethoxy}cyclohexanecarbonyl)aminoH3S)-methylbutyricacid.

cis/diastereomer mixture C26H41N3O5 (475.63), MS(ESI): 476.
V

We claim:
1. A compound of the formula l

Ring A is (C3-C8)-cycloalkanediyi or (C3-C8)-cycloaIkenediyI, where in
the cycloalkane- or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms;
R1.R2 independently of one another are H, (C1-6alkyl, (C3-C8)-cycloalkyl or (C6-C10)-aryl;
R3 is (C3-C6)-cycloalkyl or (C1|-C12)-alkyl which are optionally
substituted by (C6-C10o)-aryl, (C5-C6)-heteroaryl or (C3-C6)-cycloalkyl, where aryl, heteroaryl or cycloalkyl for their part may be substituted by (C1-C6)J-alkyI, (C1-6)J-alkoxy, CI, Br, I, CO-
(C1-6)-alkyl, CO-0(Ci-Ce)-alkyl, CO-NH(C1-6)-alkyl or CO-
N((C1-6)-alkyl)2;
X is (C1-6)-alkanediyl, where in the alkanediyl group one or more
carbon atoms may be replaced by oxygen atoms;
Y1 is CO or a bond;

Y2 is NH, (C1-6)-alkanediyl, where in the alkanediyl group one or
more carbon atoms may be replaced by oxygen atoms;
R4 is(C1-C8)-alkyi;
R5 isHf(C1-6-alkyl;
R6 is H;
and its physiologically acceptable salts. 2. A compound of the formula I as claimed in claim 1 in which
Ring A is (C3-C8)-cycloalkane-1,3-diyl;
R1,R2 independently of one another are H, (C1-6)-alkyl, (C3-C8)-cycloalkyl or (C6-C10)-aryl;
R3 is (C1-6)-cycloalkyl which is optionally substituted by phenyl,
where phenyl for its part may be substituted by (C1-6)-alkyl;
X is (C1-6)-alkanediyl, where in the alkanediyl group one carbon
atom may be replaced by an oxygen atom;
Y1 is CO or a bond;
Y2 is NH, (C1-6)-alkanediyl, where in the alkanediyl group one
carbon atom may be replaced by an oxygen atom;
R4 is (Ci-C8)-alkyl;

R5 is H, (C1-6)-alkyl;
R6 is H.
3. A compound of the formula I as claimed in claim 1 or 2, in which
Ring A is cyclohexane-1,3-diyl;
R1.R2 independently of one another are H, (C1-6)-alkyl, (C3-C8)-cycloalkyl or phenyl;
R3 is (C1-C12)-alkyl which is optionally substituted by phenyl, where
phenyl for its part may be substituted by methyl;
X is (C1-6)-alkanediyl, where in the alkanediyl group the carbon
atom adjacent to ring A may be replaced by an oxygen atom;
Y1 is CO or a bond;
Y2 is NH, (C1-C6)-alkanediyl, where in the alkanediyl group one
carbon atom may be replaced by an oxygen atom;
R4 is (C1-6-alkyl;
R5 isHor(C1-6)-alkyl;
R6 isH.
4. A compound of the formula I as claimed in any of claims 1 to 3, in which

Ring A is cyclohexane-1,3-diyl;
R1 is H;
R2 is (C1-6-alkyl, (C3-C8)-cyc!oalkyl or phenyl;
R3 is (C1-C8)-alkyl which is optionally substituted by phenyl, where
phenyl for its part may be substituted by methyl;
X is ((CH2)2)0;
Y1 is CO or a bond;
Y2 isNH, (C1-6-alkanediyl;
R4 is (C1-6-alkyl;
R5 is H, (C1-6-alkyl;
R6 is H.
5. A compound of the formula I as claimed in claims 1 to 4, wherein the bond X-ring A-Yi is cis-configured.
6. A pharmaceutical, comprising one or more of the compounds of the formula I as claimed in one or more of claims 1 to 5.
7. A pharmaceutical, comprising one or more of the compounds of the formula I as claimed in one or more of claims 1 to 5 and one or more active compounds which have a favorable effect on metabolic disorders or associated diseases.

8. A pharmaceutical comprising one or more of the compounds of the formula I as claimed in one or more of claims 1 to 5 and one or more antidiabetics.
9. A pharmaceutical comprising one or more of the compounds of the formula I as claimed in one or more of claims 1 to 5 and one or more lipid modulators.
10. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders.
11. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of disorders in which insulin resistance plays a role.
12. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of diabetes mellitus and the associated sequelae.
13. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of dyslipidemias and their sequelae.
14. The use of the compounds of the formula I as claimed in one or more of claims 1 to 5 for the treatment and/or prevention of conditions associated with the metabolic syndrome.
15. The use of the compounds as claimed in one or more of claims 1 to 5 in combination with at least one further active compound for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders.
16. The use of the compounds as claimed in one or more of claims 1 to 5 in combination with at least one further active compound for the treatment and/or prevention of disorders in which insulin resistance plays a role.

17. A process for preparing a pharmaceutical comprising one or more compounds as claimed in one or more of claims 1 to 5, which comprises mixing the active compound with a pharmaceutically suitable carrier and bringing this mixture into a form suitable for administration.

Description
Cycloalkyl-substituted alkanoic acid derivatives, methods for the production thereof, and use thereof as a medicament
The invention relates to arylcycloalkyl-substituted alkanoic acid derivatives and to their physiologically acceptable salts and physiologically functional derivatives.
Compounds of a similar structure have already been described in the prior art for the treatment of hyperlipidemia and diabetes (WO 2000/64876).
It was an object of the invention to provide compounds which allow a therapeutically exploitable modulation of the lipid and/or carbohydrate metabolism and are thus suitable for the prevention and/or treatment of diseases such as type 2 diabetes and atherosclerosis and the various sequelae thereof.
Surprisingly, a series of compounds which modulate the activity of PPAR receptors has been found. In particular, the compounds are suitable for the activation of PPARalpha and PPARgamma, and the extent of the relative activation can be different depending on the compounds.
Accordingly, the invention relates to compounds of the formula I

in which
Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, where in the
cycloalkane- or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms;

R1, R2 independently of one another are H, C1-6-a!kyI, (C3-C8)-cycloalkyl or(C6-C10)-aryi;
R3 is (C3-C6)-cycloalkyl or (C1-C12)-alkyl which are optionally substituted
by (C6-C10)-aryl, (C1-C6)-heteroaryl or (C3-C6)-cycloalkyl, where aryl, heteroaryl or cycloalkyl for their part may be substituted by (C1-C6)-alkyl, C1-6-alkoxy, CI, Br, I, CO-(C1-C6)kyl, CO-0C1-6-alkyl, CO-NH(1-6)alkyl or CO-N(C1-6-alkyl)2;
X is C1-6-alkanediyl, where in the alkanediyl group one or more
carbon atoms may be replaced by oxygen atoms;
Y1 is CO or a bond;
Y2 is NH, (C1-C12)-alkanediyl, where in the alkanediyl group one or more
carbon atoms may be replaced by oxygen atoms;
R4 is (C1
-C8)-alkyl;
R5 is H, C1-6-alkyl;
R6 is H;
and their physiologically acceptable salts.
Preference is given to compounds of the formula I whose substituents X and Y1 are bonded to the ring A in positions 1 and 3. (X - Ring A - Y1).

Preference is also given to compounds of the formula I in which Ring A is (C3-C8)-cycloalkane-1,3-diyl;
R1, R2 independently of one another are H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or(C6-Cio)-aryl;
R3 is (C1-C12)-cycloalkyl which is optionally substituted by phenyl, where
phenyl for its part may be substituted by C1-6-alkyI;
X is (C1-C6)-alkanediyl, where in the alkanediyl group one carbon atom
may be replaced by an oxygen atom;
Y1 is CO or a bond;
Y2 is NH, C1-6-alkanediyl, where in the alkanediyl group one carbon
atom may be replaced by an oxygen atom;
R4 is(C1-C8)-alkyl;
R5 is H, C1-6-alkyl;
R6 is H.
Particular preference is given to compounds of the formula I in which
Ring A is cyclohexane-1,3-diyl;
R1, R2 independently of one another are H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or phenyl;

R3 is (C1-C12)-alkyl which is optionally substituted by phenyl, where
phenyl for its part may be substituted by methyl;
X is (C1-6)-alkanediyl, where in the alkanediyl group the carbon atom
adjacent to ring A may be replaced by an oxygen atom;
Y1 is CO or a bond;
Y2 is NH, (C1-C6)-alkanediyl, where in the alkanediyl group one carbon
atom may be replaced by an oxygen atom;
R4 is (C1-C8)-alkyl;
R5 isH or(Ci-C4)-alkyl;
R6 is H.
Very particular preference is given to compounds of the formula I
in which
Ring A is cyclohexane-1,3-diyl;
R1 is H;
R2 is C1-6-alkyl, (C3-C8)-cycloalkyl or phenyl;
R3 is (C1-C8)-alkyl which is optionally substituted by phenyl, where phenyl
for its part may be substituted by methyl;

X is ((CH2)2)0;
Y1 is CO or a bond;
Y2 is NH, (C1-C4)-alkanediyl;
R4 is C1-6-alkyl;
R5 is H, (C1-C4)-alkyl;
R6 is H.
The bond to ring A may be either cis or trans, preference is given to the cis-bond.
The present invention also encompasses all combinations of the "preferred embodiments" of the invention described herein.
The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5 and R6 can be straight-chain or branched.
Aryl refers to an aromatic, carbocyclic, mono- or bicyclic ring system which contains from 6 to 10 atoms in the ring or in the rings.
Heteroaryl is a mono- or bicyclic aromatic ring system having from 4 to 11 ring members, in which at least one atom in the ring system is a heteroatom from the group of N, O and S.
The compounds of the formula I contain at least two centers of asymmetry and may contain more. The compounds of the formula I may therefore be present in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and diastereomer mixtures. The present invention encompasses all of these isomeric forms of the compounds of the formula I. These isomeric forms may,

even when some of them are not described expresses verbis, be obtained by known methods.
Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater solubility in water compared with the starting or base compounds. 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 acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts) and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutical^ acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester which is able, on administration to a mammal such as, for example, to a human, to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.
Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves have activity or not.

The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the scope of the invention and are a further aspect of the invention.
All references hereinafter to "compound(s) of formula I" refer to compound(s) of the formula I as described above, and to the salts, solvates and physiologically functional derivatives thereof as described herein.
Use
This invention relates further to the use of compounds of the formula I and their pharmaceutical compositions as PPAR receptor ligands. The PPAR receptor ligands of the invention are suitable as modulators of the activity of the PPAR receptors.
Peroxisome proliferator-activated receptors (PPAR) are transcription factors which can be activated by ligands and belong to the class of nuclear hormone receptors. There are three PPAR isoforms, PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes (Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Motojima K, Cell Struct Fund, 1993 Oct, 18(5), 267-77).
There exist two variants of PPARgamma, PPARgammai and -gamma2, which are the result of alternative use of promoters and differential mRNA splicing (Vidal-Puig et al.f J. Clin. Invest., 97:2553-2561, 1996). The various PPAR receptors have a different tissue distribution and modulate different physiological functions. The PPAR receptors play a key role in different aspects of the regulation of a multitude of genes, whose gene products are crucially involved directly or indirectly in lipid and carbohydrate metabolism. Thus, for example, PPARalpha receptors play an important role in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARgamma is crucially involved, for example, in the regulation of adipose cell differentiation.
In addition, PPAR receptors are also involved in the regulation of many further physiological processes, including those which are not directly connected with carbohydrate or lipid metabolism. The activity of the different PPAR receptors can be modulated to varying extents by various fatty acids, fatty acid derivatives and synthetic compounds. For relevant reviews concerning functions, physiological effect and pathophysiology, see: Joel Berger et al., Annu. Rev. Med., 2002, 53,

409 - 435; Timothy Wilson et alM J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al., Recent Prog Horm Res., 2001, 56, 239-63. The present invention relates to compounds of the formula I which are suitable for modulating the activity of PPAR receptors, especially the activity of PPARalpha and PPARgamma. Depending on the profile of the modulation, the compounds of the formula I are suitable for the treatment, control and prophylaxis of the indications described hereinafter, and for a series of other, connected pharmaceutical applications (see, for example, Joel Berger et al., Annu. Rev. Med., 2002, 53, 409 - 435; Timothy Wilson et al., J. Med. Chem., 2000, Vol. 43(4), 527-550; Steven Kliewer et al., Recent Prog Horm Res., 2001, 56, 239-63; Jean-Charles Fruchart, Bart Staeis and Patrick Duriez: PPARS, Metabolic Disease and Arteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARs in health and disease, NATURE, VOL. 405, 25 MAY 2000, 421-4; Ines Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staeis: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12:2001, 245-254).
Compounds of this type are particularly suitable for the treatment and/or prevention of
1. - disorders of fatty acid metabolism and glucose utilization disorders
- disorders in which insulin resistance plays a role
2. Diabetes mellitus, in particular type 2 diabetes, including the prevention of the
associated sequelae.
Particular aspects in this connection are
- hyperglycemia
- improvement in insulin resistance
- improvement in glucose tolerance
- protection of the p-cells of the pancreas
- prevention of macro- and microvascular disorders
3. Dyslipidemias and their sequelae, such as, for example, atherosclerosis,
coronary heart disease, cerebrovascular disorders, etc, especially those (but
not restricted to those) which are characterized by one or more of the following
factors:
- high plasma triglyceride concentrations, high postprandial plasma
triglyceride concentrations

- low HDL cholesterol concentrations
- low ApoA lipoprotein concentrations
- high LDL cholesterol concentrations
- small dense LDL cholesterol particles
- high ApoB lipoprotein concentrations
4. Various other conditions which may be associated with metabolic syndrome
are such as:
- obesity (excess weight), including central obesity
- thromboses, stages of hypercoagulability and prethrombosis (arterial and venous)
- high blood pressure
- heart failure, such as, for example, (but not restricted to that) in the state after myocardial infarction, hypertensive heart disease or cardiomyopathy
5. Further disorders or conditions in which, for example, inflammatory reactions or
cell differentiation play a role:
- atherosclerosis, such as, for example, (but not restricted to) coronary sclerosis including angina pectoris or myocardial infarction, stroke
- vascular restenosis or reocclusion
- chronic inflammatory bowel diseases, such as, for example, Crohn's disease and ulcerative colitis
- pancreatitis
- other inflammatory states
- retinopathy
- adipose cell tumors
- lipomatous carcinomas such as, for example, liposarcomas
- solid tumors and neoplasms, such as, for example, (but not restricted to) carcinomas of the gastrointestinal tract, of the liver, of the biliary tract and of the pancreas, endocrine tumors, carcinomas of the lungs, of the kidneys and the urinary tract, of the genital tract, prostate carcinomas, etc.
- acute and chronic myeloproliferative disorders and lymphomas
- angiogenesis
- neurodegenerative diseases
- Alzheimer's disease
- multiple sclerosis
- Parkinson's disease
- erythemato-squamous dermatoses such as, for example, psoriasis
- acne vulgaris

- other skin disorders and dermatological conditions which are modulated by PPAR
- eczemas and neurodermatitis
- dermatitis, such as, for example, seborrheic dermatitis or photodermatitis
- keratitis and keratoses, such as, for example, seborrheic keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or keratosis follicularis
- keloids and keloid prophylaxis
- warts, including condylomata or condylomata acuminata
- human papilloma virus (HPV) infections, such as, for example, venereal papillomata, viral warts, such as, for example, molluscum contagiosum, leukoplakia
- papular dermatoses, such as, for example, lichen planus
- skin cancer, such as, for example, basal-cell carcinomas, melanomas or cutaneous T-cell lymphomas
- localized benign epidermal tumors, such as, for example, keratoderma, epidermal naevi
- chilblains
- high blood pressure
- syndrome X
- polycystic ovary syndrome (PCOS)
- asthma
- osteoarthritis
- lupus erythematosus (LE) or inflammatory rheumatic disorders, such as, for example, rheumatoid arthritis
- vasculitis
- wasting (cachexia)
- gout
- ischemia/reperfusion syndrome
- acute respiratory distress syndrome (ARDS) ("shock lung")
Formulation
The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.001 mg to

100 mg (typically from 0.01 mg to 50 mg) per day and per kilogram of body weight, for example 0.1-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.001 mg to LOmg/kg, which can suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active compound. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated slow-release formulations also belong within the scope of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical preparations for oral administration may be in the form of separate units such as, for example, capsules, wafers, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
The pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place 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 blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active compound is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active compound in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active compound concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active compound to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).
The compounds of the formula I act favorably on metabolic disorders. They have a positive effect on lipid and sugar metabolism and, in particular, reduce the concentration of triglycerides, and they are suitable for preventing and treating type II diabetes and arteriosclerosis and their various sequelae.
Combinations with other medicaments
The compounds of the invention can be administered alone or in combination with one or more further pharmacologically active substances which, for example, act favorably on metabolic disorders or diseases frequently associated therewith. Such medicaments are, for example,

1. medicaments which lower blood glucose, antidiabetics,
2. active compounds for the treatment of dyslipidemias,
3. antiatherosclerotic medicaments,
4. antiobesity agents,
5. antiinflammatory active compounds
6. active compounds for the treatment of malignant tumors
7. antithrombotic active compounds
8. active compounds for the treatment of high blood pressure
9. active compounds for the treatment of heart failure and
10. active compounds for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.
They may be combined with the compounds of the formula I according to the invention in particular for synergistic improvement of the effect. Administration of the active compound combination may take place either by separate administration of the active compounds to the patients or in the form of combination products in which a plurality of active compounds are present in one pharmaceutical preparation.
Mention may be made by way of example of:
Antidiabetics
Suitable antidiabetics are disclosed, for example, in the Rote Liste 2001, chapter 12 or in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2003. Antidiabetics include all insulins and insulin derivatives, such as, for example, Lantus® (see www.lantus.com) or Apidra®, and other fast-acting insulins (see US 6,221,633), GLP-1 receptor modulators as described in WO 01/04146 or else, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S. The orally active hypoglycemic active compounds include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, oral GLP-1 agonists, DPP-IV inhibitors, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenosis, modulators of glucose uptake, compounds which alter lipid metabolism and lead to alteration of the lipid compostion of the blood, compounds

which reduce food intake or food uptake, PPAR and PXR modulators and active compounds which act on the ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the compounds of the formula I are
administered administered in combination with insulin.
In one embodiment of the invention, the compounds of the formula I are in
combination with substances which influence hepatic glucose production such as,
for example, glycogen phosphorylase inhibitors (see: WO 01/94300,
WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188).
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 an active compound which acts on the ATP-dependent
potassium channel of the beta cells, such as, for example, tolbutamide,
glibenclamide, glipizide, glimepiride or repaglinide.
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, ciglitazone,
pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr.
Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-
quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in
combination with a DPPIV inhibitor as described, for example, in W098/19998,
W099/61431, W099/67278, W099/67279, WO01/72290, WO 02/38541,
WO03/040174, in particular P 93/01 (1-cyclopentyl-3-methyl-1-oxo-2-
pentaneammonium chloride), P-31/98, LAF237 (1-[2-[3-hydroxyadamant-1-
yIamino)acetyl]pyrrolidine-2-(S)-carbonitrile), TS021 ((2S, 4S)-4-fluoro-1-[[(2-
hydroxy-1,1-dimethylethyl)amino]acetyl]pyrrolidine-2-carbonitrile
monobenzenesulfonate).
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARgamma agonist such as, for example, rosiglitazone, pioglitazone.

In one embodiment, the compounds of the formula I are administered in combination with compounds with an inhibitory effect on SGLT-1 and/or 2, as disclosed directly or indirectly for example in PCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455.
In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor such as, for example, miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
Lipid modulators
In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor (see, for example, US 6,245,744, US 6,221,897, US 6,277,831, EP 0683 773, EP 0683 774).
In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent, such as, for example, cholestyramine, colesevelam.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, as described, for example, in WO 0250027, or ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see, for example, US 6,342,512).

In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6); Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt/Main). Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARalpha agonist.
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, AZ 242 (Tesaglitazar, (S)-3-(4-[2-(4-methane-
sulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionic acid), BMS 298585 (N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]phenyl]methyl]glycine) or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, W096/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I are administered in combination with nicotinic acid or niacin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example CP-529, 414 (torcetrapib).
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor.

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.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist.
Antiobesity agents
In one 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, the other active compound is fenfluramine or dexfenfluramine. In another embodiment, the other active compound is sibutramine.
In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.:Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists (for example N-{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}-naphthalene-1-sulfonamide, hydrochloride (CGP 71683A)), MC4 agonists (for example N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexa-

hydropyrazolo[4,3-c]pyridin-5-yl)-1-(4«chlorophenyl)-2-oxoethyl]-l-amino-
1,2,3,4-tetrahydronaphthalene-2-carboxamide (WO 01/91752)), orexin antagonists
(for example 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea
hydrochloride (SB-334867-A)), H3 agonists (for example 3-cyclohexyl-
1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic
acid salt (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 (for example urocortin), urocortin agonists,
(33 agonists (for example 1-(4-chloro-3-methanesulfonylmethylphenyl)-
2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol, hydrochloride
(WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A
agonists (for example {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-
thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt
(WO 99/15525)); serotonin reuptake inhibitors (for example dexfenfluramine),
mixed serotoninergic and noradrenergic compounds (for example WO 00/71549),
5HT agonists (for example 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt
(WO 01/09111)), bombesin agonists, galanin antagonists, growth hormone (for
example human growth hormone), growth-hormone-releasing compounds
tert-butyl (6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-
1H-isoquinoline-2-carboxylate (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), decoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors (for example WO 00/40569), PPAR modulators (for example WO 00/78312), RXR modulators or TR-/3 agonists.
In one embodiment of the invention, the other active compound is leptin.
In one embodiment, the other active compound is dexamphetamine, amphetamine, mazindol or phentermine.
In one embodiment, the compounds of the formula I are administered in combination with medicaments having effects on the coronary circulation and the vascular system, such as, for example, ACE inhibitors (e.g. ramipril), medicaments

which act on the angiotensin-renin system, calcium antagonists, beta blockers, etc.
In one embodiment, the compounds of the formula I are administered in combination with medicaments having an antiinflammatory effect.
In one embodiment, the compounds of the formula I are administered in combination with medicaments which are employed for cancer therapy and cancer prevention.
It is self-evident that any suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is regarded as falling within the scope of protection conferred by the present invention.
The activity of the compounds was tested as follows:
Determination of EC50 values of PPAR agonists in the cellular PPARalpha test
Principle
The potency of substances which bind to human PPARalpha and activate it in an agonistic manner is analyzed using a stably transfected HEK cell line (HEK= human embryo kidney) which is referred to here as PPARalpha reporter cell line. It contains two genetic elements, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) which mediates expression of the luciferase reporter element depending on a PPARalpha ligand. The stably and constitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD binds in the cell nucleus of the PPARalpha reporter cell line via the GAL4 protein portion to the GAL4 DNA binding motif 5'-upstream of the luciferase reporter element which is integrated in the genome of the cell line. There is only little expression of the luciferase reporter gene without addition of a PPARalpha ligand if fatty acid-depleted fetal calf serum (cs-FCS) is used in the test. PPARalpha ligands bind and activate the PPARalpha fusion protein and thereby bring about expression of the luciferase reporter gene. The luciferase which is formed can be detected by means of chemiluminescence via an appropriate substrate.

Construction of the cell line
The PPARalpha reporter cell line was prepared in 2 stages. Firstly, the luciferase reporter element was constructed and stably transfected into HEK cells. For this purpose, five binding sites of the yeast transcription factor GAL4 (in each case 5'-CGGAGTACTGTCCTCCGAG-3') were cloned in 5'-upstream of a 68 bp-long minimal MMTV promoter (Accession #V01175), The minimal MMTV promoter section contains a CCAAT box and a TATA element in order to enable efficient transcription by RNA polymerase II. The cloning and sequencing of the GAL4-MMTV construct took place in analogy to the description of Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Then the complete Photinus pyralis luciferase gene (Accession # M15077) was cloned in 3'-downstream of the GAL4-MMTV element. After sequencing, the luciferase reporter element consisting of five GAL4 binding sites, MMTV promoter and luciferase gene was recloned into a plasmid which confers zeozin resistance in order to obtain the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfected into HEK cells in accordance with the statements in Ausubel, F.M. et al. (Current protocols in molecular biology, Vol. 1-3, John Wiley & Sons, Inc., 1995). Then zeozin-containing medium (0.5 mg/ml) was used to select a suitable stable cell clone which showed very low basal expression of the luciferase gene. In a second step, the PPARalpha fusion protein (GR-GAL4»humanPPARalpha-LBD) was introduced into the stable cell clone described. For this purpose, initially the cDNA coding for the N-terminal 76 amino acids of the glucocorticoid receptor (Accession # P04150) was linked to the cDNA section coding for amino acids 1-147 of the yeast transcription factor GAL4 (Accession # P04386). The cDNA of the ligand-binding domain of the human PPARalpha receptor (amino acids S167-Y468; Accession #S74349) was cloned in at the 3' end of this GR-GAL4 construct. The fusion construct prepared in this way (GR-GAL4-humanPPARalpha-LBD) was recloned into the plasmid pcDNA3 (from Invitrogen) in order to enable constitutive expression therein by the cytomegalovirus promoter. This plasmid was linearized with a restriction endonuclease and stably transfected into the previously described cell clone containing the luciferase reporter element. The finished PPARalpha reporter cell line which contains a luciferase reporter element and constitutively expresses the PPARalpha fusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by selection with zeozin (0.5 mg/ml) and G418 (0.5 mg/ml).
Test procedure

The activity of PPARalpha agonists is determined in a 3-day test, described below:
Day 1
The PPARalpha reporter cell line is cultivated up to 80% confluence in DMEM (#41965-039, Invitrogen) with the following additives: 10% cs-FCS (fetal calf serum, #SH-30068.03, Hyclone), 0.5 mg/ml of zeozin (#R250-01, Invitrogen), 0.5 mg/ml of G418 (#10131-027, Invitrogen), 1% penicillin streptomycin solution (#15140-122, Invitrogen) and 2mM of L-glutamine (#25030-024, Invitrogen). Cultivation is carried out in standard cell culture bottles (# 353112, Becton Dickinson) in a cell culture incubator at 37°C in the presence of 5% C02. The 80% confluent cells are washed once with 15 ml of PBS (#14190-094, Invitrogen), treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C for 2 min, taken up in 5 ml of the DMEM medium described and counted in a cell counter. After dilution to 500 000 cells/ml, in each case 35 000 cells are sown into each well of a 96-well microtiter plate having a clear plastic bottom (#3610, Corning Costar). The plates are incubated in a cell incubator at 37°C and 5% CO2 for 24 h.
Day 2
The PPARalpha agonists to be tested are dissolved in DMSO at a concentration of 10 mM. This stock solution is diluted in DMEM (#41965-039, Invitrogen) to which 5% of cs-FCS (#SH-30068.03, Hyclone), 2 mM of L-glutamine (#25030-024, Invitrogen) and the antibiotics already described (zeozin, G418, penicillin and streptomycin) are added.
Test substances are tested at 11 different concentrations in the range of from 10 nM to 100 pM. More potent compounds are tested in concentration ranges of from 1 pM to 10 pM or between 100 nM and 1 pM.
The medium of the PPARalpha reporter cell line sown on day 1 is completely removed by aspiration, and, immediately, the test substances diluted in medium are added to the cells. Dilution and addition of the substances are carried out using a robot (Beckman FX). The end volume of the test substances diluted in medium is 100 pi per well of a 96-well microtiter plate. The DMSO concentration in the test is below 0.1 % v/v to prevent cytotoxic effects of the solvent. To demonstrate that the test is working in each individual plate, a standard PPARalpha agonist, which is also diluted to 11 different concentrations, was

To demonstrate that the test is working in each individual plate, a standard PPARalpha agonist, which is also diluted to 11 different concentrations, was added to each plate. The test plates are incubated in an incubator at 37°C and 5% C02for24h.
Day 3
The PPARalpha receptor cells treated with the test substances are removed from the incubator and the medium is aspirated off. The cells are lyzed by pipetting 50 IJ\ of Bright Glo reagent (from Promega) into each well of a 96-well microtiter plate. After incubation at room temperature in the dark for 10 minutes, the microtiter plates are measured in the luminometer (Trilux from Wallac). The measuring time for each well of a microtiter plate is 1 sec.
Evaluation
The crude data of the luminometer are exported into a Microsoft Excel file. Dose-activity curves and EC50 values of PPAR agonists are calculated using the program XL.Fit according to the instructions of the manufacturer (IDBS).
The PPARalpha EC50 values for the compounds of examples 1 to 15 in this assay are in the range from 0.04 nM to > 10 jaM.
The results for the activity of some compounds of the formula I according to the invention are listed in table I below:

It is evident from table I that the compounds of the formula i according to the invention activate the PPARalpha receptor, thus effecting, for example, analogously to clinically used fibrates, a lowering of the triglyceride concentration in the organism (see, for example, J.-Ch. Fruchard et al.: PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001; S. Kersten et al.: Roles of PPARs in health and disease, NATURE, VOL 405, 25 MAY 2000, 421-4; I. Pineda et al.: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001,245-254).
Determination of EC50 values of PPAR agonists in the cellular PPARgamma test
Principle
A transient transfection system is employed to determine the cellular PPARgamma activity of PPAR agonists. It is based on the use of a luciferase reporter plasmid (pGL3basic-5xGAL4-TK) and of a PPARgamma expression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids are transiently transfected into human embryonic kidney cells (HEK cells). There is then expression in these cells of the fusion protein GAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of the reporter plasmid. In the presence of a PPARgamma-active ligand, the activated fusion protein GAL4-humanPPARgammaLBD induces expression of the luciferase reporter gene, which can be detected in the form of a chemiluminescence signal after addition of a luciferase substrate. As a difference

from the stably transfected PPARalpha reporter cell line, in the cellular PPARgamma test the two components (luciferase reporter plasmid and PPARgamma expression plasmid) are transiently transfected into HEK cells because stable and permanent expression of the PPARgamma fusion protein is cytotoxic.
Construction of the plasmids
The luciferase reporter plasmid pGL3basic-5xGAL4-TK is based on the vector pGL3basic from Promega. The reporter piasmid is prepared by cloning five binding sites of the yeast transcription factor GAL4 (each binding site with the sequence 5'-CTCGGAGGACAGTACTCCG-3'), together with a 160 bp-long thymidine kinase promoter section (Accession # AF027128) 5'-upstream into pGL3basic. 3'-downstream of the thymidine kinase promoter is the complete luciferase gene from Photinus pyralis (Accession # M15077) which is already a constituent of the plasmid pGL3basic used. The cloning and sequencing of the reporter plasmid pGL3basic-5xGAL4-TK took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). The PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD was prepared by first cloning the cDNA coding for amino acids 1-147 of the yeast transcription factor GAL4 (Accession # P04386) into the plasmid pcDNA3 (from Invitrogen) 3'-downstream of the cytomegalovirus promoter. Subsequently, the cDNA of the ligand-binding domain (LBD) of the human PPARgamma receptor (amino acids I152-Y475; Accession # g1480099) was cloned 3'-downstream of the GAL4 DNA binding domain. Cloning and sequencing of the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD again took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Besides the luciferase reporter plasmid pGL3basic-5xGAL4-TK and the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD, also used for the cellular PPARgamma test are the reference plasmid pRL-CMV (from Promega) and the plasmid pBluescript-SK(+) from Stratagene. All four plasmids were prepared using a plasmid preparation kit from Qiagen, which ensures a plasmid quality with a minimal endotoxin content, before transfection into HEK cells.

Test procedure
The activity of PPARgamma agonists is determined in a 4-day test which is described below. Before the transfection, HEK cells are cultivated in DMEM (#41965-039, Invitrogen) which is mixed with the following additions: 10% FCS (#16000-044, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen).
Day 1
Firstly, solution A, a transfection mixture which contains all four plasmids previously described in addition to DMEM, is prepared. The following amounts are used to make up 3 ml of solution A for each 96-well microtiter plate for one test: 2622 |jl of antibiotic- and serum-free DMEM (# 41965-039, Invitrogen), 100 pi of reference plasmid pRL-CMV (1 ng/pl), 100 pi of luciferase reporter plasmid pGL3basic-5xGAL4-TK (10 ng/pl), 100 pi of PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD (100 ng/pl) and 78 pi of plasmid pBluescript-SK(+) (500 ng/pl). Then 2 ml of solution B are prepared by mixing 1.9 ml of DMEM-(# 41965-039, Invitrogen) with 100 pi of PolyFect transfection reagent (from Qiagen) for each 96-well microtiter plate. Subsequently, 3 ml of solution A are mixed with 2 ml of solution B to give 5 ml of solution C, which is thoroughly mixed by multiple pipetting and incubated at room temperature for 10 min. 80%-confluent HEK cells from a cell culture bottle with a capacity of 175 cm2 are washed once with 15 ml of PBS (#14190-094, Invitrogen) and treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C for 2 min. The cells are then taken up in 15 ml of DMEM (#41965-039, Invitrogen) which is mixed with 10% FCS (# 16000-044, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). After the cell suspension has been counted in a cell counter, the suspension is diluted to 250 000 cells/ml. 15 ml of this cell suspension are mixed with 5 ml of solution C for one microtiter plate. 200 pi of the suspension are seeded in each well of a 96-well microtiter plate with a clear plastic base (#3610, Corning Costar). The plates are incubated in a cell culture incubator at 37°C and 5% C02 for 24 h.

Day 2
PPAR agonists to be tested are dissolved in DMSO in a concentration of 10 mM.
This stock solution is diluted in DMEM (# 41965-039, Invitrogen) which is mixed with 2% Ultroser (#12039-012, Biosepra), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Test substances are tested in a total of 11 different concentrations in the range from 10 |JM to 100 pM. More potent compounds are tested in concentration ranges from 1 ptol0pM.
The medium of the HEK cells transfected and seeded on day 1 is completely removed by aspiration, and the test substances diluted in medium are immediately added to the cells. The dilution and addition of the substances is carried out by a robot (Beckman FX). The final volume of the test substances diluted in medium is 100 pi per well of a 96-well microtiter plate. Each plate is charged with a standard PPARgamma agonist, which is likewise diluted in 11 different concentrations, in order to demonstrate the functioning of the test in each individual plate. The test plates are incubated in an incubator at 37°C and 5% C02for 48 h.
Day 4
After removal of the medium by aspiration, 50 \i\ of Dual-Glo™ reagent (Dual-
Glo™ Luciferase Assay System; Promega) are added to each well in accordance with the manufacturer's instructions in order to lyze the cells and provide the substrate for the firefly luciferase (Photinus pyralis) formed in the cells. After incubation at room temperature in the dark for 10 minutes, the firefly luciferase-mediated chemiluminescence is measured in a measuring instrument (measuring time/well 1 sec; Trilux from Wallac). Then 50 pi of the Dual-Glo™ Stop & Glo reagent (Dual-Glo™ Luciferase Assay System; Promega) is added to each well in order to stop the activity of the firefly luciferase and provide the substrate for the Renilla luciferase expressed by the reference plasmid pRL-CMV. After incubation at room temperature in the dark for a further 10 minutes, the chemiluminescence mediated by the Renilla luciferase is again measured for 1 sec/well in the measuring instrument.
Evaluation

The crude data from the luminometer are transferred into a Microsoft Excel file.
The firefly/Renilla luciferase activity ratio is determined for each measurement
derived from one well of the microtiter plate. The dose-activity curves and EC50
values of PPAR agonists are calculated from the ratios by the XL.Fit program as
specified by the manufacturer (IDBS).
PPARgamma EC50 values in the range from 160 nM to >10 //M were measured
using the PPAR agonists described in this application.
The compounds of the formula I of the invention may be obtained according to the
following reaction schemes:

configured.
The broken line indicates the point of attachment to the substituent.
The invention furthermore provides processes for preparing the compounds of the formula I which are obtained in accordance with the reaction schemes A, B and C below:

The compound of the general formula A in which R4 is as defined above is deprotonated with n-butyllithium in tetrahydrofuran at -78°C, and compound B is then added at this temperature, giving a compound of the general formula C.
The compound C is then reacted with tetrabutylammonium fluoride solution in tetrahydrofuran to give compound D. The latter is hydrogenated with hydrogen

over pailadium-on-carbon, giving compound E. Compound E is deprotonated with sodium hydride in dimethylformamide, allyl bromide is added and the mixture is stirred at room temperature for a number of hours, giving compound F. The latter is reacted with osmium tetroxide and sodium periodate in diethyl ether, giving aldehyde G.
Compound G is then stirred with a primary amine R3-NH2, where R3 is as defined
above, and sodium borohydride in methanol at 0°C, worked up and then reacted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, to give the compound of the general formula H.
To cleave the tert-butyl ester, compound H is stirred at room temperature in trifluoroacetic acid for a number of hours, giving the compound of the general formula J.
Using this process, it is possible to synthesize the compounds of Examples 1 to 8.

Compound B (see process A) is reacted with the compound of the general formula K to give compound C where R4 = H. The latter compound is hydrogenated with hydrogen over palladium-on-carbon, giving compound L.
Compound L is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0°C and then reacted with an alkyl iodide of the general formula R4-I, where R4 may have the meaning described above. After work-up, this compound is then again deprotonated with lithium diisopropylamide in tetrahydrofuran at 0°C and subsequently reacted with an alkyl iodide of the general formula R5-I, where R5 may have the meaning described above, giving the compound of the general formula M.

Compound M is reacted with tetrabutylammonium fluoride in tetrahydrofuran to give compound N which is deprotonated with sodium hydride in dimethylformamide and reacted with allyl bromide to give compound O. The latter is converted with osmium tetroxide and sodium periodate in diethyl ether to give compound P.
Compound P is then stirred with a primary amine of the general formula R3-NH2,
where R3 is as defined above, and sodium borohydride in methanol at 0°C, worked up and then reacted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, giving the compound of the general formula Q.
To cleave the tert-butyl ester, compound Q is stirred in trifluoroacetic acid at room temperature for a number of hours, giving the compound of the general formula R.
Using this process, it is possible to synthesize the compounds of Examples 9 to 12.

Compound S is stirred at room temperature in methanol with sodium methoxide. After work-up, the product is converted with tert-butyldiphenylsilyl chloride and imidazole in dimethylformamide at room temperature into compound T.
Compound T is stirred in isopropanol with sodium hydroxide at 60°C for 1 hour. After work-up, the product is reacted in dimethylformamide with a tert-butyl ester of an a-amino acid, hydroxybenzotriazole, diisopropylethylamine and 0-[cyano(ethoxycarbonyl)methyieneamino]-1,1,3,3,-tetramethyluronium tetrafluoroborate (TOTU), giving the product of the general formula U in which R4 and R5 are as defined above.
Compound U is reacted with tetrabutylammonium fluoride in tetrahydrofuran, giving compound V. The latter is deprotonated with sodium hydride in dimethylformamide and alkylated with ally! bromide, giving compound W. The

terminal double bond is then cleaved with osmium tetroxide and sodium periodate in diethyl ether, giving aldehyde X.
Compound X is reacted with a primary amine of the general formula R3-NH2,
where R2 is as defined above, in methanol with sodium borohydride, worked up and then converted in dimethylformamide with an isocyanate of the general formula R2-NCO, where R2 is as defined above, into compound Y. The latter is converted by stirring in trifluoroacetic acid into product Z.
Using this process, it is possible to synthesize Examples 13 to 15.
Other compounds of the formula I can be prepared analogously or by known processes.
The examples adduced below serve to illustrate the invention, but without limiting it.
The syntheses of the example compounds are described below.
Example 1
4-[cis-3-{2-[3-Cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyric acid

9.3 ml of tert-butyl diethylphosphonoacetate are dissolved in 80 ml of dimethylformamide, and 1.38 g of sodium hydride (60% strength in paraffin oil) are

added a little at a time at 0°C. The suspension is stirred at 0°C for 15 minutes, and 4.02 ml of ethyl iodide are then added. The mixture is stirred at room temperature for 12 hours. 250 ml of ethyl acetate are then added, and the reaction mixture is washed three times with in each case 150 ml of water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1. This
gives 6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate as an oil. C13H27O5P
(294.33), 1H-NMR (CDCI3, 8 = ppm): 4.15 (q, 4H), 2.73 (ddd, 1H), 2.0-1.8 (m, 2H), 1.49 (s, 9H), 1.35 (q, 6H), 1.00 (t, 3H).
cis-3-Allylcyclohexanol

cis/racemate cis/racemate
87 ml of a 1 molar solution of lithium diisobutylaluminum hydride in n-hexane are dissolved in 100 ml of diethyl ether, and 7 ml of isopropanol are added at 0°C. After the evolution of gas has ended, 12.4 g of 3-allylcylohexanone, dissolved in 50 ml of diethyl ether, are added. The mixture is stirred at room temperature for 48 hours. The reaction mixture is quenched by addition of 1M hydrochloric acid and the aqueous phase is saturated with sodium chloride and extracted five times with in each case 200 ml of ethyl acetate. The combined organic phases are washed with 2N sodium hydroxide solution and dried over magnesium sulfate, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 15:1=> 5:1. This gives 6.8 g
of cis-3-allylcyclohexanol as an oil. C9H16O (140.23), MS(ESI): 141 (M+H+), Rf(n-
heptane:ethyl acetate = 2:1) = 0.22.
(cis-3-Allylcyclohexyloxy)-tert-butyl-diphenylsilane

6.8 g of cis-3-aIlylcyclohexanol and 15 ml of tert-butyldiphenylsilyl chloride, 5 g of imidazole and 200 mg of dimethylaminopyridine are dissolved in 100 ml of dimethylformamide and stirred at room temperature for 12 hours. 400 ml of methyl tert-buthyl ether are added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 20.5 g of (cis-3-
allylcyclohexyloxy)tert-butyl-diphenylsilane as an oil. C2sH340Si (378.64), MS(ESI): 379 (M+H+), Rf(n-heptane:ethyl acetate = 2:1) = 0.93.

cis/racemate cis/racemate
5.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenylsilane are dissolved in 100 ml of diethyl ether, and 9.4 g of sodium periodate, dissolved in 100 ml of water, are added. At 0°C, 15 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 5 hours, a further 5g of sodium periodate are added, and the mixture is stirred at room temperature for another 3 hours. The reaction mixture is then diluted by addition of 300 ml of methyl tert-buthyl ether and washed with saturated

sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 6 g of [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde as a yellow-brown oil.
C24H3202Si (380.61), MS(ESI): 381 (M+H+), Rf(n-heptane:ethyl acetate = 5:1) =
0.44.

6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate are dissolved in 90 ml of tetrahydrofuran, and 7.32 ml of a 2.7 M solution of n-butyllithium in n-hexane are added at -20°C. After 1 hour of stirring at -20°C, 4.36 g of [cis-3-(tert-butyl-diphenylsi!anoxy)cyclohexyl]acetaldehyde, dissolved in 40 ml of tetrahydrofuran, are added dropwise. The reaction mixture is slowly warmed to room temperature. 50 ml of water are then added, and the mixture is extracted three times with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n«heptane:ethyl acetate = 30:1. This gives 3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenyl-
silanyloxy)cyclohexyl]-2-ethylbut-2-enoate as an oil. C32H4603Si (506.81), Rf(n-
heptane:ethyl acetate = 5:1) = 0.73.
tert-Butyl 2-ethyl-4~(cis-3-hydroxycyclohexyl)but-2-enoate

1.3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2-ethylbut-2-enoate are dissolved in 20 ml of tetrahydrofuran, and 15.7 ml of a 1M solution of • tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 30:1 => ethyl acetate. This gives 1.65 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl]but-
2-enoate as an oil. C16H28O3 (268.40), Rf(n-heptane:ethyl acetate = 5:1) = 0.07. tert-Butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate

1.65 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)but-2-enoate are dissolved in 50 ml of methanol, and 100 mg of Perlmans catalyst are added. The mixture is stirred under an atmosphere of hydrogen for 24 hours. The catalyst is filtered off through Ceiite, and the filtrate is then concentrated under reduced pressure. This gives 1.49 g of tert-butyl 2~ethyl-4-(cis-3-hydroxycyclohexyl)butyrate as a colorless
oil. C16H30O3 (270.40), Rf(n-heptane:ethyl acetate = 5:1) = 0.10. tert-Butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate

1.19 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate are dissolved in 50 ml of dimethylformamide, and 210 mg g of sodium hydride (60% strength in paraffin oil) are added. The suspension is stirred at room temperature for 15 minutes, and 1.6 ml of allyl bromide are then added. After one hour, a further 320 mg of sodium hydride are added. After 12 hours of stirring at room temperature, another 320 mg of sodium hydride and then 1.6 ml of allyl bromide are metered in. Stirring at room temperature is continued for a further 12 hours. After addition of 200 ml of methyl tert-butyl ether, the mixture is washed three times with in each case 100 ml of water and the organic phase is separated off and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 60:1 => 30:1. This gives 770 mg of tert-butyl 4-(cis-3-
allyloxycyclohexyl)-2-ethylbutyrate as an oil. C19H34O3 (310.48), Rf(n-
heptane:ethyl acetate = 5:1) = 0.48.

770 mg of tert-butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate are dissolved in 50 ml of diethyl ether, and 1.59 g of sodium periodate, dissolved in 50 ml of water, are added. At 0°C, 2.56 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 9 hours, a further 12.8 ml of the osmium tetroxide solution are added, and

stirring at room temperature is continued for a further 3 hours. 200 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 710 mg of tert-butyl 2-
ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate as a yellow-brown oil. C18H32O4 (312.45), Rf(n-heptane:ethyl acetate = 5:1) = 0.15.
tert-Butyl 4-(cis-3-{2-[3-cyclohexyl»1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyrate

380 mg of the aldehyde tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate
and 0.14 ml of 4-methylbenzylamine are dissolved in 5 ml of methanol. 400 mg of
4 A molecular sieve, which had been dried by heating, is added, and the mixture is
stirred at room temperature for two hours. 55 mg of sodium borohydride are then
added to the reaction mixture. After 30 minutes, the molecular sieve is removed by
filtration of the mixture through Celite. The filtrate is concentrated under reduced
pressure. The residue is dissolved in 8 ml of dimethylformamide, and 0.11 ml of
cyclohexyl isocyanate is added. After 12 hours, the dimethylformamide is removed
under reduced pressure and the residue is purified on silica gel using the mobile
phase n-heptane:ethyl acetate = 9:1 => 7:1. This gives 160 mg of the urea tert-
butyl 4-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-
ethylbutyrate as an oil. C33H54N2O4 (542.81), MS(ESI): 543 (M + H+).
4-(cis-3-{2-[3-cycIohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyric acid

160 mg of tert-butyl 4-(cis-3-{2-[3-cyciohexyl-1-(4-methylbenzyl)ureido]-ethoxy}cyclohexyl)-2-ethylbutyrate are dissolved in 16 ml of dichloromethane, and 4 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 12 hours. 50 ml of toluene are then added, and the solvents are removed under reduced pressure. The residue is purified by RP-HPLC. Freeze drying gives 123 mg of 4-(cis«3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-
ethylbutyric acid as a colorless oil. C29H46N2O4 (486.70), MS(ESI): 487 (M + H+).
Example 2
Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, heptylamine and butyl isocyanate gave 4-{cis-3-[2-(3-butyl-1-heptylureido)ethoxy]cyclohexyl}-2-ethylbutyricacid.

Example 3
Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, heptylamine and cyclohexyl isocyanate gave 4-{cis-3-[2-(3-cyclohexyl-1-heptylureido)ethoxy]cyclohexyl}-2-ethylbutyricacid.

C28H52N2O4 (480.74), MS(ESI): 481 (M + H+).
Example 4
Analogously to Example 1, tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclo-hexyl]butyrate, p-methylbenzylamine and butyl isocyanate gave 4-(cis-3-{2-[3-butyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)»2-ethylbutyricacid.

Example 5
Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide,
[cis-3-(tert-butyl-diphenylsilanyloxy)cycIohexyl]acetaldehyde, heptylamine and
butyl isocyanate gave 2-(2-{cis-3-[2-(3-butyl-1-
heptylureido)ethoxy]cyclohexyl}ethyl)-3-methylbutyricacid.

C27H52N2O4 (468.73), MS(ESI): 469 (M + H+).
Example 6
Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide,
[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, heptylamine and
cyclohexyl isocyanate gave 2-(2-{cis-3-[2-(3-cyclohexyl-1 -
heptylureido)ethoxy]cyclohexyl}ethyl)-3-methylbutyricacid.

C29H54N2O4 (494.76), MS(ESI): 495 (M + H+).

Example 7
Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide,
[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, p-benzylamine and
butyl isocyanate gave 2-[2-(cis-3-{2-[3-butyl-1-(4-
methylbenzyl)ureido]ethoxy}cyclohexyl)ethyl]-3-methylbutyricacid.

C28H46N2O4 (474.69), MS(ESI): 475 (M + H+).
Example 8
Analogously to Example 1, tert-butyl diethylphosphonoacetate, isopropyl iodide, [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde, p-methylbenzylamine and cyclohexyl isocyanate gave 2-[2-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)ethyl)-3-methylbutyric acid.

C30H48N2O4 (500.73), MS(ESI): 501 (M + H+).
Example 9
tert-Butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]but-2-enoate

butyl-diphenylsilanyloxy)cyclohexyl]butanoate as an oil. C3oH4403Si (480.75), MS(ESI): 481 (M+H+).
tert-Butyl4-[cis-3-(tert-butyl-diphenylsilany^

2 g of tert-butyl 4«[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyI]butanoate are dissolved in 20 ml of tetrahydrofuran, and 3.1 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to -30°C, and 1.6 ml of methyl iodide are added. The mixture is allowed to warm to room temperature over a period of 12 hours. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 2.1 g of the monomethylated product. This product is dissolved in 20 ml of tetrahydrofuran, and 6 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to 0°C, and, after 10 minutes at 0°C, 2.5 ml of methyl iodide are added. The mixture is allowed to warm to room temperature over a period of 12 hours. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 1.8 g of tert-butyl 4-[cis«3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate as an
oil. C32H4803Si (508.82), Rf(n-heptane:ethyl acetate = 5:1) = 0.49.

tert-Butyl4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate

2 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate are dissolved in 10 ml of tetrahydrofuran, and 8 ml of a 1 M solution of tetrabutylammonium fluoride and tetrahydrofuran are added. The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 20:1 => 1:1. This gives 730 mg of tert-butyl 4-[cis-3-hydroxycyclohexyl)-
2,2-dimethylbutyrate as an oil. C16H30O3 (270.42), Rf(n-heptane:ethyl acetate =
5:1) = 0.22.
Analogously to Example 1, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-heptylamine and butyl isocyanate gave 4-{cis-3-[2-(3-butyl-1-heptylureido)ethoxy]cyclohexyl)-2,2-dimethylbutyricacid.

Example 10
Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-methylbenzylamine and butyl isocyanate gave 4-(cis-3-{2-[3-butyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2,2-dimethylbutyric acid.

C27H44N2O4 (460.66), MS(ESI): 461 (M + H+).
Example 11
Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-heptylamine and cyclohexyl isocyanate gave 4-{cis-3-[2-(3-cyclohexyl-1«heptylureido)ethoxy]cyclohexyl}-2,2-dimethylbutyrate.

C28H52N2O4 (480.74), MS(ESI): 481 (M + H+).
Example 12
Analogously to Example 9, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate, p-methylbenzylamine and cyclohexyl isocyanate gave 4-(cis-3-

{2-[3-cyclohexyl-1-(4-methyibenzyl)ureido]ethoxy}cyciohexyl)-2,2-dim acid.

C29H46N2O4 (486.70), MS(ESI): 487 (M + H+).
Example 13
Methyl cis-3-(tert-butyl-diphenylsi!anyloxy)cyclohexanecarboxylate

22 g of 6-oxabicycio[3.2.1]octan-7-one are dissolved in 200 ml of methanol, and 10% strength sodium methoxide solution is added until a pH of 10 is reached. The mixture is stirred at room temperature for 30 minutes and then neutralized by addition of dilute acetic acid, and the mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, dried over magnesium sulfate and then concentrated under reduced pressure. This gives 21 g of the methyl ether as a colorless oil. This is dissolved in 200 ml of dimethylformamide, 43 g of tert-butyldiphenylsilyi chloride, 13 g of imidazole and 1 g of dimethylaminopyridine are added and the mixture is stirred at room temperature for 12 hours. The solvent is removed under reduced pressure and the residue is taken up in methyl tert-butyl ether and washed with water. The organic phase is dried over magnesium sulfate and the solvent is then removed. This gives 56.8 g of methyl cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarboxylate as a yellow oil.

C24H3203Si (396.61), MS(ESI): 397 (M+H+).
tert-Butyl cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarbonyl]amino}-(3S)-methylbutyrate

36.8 g of cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarboxyIic acid are dissolved in 150 ml of isopropanol, and 8g of sodium hydroxide, dissolved in 50 ml of water, are added. The mixture is heated at 60°C for 1 hour. The reaction mixture is cooled and neutralized by addition of 2N hydrochloric acid. The reaction mixture is concentrated under reduced pressure and extracted with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 34 g of the free acid as a colorless oil (Rf(ethyl acetate) = 0.63). This is dissolved in 250 ml of dimethylformamide, and 18.6 g of ferf-butyl L-valinate hydrochloride are added. At 0°C, 29.1 g of 0-[cyano(ethoxycarbonyl)methyleneamino]-1,1,3,3,-tetramethyluronium tetrafluoroborate are added. After 10 minutes, the ice bath is removed and 23.9 g of hydroxybenzotriazole and 61.8 ml of Hunig base are added. The mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the resulting residue is dissolved in ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate 2:1. This gives 43.0 g of tert-butyl 2-{[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexanecarbonyl]-amino}-(3S)-methylbutyrate as a yellow
oil. C32H47N04Si (537.82), MS(ESI): 538.

tert-Butyl2-[(cis-3-hydroxycyclohexanecarbonyl)aminoH3S)-methyl-butyrate

43.0 g of tert-butyl 2-{[cis«3-(tert-butyl-diphenylsilanyloxy)cyclohexane-carbonyl]amino}-(3S)-methylbutyrate are dissolved in 80 ml of tetrahydrofuran, and 80 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60°C for 3 h and then concentrated under reduced pressure, and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1 => 1:1. This gives 18 g of a white solid. Since this is still slightly impure, 8 g are subjected to another purification on silica gel. This gives 6.8 g of tert-butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-
methylbutyrate as a white solid. C16H29NO4 (299.41), MS(ESI): 300 (M+H+).
tert-Butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methyl-butyrate can be separated by chiral HPLC. This gives tert-butyl 2-[((1R,3S)-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate (Rt = 4.9 min) and tert-butyl 2-[((1S,3R)-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate (Rt = 5.7 min) as colorless lyophilisates. (Chiralpak AD/34 250 x 4.6; mobile phase n-heptane:ethanol:methanol = 20:1:1 + 0.1% trifluoroacetic acid).
tert-Butyl 2-[(cis-3-allyloxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate

2.8 g of tert-butyl 2-[(cis-3-hydroxycyclohexanecarbonyl)amino]-(3S)-methyl butyrate are dissolved in 20 ml of dimethylformamide, and 450 mg of sodium hydride (60% strength suspension in mineral oil) are added. After 10 minutes, 3.4 ml of allyl bromide are added dropwise. After 3 hours of stirring at room temperature, another 700 mg of sodium hydride are added. After 2 hours of stirring at room temperature, another 3.4 ml of allyl bromide are metered in. The mixture is stirred at room temperature for 12 hours, 200 ml of methyl tert-butyl ether are then added to the reaction mixture and the mixture is washed three times with in each case 100 ml of water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 40:1 => 10:1. This gives 900 mg of tert-butyl 2-[(cis-3-allyloxycyclohexanecarbonyl)amino]-(3S)-methylbutyrate as a
colorless oil. C19H33NO4 (339.48), MS(ESI): 340 (M+H+), Rf(n-heptane:ethyl
acetate = 1:1) = 0.58.
tert-Butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecarbonyl]amino}butyrate

900 mg of tert-butyl 2-[(cis-3-allyioxy)cyclohexanecarbonyl)amino]-(3S)-methylbutyrate are dissolved in 20 ml of diethyl ether, and 1.7 g of sodium, periodate, dissolved in 20 ml of water, are added. At 0°C, 1.6 ml of a solution of osmium tetroxide (2.5% by weight) in tert-butanol are added. The reaction mixture is stirred vigorously at room temperature for 3 hours. At 0°C, 50 ml of saturated sodium thiosulfate solution are then added. The organic phase is separated off. The aqueous phase is extracted three times with in each case 50 ml of methyl tert-butyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 1.0 g of tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecarbonyl]amino}butyrate as a colorless oil which is reacted further without purification.

C18H31NO5 (341.45), Rf(n-heptane:ethyl acetate = 1:1) = 0.19.
tert-Butyl 2-[(cis-3^2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclo-hexanecarbo hexanecarbonyl)amino]-(3S)-methylbutyrate

330 mg of tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)cyclohexanecar-
bonyI]amino}butyrate are dissolved in 3 ml of methanol, and 0.12 ml of 4-
methylbenzylamine, dissolved in 5 ml of methanol, is added. 300 mg of molecular
sieve (4 A), which had been dried by heating, are added, and the mixture is stirred
at room temperature for 2 hours. 50 mg of sodium borohydride are then added,
and stirring at room temperature is continued for another 30 minutes. The
molecular sieve is filtered off and the filtrate is concentrated under reduced
pressure. The resulting residue is dissolved in 20 ml of dimethylformamide, and
80 l are added. The mixture is stirred at room temperature for 12 hours. The
dimethylformamide is removed under reduced pressure and the residue is purified
on silica gel using the mobile phase n-heptane:ethyl acetate = 9:1 => 2:1. This
gives 320 mg of tert-butyl 2-[cis-3-{2-[3-ethyl-1 -(4-
methylbenzyl)ureido]ethoxy}cyclohexanecarbonyl)amino]-(3S)-methylbutyrate as a
light-yellow oil. C29H47N3O5 (517.72), MS(ESI): 518.
2-[(cis-3-{2-[3-Ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexane-carbonyl)amino]-(3S)-methylbutyricacid

320 mg of tert-butyl 2-[(cis-3-{2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}-cydohexanecarbonyl)amino]-(3S)-methylbutyrate are dissolved in 20 ml of dichloromethane, and 10 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 3 hours. The solvents are removed under reduced pressure and the residue is purified by RP-HPLC. This gives 115 mg of 2-[(cis-3-{2-[3-ethyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexanecarbonyl)amino]-(3S)-
methylbutyric acid as a white lyophilisate. C25H39N3O5 (461.61), MS(ESI): 462.
Example 14
Analogously to Example 13, tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)-cyclohexanecarbonyl]amino}butyrate, n-heptylamine and phenyl isocyanate gave 2-({cis-3-[2-(1-heptyl-3-phenylureido)ethoxy]cyclohexanecarbonyl}amino)-(3S)-methylbutyric acid.

cis/diastereomer mixture C28H45N3O5 (503.69), MS(ESI): 504.

Example 15
Analogously to Example 13, tert-butyl (3S)-methyl-2-{[cis-3-(2-oxoethoxy)-
cyclohexanecarbonyl]amino}butyrate, 2,2-dimethyIpropylamine and phenyl
isocyanate gave 2-[(cis-3-{2-[1-(2,2-dimethylpropyl)-3-phenylureido]-
ethoxy}cyclohexanecarbonyl)aminoH3S)-methylbutyricacid.

cis/diastereomer mixture C26H41N3O5 (475.63), MS(ESI): 476.

Documents:

2073-2005.rtf

2073-chenp-2005-abstract.pdf

2073-chenp-2005-claims.pdf

2073-chenp-2005-correspondnece-others.pdf

2073-chenp-2005-description(complete).pdf

2073-chenp-2005-form 1.pdf

2073-chenp-2005-form 26.pdf

2073-chenp-2005-form 3.pdf

2073-chenp-2005-form 5.pdf

2073-chenp-2005-form13.pdf

2073-chenp-2005-pct.pdf

« Previous Patent

Next Patent »

Patent Number

231299

Indian Patent Application Number

2073/CHENP/2005

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

04-Mar-2009

Date of Filing

26-Aug-2005

Name of Patentee

SANOFI-AVENTIS DEUTSCHLAND GmbH

Applicant Address

BRUNINGSTRASSE 50, D-65929 FRANKFURT AM MAIN,

Inventors:

#	Inventor's Name	Inventor's Address
1	STAPPER, CHRISTIAN	WALLAU STRASSE 53, 55518 MAINZ,
2	GLOMBIK, HEINER	AM LOTZENWALD 42, 65719 HOFHEIM,
3	FALK, EUGEN	VOLKLINGERWEG 15, 60529 FRANKFURT,
4	GRETZKE, DIRK	KAULBACHSTRASSE 57, 60596 FRANKFURT,
5	GOERLIZTER, JOCHEN	STEGSTRASSE 60, 60594 FRANKFURT AM MAIN,
6	KEIL, STEFANIE	AM KREISHAUS 12, 65719 HOFHEIM,
7	SCHAEFER, HANS-LUDWIG	STEINGASSE 7, 65239 HOCHHEIM,
8	WENDLER, WOLFGANG	HAINTCHENER STRASSE 12A, 65618 SELTERS,

PCT International Classification Number

C07C275/26

PCT International Application Number

PCT/EP04/01587

PCT International Filing date

2004-02-19

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	103 08 356.1	2003-02-27	Germany