OA13036A

OA13036A - Cycloalkyl derivatives comprising bioisosteric carboxylic acid groups, method for the production thereof and use thereof as a medicament.

Info

Publication number: OA13036A
Application number: OA1200500249A
Authority: OA
Inventors: Dirk Gretzke; Heiner Glombik; Eugen Falk; Jochen Goerlitzer; Stefanie Keil; Hans-Ludwig Schaefer; Christian Stapper; Wolfgang Wendler
Original assignee: Aventis Pharma Gmbh
Priority date: 2003-02-27
Filing date: 2004-02-19
Publication date: 2006-11-10
Also published as: KR20050106464A; CL2004000399A1; RU2005129996A; AR043426A1; CN100398537C; PE20050294A1; PT1601671E; CO5690552A2; ZA200505764B; JP2006519198A; PA8596601A1; DE502004009823D1; AU2004215676B2; CA2516657A1; EP1601671A1; TW200508229A; ES2330848T3; NO20054397D0; UY28208A1; TNSN05205A1

Abstract

The invention relates to cycloalkyl derivatives comprising bioisoteric carboxylic acid groups and the physiologically acceptable salts and physiologically functional derivatives thereof. Disclosed are compounds of formula (I), wherein the radicals have the indicated meanings, the physiologically acceptable salts thereof, and methods for the production thereof. Said compounds are suitable for treating and/or preventing disturbances of fatty acid metabolism, impaired glucose utilization, and disturbances in which insulin resistance plays a role.

Description

1 013036

Description

Cycloalkyl dérivatives comprising bioisosteric carboxylic acid groups, method forthe production thereof, and use thereof as a médicament

The invention relates to cycloalkyl dérivatives having bioisosteric carboxylic acidgroups and to their physiologically acceptable salts and physiologically functionaldérivatives.

Compounds of a similar structure hâve already been described in the prior art forthe treatment of hyperlipidemia and diabètes (WO 2000/64876).

It was an object of the invention to provide compounds which allow a therapeutically exploitable modulation of lipid and/or carbohydrate metabolism andare thus suitable for the prévention and/or treatment of diseases such as type 2diabètes and atherosclerosis and the various sequelae thereof.

Surprisingly, a sériés of compounds which modulate the activity of PPAR receptorshas been found. In particular, the compounds are suitable for the activation ofPPAR alpha and PPAR gamma, and the extent of the relative activation can bedifferent depending on the compounds.

Accordingly, the invention relates to compounds of the formula I R1 R2 in which

Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, where in the cycloalkanediyl or cycloalkenediyl rings one or more carbon atomsmay be replaced by oxygen atoms; 2 013036

Ri> R2 independently of one another are H, F, Br, CF3, OCF3, (Ci-C6)-alkyl,O-(Ci-C6)-alkyl, SCF3, SF5, OCF2-CHF2, O-phenyl, OH, or NO2; or R1 and R2 in juxtaposition together with the phenyl ring..are a fused, unsaturatedor completely or partially saturated bicyclic (C9-C12)-aryl or (Cg-Cn)-heteroaryl ring System; R3 is H, CF3, (CrCej-alkyl, (Ci-C6)-alkoxy, (C3-C8)-cycloalkyl or phenyl; X is (C-i-C6)-alkanediyl, where one or more carbon atoms in thealkanediyl group may be replaced by oxygen atoms; Y is (Ci-C6)-alkanediyl or (Ci-C6)-alkenediyl, where one or more CH2groups in the alkanediyl or alkenediyl group may be replaced by O,CO, S, SO or SO2 and alkanediyl or alkenediyl may be unsubstitutedor substituted by OH; Ring B is phenyl which may bë mono- or disubstituted by NO2, Cl, CN,(Ci-Ce)-alkyl, (C-i-C5)-alkoxy or tetrazole; or pyrrolidin-2-one which additionally contains a nitrogen or sulfur atomin the ring and is substituted by oxo or thioxo and may be substitutedon the nitrogen atom by R4; R4 is (Ci-C6)-alkyl, phenyl, benzyl; and their physiologically acceptable salts.

Preference is given to compounds of the formula 1 in which

Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, where in thecycloalkanediyl or cycloalkenediyl rings one carbon atom may bereplaced by an oxygen atom; R1, R2 independently of one another are H, F, Br, CF3, OCF3, (Ci-C6)-alkyl,O-(C-i-C6)-alkyl, SCF3, SF5, OCF2-CHF2, O-phenyl, OH or NO2; or 3 013036 R1 and R2 in juxtaposition together with the phenyl ring are a fused, unsaturatedor completely or partially saturated bicyclic (C9-C12)-aryl or (C9-Cn)-heteroaryl ring System; R3 is H, CF3, (Ci-C6)-alkyl, (C3-Cs)-cycloalkyl or phenyl; X is (C-t-C6)-alkanediyl, where one carbon atom in the alkanediyl group may be replaced by an oxygen atom; Y is (C-i-C6)-aIkanediyl or (Ci-C6)-alkenediyl, where one or two CH2 groups in the alkanediyl or alkenediyl group may be replaced by O,CO, S, SO or SO2 and alkanediyl or alkenediyl may be unsubstitutedor substituted by OH;

Ring B is phenyl which may be mono- or disubstituted by NO2, Cl, CN,(Ci-C6)-alkyl, (Ci-C6)-alkoxy or tetrazole; or pyrrolidin-2-one which additionally contains a nitrogen or sulfur atomin the 4-position and is substituted by oxo or thioxo in the 5-positionand may be substituted on the N1-atom by R4; R4 is (C-i-C6)-alkyl, phenyl, benzyl; and their physiologically acceptable salts.

Particular preference is given to compounds of the formula I in which

Ring A is (C3-C8)-cycloalkanediyl in which one carbon atom is replaced byan oxygen atom; R1, R2 independently of one another are H, F,’ Br, CF3, OCF3, (Ci-C8)-alkyl,O-(Ci-C6)-alkyl, SCF3, SF5, OCF2-CHF2, O-phenyl, OH or NO2; or R1 and R2 in juxtaposition together with the phenyl ring are a fused, unsaturatedor completely or partially saturated bicyclic (C9-C12)-aryl or (C9-Cn)-heteroaryl ring System; R3 is H, CF3, (CrCej-alkyl, (C3-C8)-cycloalkyl or phenyl; 4 013036 X is (Ci-CsJ-alkanediyl, where the C1 carbon atom is replaced by an oxygen atom; Y is (Ci-Ce)-alkanediyl or (Ci-C6)-alkenediyl, where one or two CH2 5 groups in the alkanediyl or alkenediyl group may be replaced by O, CO or SO2 and alkanediyl or alkenediyl may be substituted by OH;

Ring B is phenyl which may be mono- or disubstituted by NO2, Cl, CN,(Ci-Ce)-alkyl, (Ci-Ce)-alkoxy or tetrazole; or 10 pyrrolidin-2-one which additionally contains a nitrogen or sulfur atom in the 4-position and is substituted by oxo or thioxo in the 5-positionand may be substituted on the N1 -atom by R4; R4 is (C-i-C6)-alkyl, phenyl, benzyl; 15 and their physiologically acceptable salts.

Very particular preference is given to compounds of the formula I in which

20 Ring A is cyclohexane-1,3-diyl; R1, R2 are independently of one another H, F, Br, CF3, OCF3, (Ci-C6)-alkyl,O-(Ci-C6)-alkyl, SCF3, SF5, OCF2-CHF2, O-phenyl, OH or NO2; or 25 R1 and R2 in juxtaposition together with the phenyl ring are a fused, unsaturatedbicyclic (Cg-C-io)-aryl or (C9-Cio)-heteroaryl ring System; R3 is H, CF3, (Ci-C6)-alkyI, (C3-C6)-cycloalkyl or phenyl; 30 X is CH2-O; Y is (Ci-C4)-alkanediyl, O-(Ci-C4)-alkenediyl, (Ci-C4)-alkenediyl, O-(C-|- C4)-alkenediyl, O-SO2 or O-CO, where alkanediyl may be substitutedbyOH; 35

Ring B is phenyl which may be mono- or disubstituted by NO2, Cl, CN,(CvCsj-alkyl, (Ci-Cs)-alkoxy or tetrazole; or 5 013036 thiazolidin-1,4-dione which may be substituted on the N3-atom byR4; R4 is (Ci-CeJ-alkyl, phenyl or benzyl; and their physiologically acceptable salts or compounds of the formula I in which

Ring A is cyclohexane-1,3-diyl; R1, R2 independently of one another are H, F, Br, CF3, (Ci-Ce)-alkyl or O-(Ci-C6)-alkyl; or R1 and R2 together with the phenyl ring are naphthyl; R3 is (CrCey-alkyl, (C5-C6)-cycloalkyl or phenyl; is CHz-O; is (Ci-C4)-alkanediyl, O-(C1-C4)-alkanediyl, (Ci-C4)-alkenediyl, O-(CrC4)-alkenediyl, O-SO2 or O-CO, where alkanediyl may besubstituted by OH;

Ring B is phenyl which may be mono- or disubstituted by NO2, Cl, CN,(Ci-C6)-alkyl, (Ci-CeJ-aIkoxy or tetrazole; or

Ring B is thiazolidine-2,4-dione which may be substituted on the N3-atom byR4; : ' R4 is (Ci-C6)-alkyl, phenyl or benzyl; and their physiologically acceptable salts.

Very particular emphasis is also given to the compounds of the formula l in whichone or more radicals hâve the foilowing meanings:

Ring A is cyclohexane-1,3-diyl; or 6 013036 R2 is hydrogen; or R2 is hydrogen and R1 is attached in the meta- or para-position; or X is CH2-O-; or Y is -CH2-CH2-; or to those compounds where-

Ring B is thiazolidine-2,4-dione.

The présent invention also encompasses ail combinations of the “preferredembodiments” of the invention described herein.

The alkyl radicals in the substituents R1, R2, R3 and R4 can be straight-chain orbranched.

Aryl is to be understood as meaning an aromatic, carbocylic, mono- or bicyclic ringSystem 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 ringmembers, in which at least one atom in the ring System is a heteroatom from thegroup of N, O and S.

The compounds of the formula I contain at least two centers of asymmetry andmay contain more. The compounds of the formula I may therefore be présent inthe form of their racemates, racemic mixtures, pure enantiomers, diastereomersand diastereomer mixtures. The présent invention encompasses ail of theseisomeric forms of the compounds of the formula I. These isomeric forms may,even when some of them are not described expressis verbis, be obtained byknown methods.

Pharmaceutically acceptable salts are particularly suitable for medical applicationsbecause of their greater solubility in water compared with the starting or basecompounds. These salts must hâve a pharmaceutically acceptable anion or cation.Suitable pharmaceutically acceptable acid addition salts of the compounds of theinvention are salts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acids, and of organic acids suchas, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic,fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic,methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitablepharmaceutically acceptable basic salts are ammonium salts, alkali métal salts(such as sodium and potassium salts) and alkaline earth métal salts (such as 7 013036 magnésium and calcium salts) and salts of trometamol (2-amino-2-hydroxymethyl- 1,3-propanediol), diethanol-amine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the scope of the invention as usefulintermediates for the préparation or purification of pharmaceutically acceptablesalts and/or for use in nontherapeutic, for example in vitro, applications.

The term “physiologically functional dérivative” used herein refers to anyphysiologically tolerated dérivative of a compound of the formula I of the invention,for example an ester which is able, on administration to a mammal such as, forexample, to a human, to form (directly or indirectly) a compound of the formula I oran active métabolite thereof.

Physiologically functional dérivatives also include prodrugs of the compounds ofthe 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 theinvention. These prodrugs may themselves hâve activity or not.

The compounds of the invention may also exist in various polymorphous forms, forexample as amorphous and crystalline polymorphous forms. Ail polymorphousforms of the compounds of.the invention belong within the scope of the inventionand are a further aspect of the invention.

Ail référencés hereinafter to “compound(s) of formula Γ refer to compound(s) ofthe formula l as described above, and to the salts, solvatés and physiologicallyfunctional dérivatives thereof as described herein.

Use

This invention relates further to the use of compounds of the formula I and theirpharmaceutical compositions as PPAR receptor ligands. The PPAR receptorligands of the invention are suitable as modulators of the activity of the PPARreceptors.

Peroxisome proliferator-activated receptors (PPAR) are transcription factors whichcan be activated by ligands and belong to the class of nuclear hormone receptors.There are three PPAR isoforms, PPARalpha, PPARgamma and PPARdelta, whichare encoded by different genes (Peroxisome proliferator-activated receptor 8 013036 (PPAR): structure, mechanisms of activation and diverse functions: Motojima K,' Cell Struct Funct., 1993 Oct; 18(5), 267-77).

There exist two variants of PPARgamma, PPARgamma-i and gamma2, which arethe resuit of alternative use of promoters and differential mRNA splicing (Vidal-Puig et al., J. Clin. Invest., 97:2553-2561, 1996). The various PPAR receptorshâve a different tissue distribution and modulate different physiological functions.The PPAR receptors play a key rôle in different aspects of the régulation of amultitude of genes, whose gene products are crucially involved directly or indirectlyin lipid and carbohydrate metabolism. Thus, for example, PPARalpha receptorsplay an important rôle in the régulation of fatty acid catabolism or lipoproteinmetabolism in the liver, while PPARgamma is crucially involved, for example, inthe régulation of adipose cell différentiation.

In addition, PPAR receptors are also involved in the régulation of many furtherphysiological processes, including those which are not directly connected withcarbohydrate or lipid metabolism. The activity of the different PPAR receptors canbe modulated to varying extents by various fatty acids, fatty acid dérivatives andsynthetic compounds.

For relevant reviews concerning functions, physiological effect andpathophysiology, see: Joël Berger et al., Annu. Rev. Med., 2002, 53, 409 - 435;Timothy Wilson et al., J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; StevenKliewer et al., Recent Prog Horm Res., 2001, 56, 239-63.

The présent invention relates to compounds of the formula I which are suitable formodulating the activity of PPAR receptors, especially the activity of PPARalphaand PPARgamma. Depending on the profile of the modulation, the compounds ofthe formula I are suitable for the treatment, control and prophylaxis of theindications described hereinafter, and for a sériés of other, connectedpharmaceutical applications (see, for example, Joël Berger et al., Annu. Rev.Med., 2002, 53, 409 - 435; Timothy Wilson et al., J. Med. Chem., 2000, 43(4),527-550; Steven Kliewer et al., Recent Prog Horm Res., 2001, 56, 239-63; Jean-Charles Fruchart, Bart Staels and Patrick Duriez: PPARS, Metabolic Disease andArteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001; SanderKersten, Béatrice Desvergne & Walter Wahli: Rôles of PPARs in health anddisease, NATURE, VOL. 405, 25 MAY 2000, 421-424; Inès Pineda Torra, GiuliaChinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staels: Peroxisomeproliferator-activated receptors: from transcriptional control to clinical practice, CurrOpin Lipidol 12:2001, 245-254).

Compounds of this type are particularly suitable for the treatment and/orprévention of 9 013036 1. - disorders of fatty acid metabolism and glucose utilization disorders - disorders in which insulin résistance plays a rôle 2. Diabètes mellitus, in particular type 2 diabètes, including the prévention of theassociated sequelae.

Particular aspects in this connection are - hyperglycemia, - improvement in insulin résistance, - improvement in glucose tolérance, - protection of the β-cells of the pancréas - prévention of macro- and microvascular disorders 3. Dyslipidemias and their sequelae, such as, for example, atherosclerosis,coronary heart disease, cerebrovascular disorders, etc, especially those (butnot restricted to those) which are characterized by one or more of the followingfactors: - high plasma triglycéride concentrations, high postprandial plasmatriglycéride concentrations, - low HDL cholestérol concentration - low ApoA lipoprotein concentrations - high LDL cholestérol concentrations - small dense LDL cholestérol particles - high ApoB lipoprotein concentrations 4. Various other conditions which may be associated with metabolic syndromeare such as: - obesity (excess weight), including central obesity - thromboses, stages of hypercoagulability and prothrombosis (arterial andvenous) - high blood pressure - heart failure, such as, for example, (but not restricted to that) in the Stateafter myocardial infarction, hypertensive heart disease or cardiomyopathy 5. Further disorders or conditions in which, for example, inflammatory processesor cell différentiation play a rôle: - atherosclerosis, such as, for example, (but not restricted to) coronarysclerosis including angina pectoris or myocardial infarction, stroke 10 ο 730 3 6 - vascuiar restenosis or reocclusion - chronic inflammatory bowel diseases, such as, for example, Crohn’sdisease and ulcerative colitis - pancreatitis 5 - 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) io carcinomas of the gastrointestinal tract, of the liver, of the biliary tract and of the pancréas, endocrine tumors, carcinomas of the lungs, of the kidneysand the urinary tract, of the génital tract, prostate carcinomas, etc. - acute and chronic myeloproliferative disorders and lymphomas - angiogenesis 15 - neurodegenerative diseases - Alzheimeris disease - multiple sclerosis - Parkinson’s disease - erythemato-squamous dermatoses such as, for example, psoriasis 20 - acné vulgaris

- other skin disorders and dermatological conditions which are modulated byPPAR - eczemas and neurodermatitis - dermatitis, such as, for example, seborrheic dermatitis or photodermatitis 25 - keratitis and kératoses, such as, for example, seborrheic kératoses, senile kératoses, actinie keratosis, photo-induced kératoses or keratosis follicularis - keloids and keloid prophylaxis - warts, including condylomata or condylomata acuminata - human papilloma virus (HPV) infections, such as, for example, venereal 30 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 orcutaneous T-cell lymphomas 35 - localized benign epidermal tumors, such as, for example, keratoderma, epidermal naevi - chilblains - high blood pressure 013036

- syndrome X - polycystic ovary syndrome (PCOS) - asthma - osteoarthritis - lupus erythematosus (LE) or inflammatory rheumatic disorders, such as, forexample, rheumatoid arthritis - vasculitis - wasting (cachexia) - goût - ischemia/reperfusion syndrome - acute respiratory distress syndrome (ARDS) (“shock lung”)

Formulation

The amount of a compound of formula I necessary to achieve the desiredbiological effect dépends on a number of factors, for example the spécifiecompound chosen, the intended use, the mode of administration and the clinicalcondition of the patient. The daily dose is generally in the range from 0.001 mg to100 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 therange from 0.001 mg to 1.0 mg/kg, which can suitably be administered as infusionof 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions forthese purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1ngto 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 gof the active compound. Thus, ampoules for injections may contain, for example,from 1 mg to 100 mg, and single-dose formulations which can be administeredorally, 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 thecompound itself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, be acceptablein the sense that it is compatible with the other ingrédients of the composition andis not harmful for the patient’s health. The carrier may be a solid or a liquid or bothand is preferably formulated with the compound as a single dose, for example as atablet, which may contain from 0.05% to 95% by weight of the active compound.Other pharmaceutically active substances may likewise be présent, including othercompounds of formula I. The pharmaceutical compositions of the invention can be 12 013036 produced by one of the known pharmaceutical methods, which essentially consistof mixing the ingrédients with pharmacologically acceptable carriers and/orexcipients.

Pharmaceutical compositions of the invention are those suitable for oral, rectal,topical, pérorai (for example sublingual) and parentéral (for examplesubcutaneous, intramuscular, intradermal or intravenous) administration, althoughthe most suitable mode of administration dépends in each individual case on thenature and severity of the condition to be treated and on the nature of thecompound of formula I used in each case. Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preferenceis given to acid- and gastric juice-resistant formulations. Suitable coatings résistantto gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acidand methyl méthacrylate.

Suitable pharmaceutical compositions for oral administration may be in the form ofseparate 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 powdersor granules; as solution or suspension in an aqueous or nonaqueous liquid; or asan oil-in-water or water-in-oil émulsion. These compositions may, as alreadymentioned, be prepared by any suitable pharmaceutical method which includes astep in which the active compound and the carrier (which may consist of one ormore additional ingrédients) are brought into contact. The compositions aregenerally produced by uniform and homogeneous mixing of the active compoundwith a liquid and/or finely divided solid carrier, after which the product is shaped ifnecessary. Thus, for example, a tablet can be produced by compressing ormolding a powder or granules of the compound, where appropriate with one ormore additional ingrédients. Compressed tablets can be produced by tableting thecompound in free-flowing form such as, for example, a powder or granules, whereappropriate 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 producedby molding the compound which is in powder form and is moistened with an inertliquid diluent in a suitable machine.

Pharmaceutical compositions which are suitable for pérorai (sublingual)administration comprise suckable tablets which contain a compound of formula Iwith a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles 13 013036 which comprise the compound in an inert base such as gelatin and glycerol orsucrose and gum arable.

The pharmaceutical compositions suitable for parentéral administration comprisepreferably stérile aqueous préparations of a compound of formula I, which arepreferably isotonie with the blood of the intended récipient. These préparations arepreferably administered intravenously, although administration may also take placeby subeutaneous, intramuscular or intradermal injection. These préparations canpreferably be produced by mixing the compound with water and making theresulting solution stérile and isotonie with blood. Injectable compositions of theinvention generally contain from 0.1 to 5% by weight of the active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in theform of single-dose suppositories. These can be produced by mixing a compoundof the formula I with one or more conventional solid carriers, for example cocoabutter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical use on the skin are preferably inthe form of ointment, crème, lotion, paste, spray, aérosol or oil. Carriers which canbe used are petroleum jelly, lanolin, polyethylene glycols, alcohols andcombinations of two or more of these substances. The active compound isgenerally présent in a concentration of from 0.1 to 15% by weight of thecomposition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositions suitablefor transdermal uses can be in the form of single plasters which are suitable forlong-term close contact with the patient’s epidermis. Such plasters suitably containthe active compound in an aqueous solution which is buffered where appropriate,dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitableactive compound concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active compound to be released byelectrotransport or iontophoresis as described, for example, in PharmaceuticalResearch, 2(6): 318 (1986).

The compounds of the formula I act favorably on metabolic disorders. They hâve apositive effect on lipid and sugar metabolism and, in particular, reduce theconcentration of triglycérides, and they are suitable for preventing and treatingtype II diabètes and arteriosclerosis and their various sequelae. 14 013036

Combinations with other médicaments

The compounds of the invention can be administered alone or in combination withone or more further pharmacologically active substances which, for example, actfavorably on metabolic disorders or diseases frequently associated therewith.Such médicaments are, for example, 1. médicaments which lower blood glucose, antidiabetics, 2. active ingrédients for the treatment of dyslipidemias, 3. antiatherosclerotic médicaments, 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 prévention of complicationscaused by diabètes or associated with diabètes.

They may be combined with the compounds of the formula I according to theinvention in particular for synergistic improvement of the effect. Administration ofthe active compound combination may take place either by separateadministration of the active compounds to the patients or in the form ofcombination products in which a plurality of active compounds are présent in onepharmaceutical préparation.

Mention may be made by way of example of:

Antidiabetics

Suitable antidiabetics are disclosed, for example, in chapter 12 of the Rote Liste2001 or in USP Dictionary of USAN and International Drug Names, USPharmacopeia, Rockville 2003. Antidiabetics include ail insulins and insulindérivatives such as, for example, Lantus® (see www.lantus.com) or Apidra® andother fast-acting insulins (see US 6,221,633), GLP-1 receptor modulators, asdescribed in WO 01/04146, or else, for example, those disclosed in WO 98/08871of Novo Nordisk A/S. The orally active hypoglycémie active compounds include, 15 013036 preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon antagoniste, oral GLP-1agonists, DPP-IV inhibitors potassium channel openers such as, for example,those disclosed in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitorsof liver enzymes involved in the stimulation of gluconeogenesis and/orglycogenolysis, modulators of glucose uptake, compounds which alter lipidmetabolism and lead to alteration of the lipid composition in the blood, compoundswhich reduce food intake or food absorption, PPAR and PXR modulators andactive compounds which act on the ATP-dependent potassium channel of the betacells.

In one embodiment of the invention, the compounds of the formula 1 areadministered in combination with insulin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with substances which influence the hepatic glucoseproduction, such as, for example, glycogen phosphorylase inhibitors (see: WO01/94300, WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188). Inone embodiment, the compounds of the formula I are administered in combinationwith a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide orglimepiride.

In one embodiment, the compounds of the formula I are administered incombination with an active compound which acts on the ATP-dependentpotassium channel of the beta cells, such. as, for example, tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide. In one embodiment, thecompounds of the formula I are administered in combination with a biguanide suchas, for example, metformin.

In another embodiment, the compounds of the formula I are administered incombination with a meglitinide such as, for example, repaglinide.

In one embodiment, the compounds of the formula I are administered incombination with a thiazolidinedione such as, for example, ciglitazone,pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 ofDr. Reddy’s Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyi-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione. 16 013036

In one embodiment, îhe compounds of the formula I are in combination with aDPPIV inhibitor, as described, for example, in WO 98/19998, WO 99/61431, WO99/67278, WO 99/67279, WO 01/72290, WO 02/38541, WO 03/040174, inparticular P 93/01 (1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P- 5 31/98, LAF237 (1-[2-[3-hydroxyadamant-1-ylamino)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 areίο administered in combination with a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone.

In one embodiment, the compounds of the formula I are administered incombination with compounds having an inhibitory effect on SGLT-1 and/or 2, as 15 disclosed, for example, directly or indirectly in PCT/EP03/06841, PCT/EP03/13454and PCT/EP03/13455. in one embodiment, the compounds of the formula I are administered incombination with an α-glucosidase inhibitor such as, for example, miglitol or 20 acarbose.

In one embodiment, the compounds of the formula I are administered incombination with more than one of the aforementioned compounds, for example incombination with a sulfonylurea and metformin, a sulfonylurea and acarbose, 25 repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin,insulin and troglitazone, insulin and lovastatin, etc.

Lipid modulators 30 In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMGCoA reductase inhibitor such aslovastatin, fluvastatin, pravastatin, simvastatin, inastatin, itavastatin, atorvastatin,rosuvastatin. 35 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 0,683,773, EP 0,683,774). 17 013036

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorber such as, forexample, cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a cholestérol absorption inhibitor as described,for example, in WO 02/50027, or ezetimibe, tiqueside, pamaqueside.

In one embodiment of the invention, the compounds of the formula I areadministered 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 incombination with dietary fiber materials, preferably insoluble dietary fiber materials(see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp préparation fortreatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct),18(5), 230-6). Caromax is a carob-containing productfrom Nutrinova, NutritionSpecialties & Food Ingrédients GmbH, Industriepark Hôchst, 65926 Frankfurt/Main)). Combination with Caromax® is possible in onepréparation or by separate administration of compounds of the formula I andCaromax®. Caromax® can moreover be administered in the form of foodstuffssuch as, for example, in bakery products or muesli bars.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPAR alpha agonist.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a mixed PPAR alpha/gamma agonist such as, forexample, AZ 242 (tesaglitazar, (S)-3-(4-[2-(4-- methanesu!fonyloxyphenyl)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, WO99/62871, WO 01/40171, WO 01/40169, WO 96/38428, WO 01/81327, WO01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate such as, for example, fenofibrate,gemfibrozil, clofibrate, bezafibrate. 18 013036

In one embodiment of the invention the compounds of the formula I areadministered in combination with nicotinic acid and/or niacin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, for example, CP-529, 414(torcetrapib).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ACAT inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an MTP inhibitor such as, for example,implitapide.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an antioxidant.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ATP citrate lyase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a squalene synthetase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein(a) antagonist.

Antiobesity agents

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipase inhibitor such as, for example, orlistat.

In one embodiment, the other active compound is fenfluramine or dexfenfluramine.In a further embodiment, the other active compound is sibutramine.

In a further embodiment, the compounds of the formula I are administered incombination with CART modulators (see "Cocaine-amphetamine-regulated 19 013036 transcript influences energy metabolism, anxiety and gastric emptying in mice"Asakawa, A, étal., M.:Hormone and Metabolic Research (2001), 33(9), 554-558),NPY antagonists, for example N-{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethy!}naphthalene-1-sulfonamide; hydrochiùride (CGP 71683A)), MC4agonists (for example N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-1-amino- 1,2,3,4-tetrahydronaphthalene-2-carboxamide; (WO 01/91752)), orexinantagonists (for example 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea;hydrochloride (SB-334867-A)), H3 agonists (3-cycIohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid sait(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,β3 agonists (for example 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-yloxy)ethylamino]ethanoI; hydrochloride(WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-Aagonists (for example {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid sait(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 sait(WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (forexample human growth hormone), growth-hormone-releasing compounds(tert-butyl 6-benzyloxy-1 -(2-diisopropylaminoethyicarbamoyI)-3,4-dihydro-1 H-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), PPARmodulators (for example WO 00/78312), RXR modulators or TR-β agonists.

In one embodiment of the invention, the other active compound is leptin.

In one embodiment, the other active compound is dexamphetamine,amphétamine, mazindole or phentermine.

In one embodiment, the compounds of the formula I are administered in 20 013036 combination with médicaments having effects on the coronary circulation and thevascular System, such as, for example, ACE inhibitors (e.g. ramipril), médicamentswhich act on the angiotensin-renin System, calcium antagonists, beta blockers, etc.

In one embodiment, the compounds of the formula I are administered incombination with médicaments having an antiinflammatory effect.

In one embodiment, the compounds of the formula I are administered incombination with médicaments which are employed for cancer therapy and cancerprévention.

It is self-evident that any suitable combination of the compounds of the inventionwith one or more of the aforementioned compounds and optionally one or moreother pharmacologically active substances is regarded as falling within theprotection conferred by the présent invention.

The activity of the compounds was tested as follows: Détermination of EC50 values of PPAR agonists in the PPAR alpha cell test

Principle

To analyze the effectiveness of substances which bind to human PPARalpha,activating it in agonistic manner, a stably transfected HEK cell line (HEK = humanembryo kidney) designated here as “PPARalpha reporter cell line” is used. Itcontains two genetic éléments, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) whichmédiates expression of the luciferase reporter element depending on aPPARalpha ligand. The stably and constitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD binds in the cell nucléus of the PPARalpha reportercell line via the GAL4 protein portion to the GAL4 DNA binding motifs 5’-upstreamof 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 aPPARalpha ligand if fatty acid-depleted fêtai calf sérum (cs-FCS) is used in thetest. PPARalpha ligands bind and activate the PPARalpha fusion protein andthereby bring about expression of the luciferase reporter gene. The luciferasewhich is formed can be detected by means of chemiluminescence via anappropriate substrate. 21 013036

Construction of the cell line

The PPARalpha reporter cell line was prepared in 2 stages. Firstly, the luciferasereporter element was constructed and stably transfected into H EK cells. For thispurpose, five binding sites of the yeast transcription factor GAL4 (in each case 5’-CGGAGTACTGTCCTCCGAG-3’) were cloned in 5'-upstream of a 68 bp-longminimal MMTV promoter (Accession #V01175). The minimal MMTV promotersection contains a CCAAT box and a TATA element in order to enable efficienttranscription 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 thecomplété Photinus pyralis luciferase gene (Accession # M15077) was cloned in 3'-downstream of the GAL4-MMTV element. After sequencing, the luciferase reporterelement consisting of five GAL4 binding sites, MMTV promoter and luciferasegene was recloned into a plasmid which confers zeozin résistance in order toobtain the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfected into HEKcells in accordance with the statements in Ausubel, F.M. et al. (Current protocolsin 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 clonewhich 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, initiallythe 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 theligand-binding domain of frie 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 cytomégalovirus promoter.This plasmid was linearized with a restriction endonuclease and stably transfectedinto the previously described cell clone containing the luciferase reporter element.The finished PPARalpha reporter cell line which contains a luciferase reporterelement and constitutively expresses the PPARalpha fusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by sélection with zeozin (0.5 mg/ml) andG418 (0.5 mg/ml). 22 013036

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 DMEMmedium (#41965-039, Invitrogen) with the following additives: 10% cs-FCS (fêtaicalf sérum, #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, BectonDickinson) in a cell culture incubator at 37°C in the presence of 5% CO2. 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 described DMEM medium and counted in a cell counter.After dilution to 500 000 cells/ml, in each case 35 000 cells are sown into each wellof a 96-well microtiter plate having a clear plastic bottom (#3610, Corning Costar).The plates are incubated in a cell culture 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 of10 mM. This stock solution is diluted in DMEM medium (#41965-039, Invitrogen) towhich 5% of cs-FCS (#SH-30068.03, Hyclone), 2 mM of L-glutamine (#25030-024,Invitrogen) and the antibiotics already described (zeozin, G418, penicillin andstreptomycin) is added.

Test substances are tested at 11 different concentrations in the range from 10 pMto 100 pM. More potent compounds are tested in concentration ranges of from1 pM to 10 pM or between 100 nM and 1 pM. The medium of the PPARalphareporter cell line sown on day 1 is completely removed by aspiration, andimmediately, the test substances diluted in medium are added to the cells. Dilutionand addition of the substances is carried out using a robot (Beckman FX). The endvolume of the test substances diluted in medium is 100 pl per well of a 96-wellmicrotiter plate. The DMSO concentration in the test is below 0.1% v/v to preventcytotoxic effects of the solvent.

To demonstrate that the test is working in each individual plate, a standardPPARalpha agonist, which is also diluted to 11 different concentrations, wasadded to each plate. The test plates are incubated in an incubator at 37°C and 5%CO2 for 24 h. 23 Π

J

Day 3

The PPARalpha receptor cells treated with the test substances are removed fromthe incubator, and the medium is aspirated off. The cells are lyzed by pipetting 50pl of Bright Glo reagent (from Promega) into each well of a 96 well microtiter plate. 5 After incubation at room température in the dark for 10 minutes, the microtiterplates are measured in the luminometer (Trilux from Wallac). The measuring timefor each well of a microtiter plate is 1 sec.

Evaluation 10

The crude data of the apparatus for measuring luminescence are exported into aMicrosoft Excel file. Dose-activity curves and EC50 values of PPAR agonists arecalculated using the program XL.Fit according to the instructions of themanufacturer (IDBS). 15

In this assay, the PPAR alpha EC50 values for the compounds of Examples 1 to68 are in the range from 3 nM to >10 μΜ.

The results for the activity of some of the compounds of the formula I according to 20 the invention are listed in table I below:

The results for the activity of the compounds of the formula I according to theinvention are listed in table I below:

Table I

Example No. EC50 PPARalpha [nM] VIII YY 91 d O^d XXI XXIV XXVI XXVII XXXIV XXXV 1 %JO I 1251 227 709 726 114 187 25 24 013036

It is évident from table I that the compounds of the formula I according to theinvention activate the PPARalpha receptor, thus effecting, for example,analogously to clinically used fibrates, a lowering of the triglycéride concentrationin the organism (see, for example, J.-Ch. Fruchard et al,: PPARS, MetabolicDisease and Atherosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52,2001; S. Kersten et al.: Rôles of PPARs in health and disease, NATURE,VOL 405, MAY 25 2000, 421-4; I. Pineda et al.: Peroxisome proliferator-activatedreceptors: from transcriptional contrai to clinical practice, Curr Opin Lipidol 12:2001, 245-254). Détermination of EC50 values of PPAR agonists in the cellular PPARgammatest

Principle A transient transfection System is employed to détermine the cellular PPARgammaactivity 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 transientiy transfected intohumanembryonic kidney cells (HEK cells). There is then expression in these cellsof the fusion protein GAL4-humanPPARgammaLBD which binds to the GAL4binding sites of the reporter plasmid. In the presence of a PPARgamma-activeligand, the activated fusion protein GAL4-humanPPARgammaLBD inducesexpression of the luciferase reporter gene, which can be detected in the form of achemiluminescence signal after addition of a luciferase substrate. As a différencefrom the stably transfected PPARalpha reporter cell line, in the cellularPPARgamma test the two components (luciferase reporter plasmid andPPARgamma expression plasmid) are transientiy transfected into HEK cellsbecause stable and permanent expression of the PPARgamma fusion protein iscytotoxic.

Construction of the plasmids

The luciferase reporter plasmid pGL3basic-5xGAL4-TK is based on the vectorpGL3basic from Promega. The reporter plasmid is prepared by cloning five bindingsites of the yeast transcription factor GAL4 (each binding site with the sequence5'-CTCGGAGGACAGTACTCCG-3'), together with a 160 bp-long thymidinekinase promoter section (Genbank Accession # AF027128) 5’-upstream into 25 013036 pGL3basic. 3’-downstream of the thymidine kinase promoter is the complétéluciferase gene from Photinus pyraiis (Genbank Accession # M15077) which isalready a constituent of the plasmid pGL3basic used. The cloning and sequencingof the reporter plasmid pGL3basic-5xGAL4-TK took'place in analogy to thedescription in Sambrook J. et. ai. (Molecular cloning, Cold Spring HarborLaboratory Press, 1989).

The PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBDwas prepared by first cloning the cDNA coding for amino acids 1-147 of the yeasttranscription factor GAL4 (Genbank Accession # P04386) into the plasmidpcDNA3 (from Invitrogen) 3'-downstream of the cytomégalovirus promoter.Subsequently, the cDNA of the ligand-binding domain (LBD) of the humanPPARgamma receptor was cloned (amino acids I152-Y475; Accession #g 1480099) 3’-downstream of the GAL4 DNA binding domain. Cloning andsequencing of the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD again took place in analogy to the description inSambrook J. et. ai. (Molecular cloning, Cold Spring Harbor Laboratory Press,1989). Besides the luciferase reporter plasmid pGL3basic-5xGAL4-TK and thePPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD, alsoused for the cellular PPARgamma test are the référencé plasmid pRL-CMV (fromPromega) and the plasmid pBluescript SK(+) from Stratagene. Ail four plasmidswere prepared using a plasmid préparation kit from Qiagen, which ensured aplasmid quality with a minimal endotoxin content, before transfection into HEKcells.

Test procedure

The activity of PPARgamma agonists is determined in a 4-day test which isdescribed below. Before the transfection, HEK cells are cultivated in DMEM(# 41965-Q39, invitrogen) which is mixed with the following additions: 10% ECS (#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 ail four plasmidspreviously described in addition to DMEM, is prepared. The following amounts areused to make up 3 ml of solution A for each 96 well microtiter plate for one test:2622 pl of antibiotic- and serum-free DMEM (# 41965-039, Invitrogen), 100 μΙ ofréférencé plasmid pRL-CMV (1 ng/μΙ), 100 μΙ of luciferase reporter plasmid 26 013036 pGL3basîc-5xGAL4-TK (10 ng/μΙ), 100 μΐ of PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD (100 ng/μΙ) and 78 μΙ of plasmidpBluescript SK(+) (500 ng/μΙ). Then 2 ml of solution B are prepared by mixing 1.9ml of DMEM (# 41965-039, Invitrogen) with 100 μΙ of PolyFect transfection reagent(from Qiagen) for each 96 well microtiter plate. Subsequently, 3 ml of solution Aare mixed with 2 ml of solution B to give 5 ml of solution C, which is thoroughlymixed by multiple pipetting and incubated at room température for 10 min.80%-confluent HEK cells from a cell culture bottle with a capacity of 175 cm2 arewashed once with 15 ml of PBS (#14190-094, Invitrogen) and treated with 3 ml oftrypsin solution (#25300-054, Invitrogen) at 37°C for 2 min. The cells are thentaken 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 cellsuspension has been counted in a cell counter, the suspension is diluted to250,000 cells/ml. 15 ml of this cell suspension are mixed with 5 ml of solution C forone microtiter plate. 200 μΙ of the suspension are seeded in each well of a 96 wellmicrotiter plate with a clear plastic base (#3610, Corning Costar). The plates areincubated in a cell culture incubator at 37°C and 5% CO2 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 mixedwith 2% Ultroser (#12039-012, Biosepra), 1% penicillin-streptomycin solution(#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Testsubstances are tested in a total of 11 different concentrations in the range from 10μΜ to 100 pM. More potent compounds are tested in concentration ranges from 1μΜ to 10 pM.

The medium of the HEK cells transfected and seeded on day 1 is completelyremoved by aspiration, and the test substances diluted in medium are immediatelyadded to the cells. The dilution and addition of the substances is carried out by arobot (Beckman FX). The final volume of the test substances diluted in medium is100 μΙ per well of a 96 well microtiter plate. Each plate is charged with a standardPPARgamma agonist, which is likewise diluted in 11 different concentrations, inorder to demonstrate the functioning of the test in each individual plate. The testplates are incubated in an incubator at 37°C and 5% CO2 for 48 hours.

Day 4

After removal of the medium by aspiration, 50 μΙ of Dual-GIo™ reagent (Dual-GIo™ Luciferase Assay System; Promega) are added to each well in accordance 27 013036 with the manufacturer’s instructions in order to lyze the cells and provide thesubstrate for the firefly luciferase (Photinus pyralis) formed in the cells. Afterincubation at room température in the dark for 10 minutes, the firefly luciferase-mediated chemiluminescence is measured in a measuring instrument (measuring 5 time/well 1 sec; Trilux from Wallac). Then 50 pl of the Dual-GIo™ Stop & Gloreagent (Dual-GIo™ Luciferase Assay System; Promega) is added to each well inorder to stop the activity of the firefly luciferase and provide the substrate for theRenilla luciferase expressed by the référencé plasmid pRL-CMV. After incubationat room température in the dark for a further 10 minutes, a chemiluminescenceio mediated by the Renilla luciferase is again measured for 1 sec/well in the measuring instrument

Evaluation 15 The crude data from the luminometer are transferred into a Microsoft Excel file.

The firefly/Renilla luciferase activity ratio is determined for each measurementderived from one well of the microtiter plate. The dose-effect plots and EC50values of PPAR agonists are calculated from the ratios by the XL.Fit program asspecified by the manufacturer (IDBS). 20 PPARgamma EC50 values in the range from 1 nM to >10 μΜ were measured forthe PPAR agonists described in this application.

The examples given below serve to illustrate the invention, but without limiting it.

I

Ex. Ring A Ring B R1 R2 R3 X Y I 1,3-Cy Z Z Z 4-F H Me CH2-0 -O-CH2- 28 013036

Ex. Ring A Ring B R1 R2 R3 X Y Il 1,3-Cy X X X •4-F H Me CH2-0 -O-CH2- 111 1,3-Cy N 4-F H Me CH2-O -O-CH2- IV 1,3-Cy 4-F H Me CH2-0 - O-CH2- V 1,3-Cy 0-0 4-F H Me CH2-0 - O-CH2-- VI 1,3-Cy 4-F H Me CH2-0 -O-CH2- VII 1,3-Cy » ! t O^no= 4-F H Me CH2-0 -O-CH2- VIII 1,3-Cy 9' Z O 4-F H Me CH2-O -O-CH2- IX 1,3-Cy 4-F H Me CH2-0 -O-CH2- X 1,3-Cy /°-0n°2 / ! 4-F H Me CH2-O -O-CH2- XI 1,3-Cy -0-n°, o2n 4-F H Me CH2-O _O-C(=O)~ XII 1,3-Cy X X X 4-F H Me CH2-O -O-C(=O)- XIII 1,3-Cy X X X 0--, 4-F H Me CH2-0 ~O-C(=O)~ XIV 1,3-Cy O~n°! X X X 4-F H Me CH2-0 -O-C(=O)~ 29 013036

Ex. Ring A Ring B R1 R2 R3 X Y XV 1,3-Cy b™ 4-F H Me CH2-O -O-C(=O)~ XVI 1,3-Cy -~Ο-^ν 4-F H Me CH2-0 O-C(=O)~ XVII 1,3-Cy b-cs 4-F H Me CH2-0 ~O-C(=O)- XVIII 1,3-Cy -cm 4-F H Me CH2-0 _O-C(=O)~ XIX 1,3-Cy c5-no= » ! t 4-F H Me CH2-O —O-S(=O)2~ XX 1,3-Cy ci~C~)-no* Z Z Z 4-F H Me CH2-O —O-S(=O)2— XXI 1,3-Cy Z Z Z O \ 4-F H Me CH2-0 —O-S(=O)2— XXII 1,3-Cy °τ>° 4-F H Me CH2-0 -O-CH2-CH= XXIII 1,3-Cy °xv° y s 3-Me H Me CH2-0 - O-CH2-CH= XXIV 1,3-Cy O K. V O 4-F H Me CH2-O -O-CH2-CH= z · v XXV 1,3-Cy °XVs z*-N 4-F H Me CH2-0 —O-CH2-CH= XXVI 1,3-Cy °t>° z^S 4-F H Me CH2-0 -O-CH2-CH- XXVII 1,3-Cy bb 3-Me H Me CH2-0 —O-CH2-CH— XXVIII 1,3-Cy bb 3-Me H Me CH2-0 -CH2-CH(OH)- 30 013036

Ex. Ring A Ring B R1 R2 R3 X Y XXIX 1,3-cÿ o O 3-OMe H Me CH2-0 -CH2-CH(OH)~ XXX 1,3-Cy T x° y s 4-Me H Me CK2-0 ~CH2-CH(OH)~ XXXI 1,3-Cy Xs^ 3-Me H Me CH2-0 —CH2-CH2— XXXII 1,3-Cy °xv° /--s 3-OMe H Me CH2-O —CH2-CH2— XXXIII 1,3-Cy O Mz O 4-Me H Me CH2-0 —CH2-CH2— XXXIV 1,3-Cy O Mz ωΎ O 4-Me H Me CH2-0 —CH= XXXV 1,3-Cy °X> 4-Me H Me CH2-0 -CH2- XXXVI 1,3-Cy xr 3-OMe H Cy CH2-0 —CH2-CH2- XXXVII 1,3-Cy °x> y s 4-Me H Cy CH2-O -CH2-CH2- XXXVIII 1,3-Cy z' S 3-CF3 5-CF3 Et CH2-0 -CH2-CH2- XXXIX 1,3-Cy xr 2-Me 6-Me Et CH2-O -CH2-CH2- XL 1,3-Cy °X> z' S 2-CF3 H Me CH2-0 -CH2-CH2- XLI 1,3-Cy O^N Λ /-s 3-OMe H Et CH2-0 -CH2-CH2- XLII 1,3-Cy O^N π Ύ X° z' S 2-CFs H Et CH2-0 -CH2-CH2- XLIII 1,3-Cy O ''r\ y O 4-Me H Et CH2-O —CH2-CH2- 31 013036

Ex. Ring A Ring B R1 R2 R3 X Y XLIV 1,3-Cy xr '· 4-‘Pr H Et CH2-0 -CH2-CH2- XLV 1,3-Cy z' S 4-Me H 'Pr CH2-0 —CH2-CH2— XLVI 1,3-Cy Ο-,Ν Λ Ts^° 3-CF3 H Me CH2-0 —CH2-CH2— XLVIla 1 1,3-Cy O^N T>° y S 3-Me H Me CH2-0 —CH2-CH2— XLVIIb 2 1,3-Cy xr 3-Me H Me CH2-O —CH2-CH2— XLVI lia2’ 1,3-Cy °TV° / s 4-*Pr H Et CH2-0 —CH2-CH2— XLVIIIb1 1,3-Cy °TV° s 4-Pr H Et CH2-0 -CH2-CH2- XLIXa 2 1,3-Cy °t>° z' S 4-Me H Me CH2-O —CH2-CH2— XLIXb 1 1,3-Cy °T>° z' S 4-Me H Me CH2-0 —CH2-CH2— T2 1,3-Cy O^N XZ 3-Me 4-Me Et CH2-0 -CH2-CH2- TP 1,3-Cy °TV° 4-CF3 H Et CH2-O —CH2-CH2— liiz 1,3-Cy °χν° z s 2-Naphthyl- Et CH2-Ü —CH2-CH2— TiïP 1,3-Cy O Ήζ wx O i ! 3-CFs H Et CH2-0 —CH2-CH2- Tî\P 1,3-Cy O^N Λ XZ 4-lBu H Et CH2-0 -CH2-CH2- LVZ 1,3-Cy y S 3-Me 4-Me 'Pr CH2-0 —CH2-CH2- 32 013036

Ex. Ring A Ring B R1 R2 R3 X Y LVI 2 1,3-Cy Y >=° S 4-'Bu H Et CH2-0 —CH2-CH2— XviP 1,3-Cy Y x° 3-CF3 H 'Pr CH2-0 —CH2-CH2— LVIII 2 1,3-Cy Yx° ,Λ-S 4-rBu H 'Pr CH2-O —CH2-CH2— Toc2 1,3-Cy Y >-° z' S 4-‘Bu H 'Pr CH2-O —CH2-CH2— LX 2 1,3-Cy O^N π xr 4-CF3 H 'Pr CH2-O —CH2-CH2— Txf2 1,3-Cy O^N rs Xr 2-Naphthyl 'Pr CH2-O —CH2-CH2— LXII 1,3-Cy °xv° z^S 3-OMe H Me CH2-O —CH2-CH2— LXill 1,3-Cy X O^.N Χγ° 3-OMe H Me CH2-0 —CH2-CH2— LXIV 1,3-Cy Y X° z^S 4-Me H Me CH2-O —CH2-CH2— LXV 1,3-Cy X Y X° /"S 4-Me H Me CH2-O —CH2-CH2— LXVI 1,3-Cy / O^N ~ Y X° z^S 3-OMe H 'Pr CH2-0 —CH2-CH2— LXVII 1,3-Cy O 'H, ωΎ " O 3-OMe H Ph CH2-0 -CH2-CH2- 33

1,3-Cy is defined as: c/s-1,3-cyclohexanediol having the stereochemistry accordingto Cahn-Ingold-Prelog as stated in the examples.

The point of attachment of ring B to Y and the points of attachment of Y to ring A5 and ring B are shown as a broken line (—). 1 (1 R,3R) enantiomer 2 (1S.3S) enantiomer

Also described is a process for preparing the compounds of the formula Iîo according to reaction schemes A to H below:

Synthesis scheme A: Préparation of enantiomerically pure or racemic compound A9 34 013036 R2 R3 9Λ

N R3 R1

ôs/trans

Bu2SnO

CsF R2 R1

°Λ\N

XX 1.) Chirazyme L-2/vinyl acetate A2 tis/racemate 2.) chromatographieséparation A1

NaH, DMFaliyl bromide R3 θ' 1 jQl

\=N

OsO,

NalO,

A7

A6

R!O R1

BuU R1

R1

Hj/Pd R3 oXy^o*Ls^o

R1

A9

Initially, cyclohexanediol is heated with dibutyltin oxide in toluene on a waterseparator for a number of hours and then, with addition of dimethylformamide, 5 césium fluoride and an oxazole of the formula A1 in which R1, R2 and R3 are as defined above, converted by stirring at room température for a number of hoursinto a compound of the formula A2 in which R1, R2 and R3 are as defined above.

The compound of the formula A2 is reacted using Chirazyme L2 and vinyl acetate.îo This results in the formation of compounds A3 and A4, of which A4, after séparation, is reacted with alkali métal hydroxides to give a compound of thestructure A5 in which R1, R2 and R3 are as defined above.

The compound of the formula A5 or A2 is converted into an enantiomerically pure15 or racemic compound of the structure A6 in which R1, R2 and R3 are as defined above. To form the ether bond, A5 or A2 is deprotonated, for example in anaprotic solvent such as dimethylformamide, using strong bases, for example 35 013036 sodium hydride, and reacted with unsaturated bromides, for example allylbromides.

The enantiomerically pure or racemic compound of the formula A6 is, using5 osmium tetroxide and sodium periodate, converted into the enantiomerically pure or racemic compound of the structure A7 in which R1, R2 and R3 are as definedabove.

The enantiomerically pure or racemic compound of the formula A7 is convertedîo into enantiomerically pure or racemic compounds of the structure A8 in which R1, R2 and R3 are as defined above. Here, thiazolidinedione is initially deprotonated inan inert solvent using a strong base, for example n-butyllithium, and then, at -70°C, reacted with component A7, giving, after acidic work-up, for example with6N hydrochloric acid, the compound A8. 15

The enantiomerically pure or racemic compound A8 is, by hydrogénation, using,for example, palladium-on-carbon as catalyst in solvents such as methanol or ethylacetate, converted into an enantiomerically pure or racemic compound of theformula A9 in which R1, R2 and R3 are as defined above. 36 013036

Synthesis scheme B: Préparation of the compound B8

5 The compound of the formula B4 in which R1, R2 and R3 are as defined above isobtained from lactone B1 by lithium aluminum hydride réduction to diol B2,sélective silylation at the primary alcohol fonction giving compound B3,deprotonation using strong bases, for example sodium hydride in an aproticsolvent such as dimethylformamide, and alkylation with phenyloxazoyl iodides of îo the formula A1, in which R1, R2 and R3 are as defined above.

The compound of the formula B4 in which R1, R2 and R3 are as defined above isconverted into a compound of the structure B5 in which R1, R2 and R3 are asdefined above, for example by removing the silyl protective group with fluoride, for 15 example tetrabutylammonium fluoride.

Using osmium tetroxide and sodium periodate, the compound of the formula B5 isconverted into the compound of the structure B6 in which R1, R2 and R3 are asdefined above. 37 013036

The compound of the formula B6 is converted into a compound of the structure B7in which R1, R2 and R3 are as defined above. Here, thiazolidinedione is initiallydeprotonated in an inert solvent using a strong base, such as, for example, n- 5 butyllithium, and then, at -70°C, reacted with component B6 giving, after acidicwork-up, for example with 6N hydrochloric acid, compound B7.

Compound B7 is converted by hydrogénation, for example at a hydrogen pressureof 3 bar using palladium-on-carbon as catalyst in solvents such as methanol or îo ethyl acetate, into a compound of the formula B8 in which R1, R2 and R3 are asdefined above.

Synthesis scheme C: Préparation of the compound C6

38

Compounds of the formula A1 in which R1, R2 and R3 are as defined above aredissolved with cis-3-allylcyclohexanol C1 (or optionally with (1S,3S)-3-allylcyclohexanol C7) in aprotic solvents, such as dimethylformamide, and reactedwith strong bases, such as, for example, sodium hydride, giving compounds of theformula C2 in which R1, R2 and R3 are as defined above.

The compound of the formula C2 is, using osmium tetroxide and sodium periodate,converted into the compound of the structure C3 in which R1, R2 and R3 are asdefined above.

The compound of the formula C3 is converted into a compound ofthe structure C4in which R1, R2, R3 and R4 are as defined above. Here, thiazolidinedione isinitially deprotonated in an inert solvent using a strong base, such as, for example,n-butyllithium, and then, at-70°C, reacted with component C3, giving, after work-up, for example with 1N hydrochloric acid, a compound ofthe formula C4.

The compound C4 is converted into a compound of the formula C5 in which R1,R2, R3 and R4 are as defined above. Alcohol C4 is, for example, mixed with mesylchloride and triethylamine in polar solvents, such as dichloromethane, and thecrude product is, at-70°C, converted with n-butyllithium into C5.

The compound ofthe formula C5 is converted by hydrogénation, for example at ahydrogen pressure of 5 bar using palladium-on-carbon as catalyst in ethyl acetate,into a compound of the formula C6 in which R1, R2, R3 and R4 are as definedabove.

Enantiomerically pure (1S,3S)-3-allylcyclohexanol C7 can be obtained fromracemic C1 by treatment with lipase in vinyl acetate. The coproduct (1R,3R)-3-allylcyclohexanyl acetate C8 can be removed chromatographically.

Synthesis scheme D: Préparation of compound D2

39 013036

The compound of the formula A5 or A2 is converted using bases, for examplecésium hydroxide in a mixture of water and acetonitrile, using a phase-transfercatalyst, for example tetrabutylammonium iodide, with nitrobenzyl bromides of theformula D1 into enantiomerically pure or racemic compounds of the structure D2 in 5 which R1, R2 and R3 are as defined above.

Synthesis scheme E: Préparation of enantiomerically pure or racemic compoundE3 R2 R3 Λ

R3 N q_( N R1 A5 E2 10 BUjSnNj xylene E1

R1 E3

The compound of the formula A5 or A2 is, using strong bases, for example sodiumhydride, deprotonated in an aprotic solvent and reacted with cyanobenzylbromides of the formula E1, giving enantiomerically pure or racemic compounds of 15 the structure E2 in which R1, R2 and R3 are as defined above.

The compound of the formula E2 is, using a métal azide, for example tributyltînazide, converted into enantiomerically pure or racemic compounds of the structureE3 in which R1, R2, and R3 are as defined above.

Synthesis snh<=»me F: Préparation of enantiomerically pure or racemic compoundF2

The compound of the formula A5 or A2 is, using bases, for exemple pyridinereacted at about 50°C with nitrobenzoyl chlorides of the formula F1, giving 25 40 013036 enantiomerically pure or racemic compounds of the formula F2 in whieb R1, R2and R3 are as defined above.

Synthesis scbeme G: Préparation of enantiomerically pure or racemic compound5 G3

RI A5 G1 G2

R1 G3 xylene

The compound of the formula A5 or A2 is, using bases, for example pyridine,io reacted at about 50°C with cyanobenzoyl chlorides of the formula G1, giving enantiomerically pure or racemic compounds of the formula G2 in which R1, R2and R3 are as defined above.

The compound of the formula G2 is, using a métal azide, for example tributyltin15 azide, converted at about 160°C into enantiomerically pure or racemic compounds of the structure G3 in which R1, R2 and R3 are as defined above.

Synthesis scheme H: Préparation of enantiomerically pure or racemic compound H2

The compound of the formula A5 or A2 is, using bases, for example pyridine,reacted at room température with nitrobenzenesulfonyl chlorides of the formula 25 G1, giving enantiomerically pure or racemic compounds of the formula G2 in whichR1, R2 and R3 are as defined above. 41 013036

The abbreviations used dénoté:

Ac 'Bu ‘Bu

BuLi

Cy

TLC

DCI

DCM

DMAP

DMF

DMSO

EA

EDC

El eq

ESI

Et

Sat. h

HATU HOBt

HPLC

LC-MS -Me

MS

MsCI

NMR

Pd/C 'Pr nPr

Rf

RT

TBAF

TBAI acetyl isobutyl tert-butyl n-butyllithium cyclohexyl thin-layer chromatography direct Chemical ionization (MS) dichloromethane 4-A/,A/-dimethylaminopyridine N, /V-dimethylformamide dimethyl sulfoxide ethyl acetate N’-(3-dimethylaminopropyl)-N-ethylcarbodiimide x HCl électron impact ionization (MS) équivalent électron spray ionization (MS) ethyl saturated hour O-(7-azabenzotriazol-1-yl)-/V,N,/V’,/V-tetramethyluronium hexafluorophosphate

1-hydroxy-1H-benzotriazole x H2O high pressure, high performance liquid chromatography liquid-chromatography-coupled mass spectroscopy methyl mass spectroscopy methanesulfonyl chloride nuclear magnetic résonance spectroscopy palladium-on-carbon isopropyl n-propyl rétention time (TLC)room températuretetrabutylammonium fluoridetetrabutylammonium iodide 42 013036 TBDPSCI fezf-butyldiphenylsilyl chloride THF tetrahydrofuran

Other compounds of the formula I to be obtained by known processes are in5 accordance with the reaction schemes described above.

Example I 2-(4-Fluorophenyl)-5-methyl-4-[cis-3-(2-cyanobenzyloxy)cyciohexyl-io oxymethyljoxazole

zac-3-(c/s-5-methyl-2-m-tolyloxazol~4-ylmethoxy)cyclohexanol

15 21.7 g of 1,3-cyclohexanediol and 30.3 g of dibutyltin oxide are dissolved in 450 mlof toluene and, under reflux on a water separator, heated to boiling. During thereaction, the reaction volume is reduced to half the original volume. After 3 hours, 20 the reaction mixture is cooled to room température, and 300 ml of dimethylformamide, 29 g of 2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole 1and 23.5 g of césium fluoride are added. The mixture is stirred at roomtempérature for 18 hours. The reaction mixture is diluted by addition of ethylacetate and washed with saturated sodium chloride solution. The organic phase is 25 dried over magnésium sulfate, the solvent is removed under reduced pressure andthe residue is purified by flash chromatography on silica gel (n-heptane/ethylacetate = 10:1 -> 1:4). This gives 58 g of rac-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxyjcyclohexanol as a yellowish solid which is recrystallized from n-heptane/ethyl acetate. C17H20FNO3 (305.35), MS (ESI): 306 (M + H+).. 30 43 013036 (1R,3S)-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol

Chirazyme L-2vinyl acetate

5 25 g of rac-c/s-3-[2-(4-fluorophenyl)-5-methyloxazoI-4-ylmethoxy]cyclohexanol are dissolved in 320 ml of vinyl acetate, and 1.3 g of Chirazyme L-2 Lyo (BoehringerMannheim) are added. The mixture is stirred at room température for three hours(checked by LC-MS for 40-45% conversion) and the enzyme is then filtered off andwashed with ethyl acetate, and the solvent is removed under reduced pressure. îo The residue is purified by flash chromatography on silica gel (n-heptane/ethylacetate = 3:1). This gives 8 g of (1R, 3S)-3-[2-(4-f!uorophenyI)-5-methyloxazol-4-ylmethoxyjcyclohexyl acetate as a colorless oil. C19H22FNO4 (347.39), MS (ESI):348 (M + H+). The acetate is taken up in 170 ml of methanol and, after addition of27 ml of 2N aqueous sodium hydroxide solution, stirred at room température for 15 one hour. Most of the solvent is removed under reduced pressure. After addition ofin each case 150 ml of water and ethyl acetate, the organic phase is washed withsodium chloride solution. The organic phase is dried over magnésium sulfate andthe solvent is removed under reduced pressure. This gives 6.7 g of 3-(1R,3S)-3-[2- --(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyetohexanol as a yellowish solid.- 20 C17H20FNO3 (305.35), MS (ESI): 306 (M + H+). 2-(4-Fluorophenyl)-5-methyl-4-[cis-3-(2-cyanobenzyloxy)cyclohexyl- oxymethyl]oxazole

cis/racemate cis/racemate 25 44 013036

In a 25 ml two-necked flask which had been dried by heating, 0.15 g of the alcohol 3-[2-(4-fiuorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol is dissolved in 5 mlof dimethylformamide (dry), and 0.05 g of sodium hydridels added. The mixture is 5 stirred for 15 minutes, 0.19 g of 2-(bromomethyl)benzonitrile is then added, andthe mixture is stirred at room température for 24 hours. The reaction is terminatedby addition of 2 ml of 1N hydrochloric acid and the mixture is extracted with ethylacetate (2x10 ml). The combined organic phases are washed with saturatedsodium chloride solution and dried over magnésium sulfate and the solvent is then îo removed under reduced pressure. Purification by préparative HPLC gives 0.07 g ofthe desired product 2-(4-fluorophenyl)-5-methyl-4-[cis-3-(2-cyanobenzyloxy)cyclohexyloxymethyl]oxazole as a colorless oil. C25H25FN2O3 (420.48), MS (ESI): 421 (M + H+).

15 Example II 2-(4-Fluorophenyl)-5-methyl-4-[cis-3-(3-cyanobenzyloxy)cyclohexyloxy- methyljoxazole

Analogously to Example I, the alcohol 3-[2-(4-fIuorophenyl)-5-methyloxazol-4- 20 ylmethoxy]cyclohexano! and 3-(bromomethyl)benzonitrile give the compound 2-(4-fluorophenyl)-5-methyl-4-[cis-3-(3-cyanobenzyloxy)-cyclohexyloxymethyl]oxazole: cis/racemate 25 C25H25FN2O3 (420.48), MS (ESI): 421 (M + H+).

Example III 2-(4-Fluorophenyl)-5-methyl-4-[cis-3-(4-cyanobenzyloxy)cyclohexyl- oxymethyl]oxazole 30 45 013036

Analogously to Example I, the alcohol 3-[2-(4-fluorophenyl)-5-methy!oxazol-4-ylmethoxy]cyclohexanol and 4-(bromomethyl)benzonitrile give the compound 2-(4-fluorophenyl)-5-methyl-4-[cis-3-(4-cyanobenzyloxy)-cyclohexyloxymethyl]oxazole:

C25H25FN2O3 (420.48), MS (ESI): 421 (M + H+). îo The compounds synthesized in this manner (Example I -111) can be converted intothe corresponding tetrazoles:

Example IV 15 5-(2-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-yImethoxy]cyclo-hexy!oxymethyl}phenyl)-1-H-tetrazole

20 0.03 g of the nitrile 2-(4-fluorophenyl)-5-methyl-4-[cis-3-(2- cyanobenzyloxy)cyclohexyloxymethyl]oxazole are dissolved in 5 ml of xylene, 50μΙ of tributyltin azide are added and the mixture is heated under reflux at 160°C for24 hours. The reaction is terminated by addition of 1 ml of trifluoroacetic acid (in 1ml of methanol), 3 ml of water are added and the mixture is extracted with ethyl 25 acetate (2x10 ml). The combined organic phases are washed with saturated sodium chioride solution and dried over magnésium sulfate, and the solvent is thenremoved under reduced pressure. Purification by préparative HPLC gives 0.02 g ofthe desired 5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4- ylmethoxy]cyclohexyloxy-methyl}phenyl)-1-H-tetrazole as an amorphous solid. 30 C25H26FN5O3 (463.51), MS (ESI): 464 (M + H+). 46 013036

Example V 5-(3-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-5 ylmethoxy]cyc!ohexyloxymethyl}phenyl)-1 H-tetrazole

Analogously to Example IV, 2-(4-fluorophenyl)-5-methyl-4-[cis-3-(3-cyanobenzyloxy)cyclohexyloxymethyl]oxazole from Example II gave, by réactionwith tributyltin hydride, 5-(3-{cis-3-[2-(4-fluorophenyI)-5-methyloxazol-4- îo ylmethoxy]cyclohexyloxymethyl}phenyl)-1 H-tetrazole:

N cis/racemate 15 C25H26FN5O3 (463.51), MS (ESI): 464 (M + H+).

Example VI 5-(4-{cis-3-[2-(4-FIuorophenyl)-5-methyloxazol-4-ylmethoxy]cyclo-20 hexyloxymethyl}phenyl)-1 H-tetrazole

Analogously to Example IV, 2-(4-fluorophenyl)-5-methyl-4-[cis-3-(4-cyanobenzyloxy)cyclohexyloxymethyl]oxazole from Example III gave, by reactionwith tributyltin hydride, 5-(4-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4- 25 ylmethoxy]cyclohexyloxymethyl}phenyl)-1 H-tetrazole:

N

N-N cis/racemate C25H26FN5O3 (463.51), MS (ESI): 464 (M + H+). 30 47 013036

Example VII 2-(4-Fluorophenyl)-5-methyl-4-[cis-3-(2-nitrobenzyloxy)cyclohexyloxy- methyljoxazole

cis/racemate cis/racemate 0.1 g of 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol isdissolved in 3 ml of acetonitrile, and 0.21 g of 2-nitrobenzyl bromide and 0.36 g of îo tetrabutylammonium iodide are added. 0.57 ml of césium hydroxide solution (50%strength solution in water) is added dropwise, and the two-phase mixture is stirredvigorously at room température, for 12 hours. The reaction is checked (LCMS),showing the formation of the desired product, in addition to unreacted alcohol 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol. By addition of a further 15 0.2 g of 2-nitrobenzyl bromide (2 eq) at room température and stirring at room température for a further 12 hours, the reaction is terminated by addition of 2 ml of1N hydrochloric acid and the mixture is extracted with ethyl acetate (2x10 ml).The combined organic phases are washed with saturated sodium chloride solutionand dried over magnésium sulfate. Purification by HPLC gives 0.05 g of the 20 compound 2-(4-fluorophenyl)-5-methyl-4-[cis-3-(2- nitrobenzyloxy)cyclohexyloxymethyl]oxazole as a clear colorless oil. C24H25FN2O5 (440.47), MS (ESI): 441 (M + H+).

Example VIH 25 2-(4-Fluorophenyl)-5-methyl-4-[cis-3-(3-nitrobenzyloxy)cyclohexyloxy- methyljoxazole

Analogously to Example VII, 3-[2-(4-fluorophenyl)-5-methyloxazol-4-30 ylmethoxyjcyclohexanol and 3-nitrobenzyl bromide gave the compound 2-(4- fluorophenyl)-5-methyl-4-[cis-3-(3-nitrobenzyloxy)cyclohexyloxy-methyl]oxazole below: 48 013036

no2 cis/racemate C24H25FN2O5 (440.47), MS (ESI): 4415

Example IX 10 2-(4-Fluorophenyl)-5-methyl-4-[cis-3-(4-nitrobenzyloxy)cyclohexyloxy~ methyl]oxazole

Analogously to Example VU, 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and 4-nitrobenzyl bromide gave the compound 2-(4-fluorophenyl)-5-methyl-4-[cis-3-(4-nitrobenzyloxy)cyclohexyloxy-methyl]oxazolebelow: 15

cis/racemate C24H25FN2O5 (440.47), MS (ESI): 441

Example X 2-(4-FIuorophenyl)-4-[c/s-3-(2-methoxy-5-nitrobenzyloxy)cyclohexyloxy-methyl]-5- methyioxazole

Analogously to Example VII, cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxyjcyclohexanol and 2-methoxy-5-nitrobenzy! bromide gave the compound2-(4-fluorophenyl)-4-[cis-3-(2-methoxy-5-nitrobenzy!oxy)cycIo-hexyloxymethyl]-5-methyloxazole below: 30 49 013036

no2 cis/racemate C25H27FN2O6 (470.50), MS (ESI): 471 (M + H+)

Example XI c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3,5-dinitrobenzoate

0.5 g of 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol isdissolved in 3 ml of pyridine and, at 0°C, 0.6 g of 3,5-dinitrobenzoyl chloride is 15 added. The reaction mixture is then heated at 50°C for 10 minutes. The reaction ischecked (LCMS) showing the formation of the desired product, in addition tounreacted alcohol c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4- ylmethoxyjcyclohexanol. After a further 10 minutes of stirring at room température,the reaction is terminated by addition of 5 ml of concentrated hydrochloric acid, 20 and the crude product is filtered off with suction, taken up in ethyl acetate, washedwith saturated sodium bicarbonate and sodium chloride solution and dried overmagnésium sulfate. Purification by HPLC gives 0.15 g of the compound c/s-3-[2-(4-fluoropheny!)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3,5-dinitrobenzoate asyellow solid. 25 C24H22FN3O8 (499.46), MS (ESI): 500 (M + H+).

Example XII 50 013036 c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-methyl-5-nitrobenzoate

Analogously to Exampie XI, cz's-3-[2-(4-fluorophenyl)-5-methyloxazol-4-5 ylmethoxy]cyclohexanol and 3-methyl-5-nitrobenzoyl chloride gave the compound c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-methyl-5-nitrobenzoate below:

io cis/racemate C25H25FN2O6 (468.48), MS.(ESI): 469 (M + H+).

Example XIII 15 czs-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-nitrobenzoate

Analogously to Example XI, czs-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxyjcyclohexanol and 3-nitrobenzoyl chloride gave the compound czs-3-[2- 20 (4-fluorophenyI)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-nitrobenzoate below:

cis/racemate 25 C24H23FN2O6 (454.46), MS (ESI): 455 (M + H+).

Example XIV c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 2-nitrobenzoate 30 51 013036

Analogously to Example XI, czs-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and 2-nitrobenzoyl chloride gave the compound c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 2-nitrobenzoate below:

cis/racemate C24H23FN2O6 (454.46), MS (ESI): 455 (M + H+).

io Example XV czs-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexy! 3-cyanobenzoate

Analogously to Example XI, c/s-3-[2-(4-fluorophenyl)-5-methyIoxazol-4-15 ylmethoxy]cyclohexanol and 3-cyanobenzoyl chloride gave the compound czs-3-[2- (4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-cyanobenzoate below:

20 0.1 g of 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol is dissolved in 3 ml of pyridine and, at 0°C, 0.1 g of 3-cyanobenzoyl chloride isadded. The reaction mixture is then heated at 50°C for 10 minutes. The reaction ischecked (LCMS), showing the formation of the desired product in addition tounreacted alcohol c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4- 25 ylmethoxy]cyclohexanol. After addition of a further 0.9 g of 3-cyanobenzoyl chloride and 30 minutes of stirring at room température, the reaction is terminatedby addition of 5 ml of concentrated hydrochloric acid, the mixture is extracted withethyl acetate and the organic phase is washed with saturated sodium bicarbonateand sodium chloride solution and dried over magnésium sulfate. Purification by 52 013036 HPLC gives 0.1 g of the compound c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxyjcyclohexyl 3-cyanobenzoate as a brown solid. C25H23FN2O4 (434.47), MS (ESI): 435 (M + H+).

Example XVI c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 4-cyanobenzoate

Analogously to Example XI, czs-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and 4-cyanobenzoyl chloride gave the compound czs-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 4-cyanobenzoate below:

C25H23FN2O4 (434.47), MS (ESI): 435 (M + H+).

The compounds synthesized in this manner (Examples XV - XVI) can beconverted into the corresponding tetrazoles by reaction with tributyltin azide.

Example XVII czs-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-( 1 H-tetrazol-5-yl)benzoate O U (^H^SnN, —-

cis/racemate 0.06 g of czs-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-cyanobenzoate is dissolved in 5 ml of xylene, 150 pm of tributyltin azide are addedand the mixture is heated under reflux at 160°C for 24 hours. The reaction isterminated by addition of 1 ml of trifluoroacetic acid (in 1 ml of methanol), 3 ml ofwater are added and the mixture is extracted with ethyl acetate (2x10 ml). The 53 013036 combined organic phases are washed with saturated sodium chloride solution anddried over magnésium sulfate, and the solvent is then removed under reducedpressure. Purification by préparative HPLC gives 0.04 g of the desired c/s-3-[2-(4-fluorophenyl)-5-methyloxazoI-4-ylmethoxy]cyclohexyl 3-(1H-tetrazol-5-yl)benzoate 5 as an amorphous solid. C25H24FN5O4 (477.49), MS (ESI): 478 (M + H+).

Example XVIII io c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 4-cyanobenzoate

Analogously to Example XVII, c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 4-cyanobenzoate and tributyltin hydride gave c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 4-cyanobenzoate:

C25H24FN5O4 (477.49), MS (ESI): 478 (M + H+).

Example XIX c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 4-methyl-3-nitrobenzenesulfonate 25

0.1 g of c/s-3-[2-(4-fluorophenyI)-5-methyloxazol-4-ylmethoxy]cyclohexyl and 0.15of 4-methyl-3-nitrobenzenesulfonyl chloride are dissolved in 10 ml of dry 30 chloroform and, at 0°C, 2 ml of pyridine are added. The reaction mixture is then 54 013036 stirred at room température for 12 hours. The reaction is checked (LCMS),showing the formation of the desired product, in addition to unreacted alcohol cis- 3-[2-(4-fluorophenyl)-5-methyloxâzol-4-ylmethoxy]cyclohexanol. After a further 10minutes of stirring at room température, the reaction is terminated by addition of 2 5 ml of concentrated hydrochloric acid, the mixture is extracted with dichloromethaneand the extract is washed with saturated sodium bicarbonate and sodium chloridesolution and dried over magnésium sulfate. Purification by HPLC gives 0.14 g ofthe compound c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 4-methyl-3-nitrobenzenesulfonate as a viscous oil 10 C24H25FN2O7S (504.53), MS (ESI): 505 (M + H+).

Example XX c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-yImethoxy]cyclohexyl 2-chloro-5- 15 nitrobenzoate

Analogously to Example XIX, c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxyjcyclohexyl and 2-chloro-5-nitrobenzenesulfonic acid gave thecompound c/s-3-[2-(4-fiuorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 2- 20 chloro-5-nitrobenzenesulfonate:

cis/racemate 25 C23H22FCIN2O7S (524.95), MS (ESI): 525 (M + H+).

Example XXI cis-3-[2-(4-FluorophenyI)-5-methyloxazol-4-ylmethoxy]cyclohexyl 4-methoxy-2-30 nitrobenzesulfonate

Analogously to Example XIX, c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol and 4-methoxy-2-nitrobenzenesulfonic acid gave c/s-3-[2- 55 013036 (4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 4-methoxy-2-nitrobenzenesulfonate;

5 cis/racemate C24H25FN2O8S (520.53), MS (ESI): 521 (M + H+) 10

Example XXII 5-(2-{c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}- ethylidene)thiazolidine-2,4-dione 4-(c/s-3-allyloxycyclohexyloxymethyl)-2-(4-fIuorophenyl)-5-methyloxazole 15

cis/racemate

NaH, DMF er^ —

2 g of c/s-3-[2-(4-fIuorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol aredissolved in 15 ml of dimethylformamide, and 0.3 g of sodium hydride is added. 20 After 30 minutes, 2.4 g of allyl bromide are added dropwise. The mixture is stirredat room température for 5 hours. 15 ml of 1N hydrochloric acid are then added tothe reaction mixture, and the mixture is washed three times with 15 ml of ethylacetate. The organic phase is dried over magnésium sulfate and the solvent isthen removed under reduced pressure. The residue is purified by RP-HPLC. This 25 gives 2.4 g of 4-(c/s-3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5- methyloxazole as a yellowish oil. C20H24FNO3 (345.42), MS (ESI): 346 (M + H+) [c/'s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde 56 013036

2.0 g of 4-(c/s-3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyl-oxazole 5 are dissolved in 50 ml of diethyl ether, and 3.8 g of sodium periodate, dissolved in50 ml of water, are added. At 0°C, 1 ml of an osmium tetroxide solution (2.5% byweight in tert-butanol) is added, and the mixture is stirred vigorously at roomtempérature. After 8 hours, 100 ml of methyl tert-butyl ether are added, and themixture is washed with a saturated sodium thiosulfate solution. The organic phase îo is dried over magnésium sulfate and the solvent is removed under reducedpressure. The residue is purified on silica gel (n-heptane:ethyl acetate = 1:1 -> 1:5). This gives 1.4 g of [c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde as a colorless oil. C20H25NO4 (343.42), MS(ESI): 344 (M + H+), Rf(n-heptane:ethylacetate = 1:1) = 0.25. 15 5-(2-{c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}- ethylidene)thiazolidine-2,4-dione

BuLi

66 mg of thiazolidinedione are dissolved in 10 ml of tetrahydrofuran and, at-78°C,0.11 ml of a 2.7 M solution of n-butyllithium in n-hexane is added. The mixture isstirred at -78°C for 30 minutes, and 150 mg of [c/'s-3-[2-(4-fluorophenyl)-5-methyloxazoI-4-ylmethoxy]cyclohexyl]acetaldehyde, dissolved in 5 ml of 25 tetrahydrofuran, are then added. After 30 minutes of stirring at -78°C, the mixtureis allowed to warm to room température. 5 ml of 1N hydrochloric acid are added,and the mixture is extracted three times with in each case 20 ml of ethyl acetate.The combined organic phases are dried over magnésium sulfate and the solvent is 57 013036 then removed under reduced pressure. The residue is purified by RP-HPLC. Thisgives 184 mg of 5-(2-{c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-oxy}ethylïdene)thiazolidine-2,4-dione as a white solid.C22H23FN2O5S (446.01), MS (ESI): 447 (M + H+).

Example XXIII 5-[2-[3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethylidene]-thiazolidine- 2,4-dione

Analogously to Example XXII, [c/s-3-(5-methyl-2-m-tolyloxazol-4- ylmethoxy]cyclohexyl]acetaldehyde and thiazolidinedione gave the compound 5- [2-[c/s-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy}- ethylidene]thiazolidine-2,4-dione:

C23H26N2O5S (442.53), MS (ESI): 443 (M + H+).

Example XXIV 5-[2-{c/s-3-{2-(4-Fluorophenyl)-5-methytoxazol-4-ylmethoxy]cyclohexyloxy}-- ethylidene]imidazolidine-2,4-dione

Analogously to Example XXII, [3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde and hydantoin gave the compound 5-[2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}- ethylidene]imidazolidine-2,4-dione: 30 58 013036

cis/racemate C22H24FN3O5 (429.45), MS (ESI): 430 (M + H+)

Example XXV 5-[2-{c/s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}- ethylidene]-2-thioxoimidazolidine-4-dione

Analogously to Example XXII, [c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde and 2-thioxoimidazolidin-4-one gave 5-[2-{c/s- 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy)cyclohexyloxy}-ethylidene)-2-thioxoimidazolidine-4-one:

cis/racemate C22H24FN3O4S (445.51), MS (ESI): 446 (M + H+)

Example XXVI 5-(2-{c/'s-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-yImethoxy]cyclohexyloxy}- ethy!)thiazolidine-2,4-dione

Hydrogénation of the compound 5-(2-{c/s-3-[2-(4-fIuorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}ethylidene)thiazolidine-2,4-dione, mentioned in Example 59 013036

Example XXII, with hydrogen gives the compound 5-(2-{c/s-3-[2-(4-fIuorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-oxy}ethyl)thiazolidine-2,4-dione:

180 mg of the unsaturated 5-(2-{c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}ethylidene)thiazolidine-2,4-dione is dissolved in 10 ml ofethyl acetate, and 20 mg of palladuium-on-carbon are added. The mixture is thenstirred at room température under a hydrogen pressure of 2 bar for 2 hours. The îo catalyst is filtered off, the solvent is removed under reduced pressure and the residue is purified by RP-HPLC. This gives 140 mg of the compound 5-(2-{c/s-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}ethyl)thiazolidine-2,4-dione as a yellowish solid. C22H25FN2O5S (448.01), MS (ESI): 449 (M + H+) 15

Example XXVII 5-{2-[(c/s-3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}thiazol-idine- 2,4-dione 20

As in Example XXVI, hydrogénation of the compound 5-[2-[c/s-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethylidene]thiazolidine-2,4-dione, -mentioned in Example-Example XXUI, with hydrogen gives the compound 5-{2-— [(c/s-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}thiazolidine-2,4-25 dione:

cis/racemate 60 013036

CasHasNaOsS (444.55), MS (ESI): 445 (M + H+)

Example XXVIII 5-{2-[c/s-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazoI-idine- 2,4-dione 4-(c/s-3-Allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyloxazole

2 g of c/s-3-allylcyclohexanol are dissolved in 30 ml of dimethylformamide, and750 mg of sodium hydride (60% strength suspension in paraffin oil) are added. 15 After 30 minutes, 6.7 g of 4-iodomethyl-5-methyl-2-(3-methylphenyl)oxazole,dissolved in 20 ml of dimethylformamide, are added dropwise. The mixture isstirred at room température for 1 hour. 200 ml of methy tert-buthyl ether are thenadded to the reaction mixture, and the mixture is washed three times with water.The organic phase is dried over magnésium sulfate and the solvent is then 20 removed under reduced pressure. The residue is purified by RP-HPLC. This gives1.56 g of 4-(c/s-3-allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyIoxazole asan oil. C21H27NO2 (325.45), MS (ESI): 326 (M + H+), Rf(n-heptane:ethylacetate =2:1) = 0.28. 25 {c/s-3-[2-(3-Methylphenyl)-5-methyloxazol-4-ylmethoxy]cycIohexyl}-acetaldehyde

cis/racemate cis/racemate 61 013036 940 mg of 4-(c/s-3-allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyloxazoleare dissolved in 50 ml of diethyl ether, and 1.86 g of sodium periodate, dissolved in50 ml of water, are added. At 0°C, 3 ml of an osmium tetroxide solution (2.5% byweight in tert-butanol) are added, and the mixture is stifred vigorously at room 5 température. After 8 hours, 100 ml of methyl tert-butyl ether are added and themixture is washed with a saturated sodium thiosulfate solution. The organic phaseis dried over magnésium sulfate and the solvent is then removed under reducedpressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 4:1. This gives 270 mg of {c/s-3-[2-(3-methylphenyl)-5- îo methyloxazol-4-ylmethoxy]cyclohexyl}acetaIdehyde as a yellow-brown oil. C20H25NO3 (327.43), MS (ESI): 328 (M + H+), Rf(n-heptane:ethylacetate = 2:1) =0.07. 5-{1-Hydroxy-2-[c/s-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]-15 ethyl}thiazolidine-2,4-dione

214 mg of thiazolidinedione are dissolved in 20 ml of tetrahydrofuran and, at-78°C, 1.4 ml of a 2.7 M solution of n-butyllithium in n-hexane are added. Themixture is stirred at -78°C for 30 minutes, and 500 mg of {c/s-3-[2-(3- 20 methylphenyl)-5-methyloxazol-4-ylmethoxy]cycIohexyl}acetaldehyde, dissolved in10 ml of tetrahydrofuran, are then added. After 30 minutes of stirring at -78°C, themixture is allowed to warm to room température. 20 ml of 1N hydrochloric acid areadded and the mixture is extracted three times with in each case 50 ml of ethylacetate. The combined organic phases are dried over magnésium sulfate and the 25 solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 420 mg of 5-{1-hydroxy-2-[c/s-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dione as a white solid. C23H28N2O5S(444.45), MS (ESI): 445 (M + H+)

30 Example XXIX 62 013036 5-(1-Hydroxy-2-{c/s-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]- cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII, {c/'s-3-[2-(3-methylphenyl-)-5-methyloxazol-4-5 ylmethoxy]cyclohexyl}acetaldehyde and thiazolididione give the compound 5-(1- hydroxy-2-{c/'s-3-[2-(3-methoxyphenyl)-5-methyloxazol-4- ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

io cis/diastereomer mixture C23H28N2O6S (460.55), MS (ESI): 461 (M + H+).

Example XXX 15 5-{1-Hydroxy-2-[c/s-3-(5-methyl-2-p-tolyIoxazol-4-ylmethoxy)-cycIohexyl]- ethyl}thiazolidine-2,4-dione

Analogously to Example XXVIII, c/s-[3-(5-methyl-2-p-tolyloxazol-4-20 ylmethoxy)cyclohexyl]acetaldehyde and thiazolididione gave the compound 5-{1 hydroxy-2-[c/s-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cycIohexyl]- ethyl}thiazolidine~2,4-dione.

25 cis/diastereomer mixture 63 013036 C23H28N2O5S (444.55), MS (ESI): 445 (M + H+).

Example XXXI 5-{2-[c/s-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}-thiazolidine- 2,4-dione

cis/racemate 5-{2-[c/s-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cycIohexyl]ethylidene}- thiazoIidine-2,4-dione.

15 344 mg of 5-{1-hydroxy-2-[c/s-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexylJethyl}thiazolidine-2,4-dione are dissolved in 20 ml ofdichloromethane, and 0.13 ml of triethylamine and and 0.12 ml of mesyl chlorideare added. The mixture is stirred at room température for two hours, and another 20 0.13 ml of triethylamine and and 0.12 ml of mesyl chloride are added. The mixture is stirred at room température for 12 hours. 100 ml of dichloromethane are added,the mixture is washed with saturated sodium bicarbonate solution and dried overmagnésium sulfate and the solvent is then removed under reduced pressure. Theresulting residue is dissolved in 10 ml of tetrahydrofuran and, at-78°C, 0.22 ml of 64 013036 a 2.7 M solution of n-butyllithium in n-hexane is added. The mixture is stirred at0°C for 30 minutes, 20 ml of 1N hydrochloric acid are then added and the mixtureis extracted three times with in each case 50 ml of ethyl acetate. The combinedorganic phases are dried over magnésium sulfate and the·solvent is then removed 5 under reduced pressure. The residue is purified by RP-HPLC. This gives 81 mg of5-{2-[Czs-3-(5-methyl-2-m-tolyloxazol-4- ylmethoxy)cyclohexyl]ethylidene}thiazolidine-2,4-dione as a white solid.C23H26N2O4S (426.54), MS (ESI): 427 (M + H+). 10 5-{2-[c/s-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}-thÎazolidine- 2,4-dione

15 81 mg of 5-{2-[c/s-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]- ethylidene}thiazolidine-2,4-dione are dissolved in 10 ml of ethyl acetate, and 10mg of paladium (10% on activated carbon) are added. The mixture is stirred underan atmosphère of hydrogen (5 bar) for 9 hours. The catalyst is then filtered offthrough Celite and the filtrate is concentrated under reduced pressure. The residue 20 is purified by RP-HPLC. This gives 60 mg of 5-{2-[c/s-3-(5-methyl-2-m-tolyloxazol- 4- ylmethoxy)cyclohexyl]-ethyl}thiazolidine-2,4-dione as a lyophilisate. C23H28N2O4S (428.55), MS (ESI): 429 (M + H+).

Example XXXII 25 ' 5- (2-{czs-3-[2-(3-Methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}-ethyl)thiazolidine-2,4-dione

Analogously to Example XXXI, 5-(1-hydroxy-2-{czs-3-[2-(3-methoxyphenyl)-5- 30 methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione gave thecompound 5-(2-{czs-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione 65 013036

C23H28N2O5S (444.55), MS (ESI): 445 (Μ + H+).

Example XXXIII 5-{2-[c/s-3-(5-Methyl-2-p-tolyloxazoI-4-ylmethoxy]cycIohexyl]ethyi}-thiazolidine-2,4- dione

Analogously to Example XXXI, 5-{1-hydroxy-2-[c/s-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyI]ethyl}thiazolidine-2,4-dione gave the compound 5-{2-[c/s-3-(5-methy!-2-p-tolyloxazol-4-ylmethoxy)cyc!ohexyl3ethyl}thiazolidine-2,4-dione.

cis/racemate C23H28N2O4S (428.55), MS (ESI): 429 (M + H+).

20 Example XXXIV 5-[1-[c/'s-3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyl]methylidene]- thiazolidine-2,4-dione 66 013036

ο cis/racemate

cis/racemate c/s-3-Hydroxymethylcyclohexanol

cis/racemate cis/racemate 10 g of 6-oxabicyclo[3.2.1]octan-7-one are dissolved in 300 ml of tetrahydrofuran,and 160 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran areadded with ice-cooling. After 30 minutes of stirring at room température, a îo saturated ammonium chloride solution is added and the pH is adjusted to neutralby addition of a 5% strength citric acid solution. The tetrahydrofuran is removedunder reduced pressure and the residue is extracted three times with in each case150 ml of ethyl acetate. The combined organic phases are dried over magnésiumsulfate and the solvent is then removed under reduced pressure. This gives 10.5 g 15 of c/s-3-hydroxymethylcyclohexanol as a colorless oil. Ο7Η14Ο2 (130.13), Rf(ethylacetate) = 0.14. c/s-3-(tert-Butyl-diphenyl-silanyloxymethyl)cyclohexanol

cis/racemate cis/racemate 67 013036 10.5 g of c/s-3-hydroxymethylcyclohexanol are dissolved in 300 ml ofdimethylformamide, and 23 ml of tert-butyl-diphenyl-silanyl chloride, 8.0 g ofimidazole and 200 mg of dimethylaminopyridine are added. The mixture is stirredat room température for 12 hours. The dimethylformamide is removed under 5 reduced pressure and the residue is dissolved in 300 ml of ethyl acetate andwashed five times with in each case 100 ml of water. The organic phase is driedover magnésium sulfate and the solvent is then removed under reduced pressure.This gives 27.0 g of cis-3-(tert-butyl-diphenyl-silanyloxymethyl)cyclohexanol as anoil. C23H32O2S1 (368.6), Rf(n-heptane:ethyl acetate = 1:1) = 0.42. 0 c/s-3-(tert-Butyl-diphenyl-silanyloxymethyl)cyclohexyloxymethyl]-5-methyl-2-p- tolyloxazole

cis/racemate

N

15 20 25 6.4 g of c/s-3-(tert-butyl-diphenyl-siianyloxymethyl)cyclohexanol and 6.5 g of 4-iodomethyl-5-methyl-2-p-tolyloxazole are dissolved in 200 ml ofdimethylformamide, and 1 g of sodium hydride (60% strength suspension inminerai oil) is added. After 1 hour of stirring at room température, another 2 g ofsodium hydride and 5 g of 4-iodomethyl-5-methyl-2-p-tolyloxazole are added. After4 hours of stirring at room température, the reaction mixture is diluted by additionof 400 ml of ethyl acetate and washed five times with in each case 200 ml ofwater. The organic phase phase is dried over magnésium sulfate and the solventis then removed under reduced pressure. The residue is purified on silica gel usingthe mobile phase n-heptane:ethyl acetate = 10:1. This gives 6.8 g of 4-c/s-3-(tert-butyl-diphenyl-silanyloxymethyl)cyclohexyloxymethyl]-5-methyl-2-p-tolyloxazole asan oil. C35H43NO3S1 (553.28), Rf(n-heptane:ethyl acetate = 2:1) = 0.50.

[(c/s-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]methanol 30 68

cis/racemate 6.8 g of 4-c/s-3-(tert-butyl-diphenyl-silanyloxymethyl)cyclohexyloxymethyl]-5-methyl-2-p-tolyloxazole are dissolved in 40 ml of tetrahydrofuran, and 40 ml of a 5 1M solution of tetrabutylammonium fluoride are added. The mixture is heated at50°C for 1 hour and the solvent is then removed under reduced pressure and theresulting residue is purified on silica gel using the mobile phase n-heptane:ethylacetate = 5:1=> 1:1. This gives 1.0 g of c/s-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]methanol as an oil. C19H25NO3 (315.42), Rf(n- îo heptane:ethyl acetate = 1:1) = 0.13. c/s-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbaldehyde

cis/racemate

At -78°C, 0.89 ml of DMSO in 1 ml of dichloromethane is added dropwise to 0.48ml of oxalyl chloride in 15 ml of dichloromethane such that the température doesnot exceed -70°C. After the addition has ended, the solution is stirred at thistempérature for 30 minutes. 1.5 g of c/s-3-(5-methyl-2-p-tolyloxazol-4- 20 yimethoxy)cyclohexyl]methanol in 2 ml of dichloromethane are then added dropwise such that the température remains below -78°C. The solution is stirred atthis température for 30 minutes. 3.2 ml of triethylamine are then added dropwise,the cooling bath is removed and the solution is warmed to 0°C. At thistempérature, 10 ml of water are added and the mixture is stirred vigorously at 25 room température. The aqueous phase is removed and extracted with dichloromethane. The combined organic phases are washed with saturated ammonium chloride solution, dried over magnésium sulfate and concentrated, 69 013036 which gives 1.50 g of c/'s-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbalde-hyde. C19H23NO3 (313.40), LCMS (ESI): 314(MH+). h 5 5-[ 1 -[c/s-3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyl]- methylidene]thiazolidine-2,4-dione

10 0.25 g of thiazolidinedione are initially charged in a three-necked flask, which had been dried by heating, dissolved in 15. ml of tetrahydrofuran and cooled to -78°C,and 2.4 ml of n-buthyllithium (1.6 M solution in n-hexane) are slowly addeddropwise such that the internai température does not exceed -65°C. The solutionis then warmed to room température, resulting in the color of the solution changing 15 to yellow. The mixture is again cooled to -70°C, and 0.4 g of c/s-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbaldehyde - dissolved in 5 ml oftetrahydrofuran - is then added dropwise, and the reaction mixture is warmed toroom température. The tertiary alcohol is formed as an adduct (reaction control(TLC and LCMS) M = 430 g/mol). Acidic work-up (5 ml 1N HCl) and extraction with 20 2 x 10 ml of ethyl acetate gives the desired élimination product after removal of the solvent under reduced pressure. The crude product is taken up in acetonitrile andthe mother liquor is filtered off, giving 0.5 g of 5-[1-[c/'s-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)çyclohexyl]-methylidene]thiazolidine-2,4-dione as a white solid.C22H24N2O4S (4Ί2.54), MS (ESI): 413 (M + H+).-- 25

Example XXXV 5-[c/s-3-(5-Methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyimethyl]thiazolidine-2,4- dione 30

The compound 5-[ 1 -[c/s-3-(5-methyI-2-tolyloxazol-4-ylmethoxy)cyclohexyI}-methylidenejthiazolidine-2,4-dione, mentioned in Example XXXIV, is obtained by 70 013036 hydrogénation of the compound 5-[c/s-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]thiazolidine-2,4-dione.

cis/racemate

0.35 g of 5-[1-[c/s-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexylJ-methylidene]thiazolidine-2,4-dione is dissolved in 12 ml of a solvent mixture ofethyl acetate and methanol (3:1), and 20 mg of palladium-on-carbon are added.The mixture is then hydrogenated at room température under a hydrogen pressure ίο of 3 bar for 2 hours. The catalyst is filtered off and the solvent is then removedunder reduced pressure and the residue is taken up in acetonitrile. The productcan be filtered off, giving 0.3 g of 5-[c/s-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]thiazolidine-2,4-dione as a white solid. C22H26N2O4S(414.52), MS (ESI): 415 (M + H+). 15

Example XXXVI 20 25 5-(2-{(c/s-3-[5-cyclohexyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]- cycIohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, c/s-3-allylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-cyclohexyl-2-(3-methoxyphenyl)oxazole gavethe compound 5-(2-{(c/s-3-[5-cyclohexyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione.

o cis/racemate 71 013036 C28H36N2O5S (512.67), MS(ESI): 513 (M+H+)

Example XXXVII 5 5-(2-{(c/s-3-[5-cyclohexyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, c/s-3-allylcydohexanol,thiazolidinedione and 4-iodomethyl-5-cyclohexyl-2-(4-methylphenyl)oxazole gave 10 the compound 5-(2-{(c/s-3-[5-cyclohexyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione.

cis/racemate 15 C28H36N2O4S (496.67), MS(ESI): 497 (M+H+).

Example XXXVIII 5-(2-{(c/s-3-[5-ethyl-2-(3,5-bis-trifluoromethylphenyl)oxazol-4-ylmethoxy]-20 cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXV,Il and Example XXXI, c/s-3-allylcycIohexanol,thiazolidinedione and 4-iodomethyl-5-ethyI-2-(3,5-bis-trifIuoromethylphenyl)oxazolegave the compound 5-(2-{(c/s-3-[5-ethyl-2-(3,5-bis-trifluoromethylphenyl)oxazol-4- 25 ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione. 72 013036

cis/racemate C25H26F6N2O4S (564.55), MS(ESI): 565 (M+H+)

Example XXXIX 5-(2-(( c/s-3-[5-ethyl-2-(2,6-bis-dimethylphenyl)oxazol-4-ylmethoxy]- cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, c/s-3-allylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-ethyl-2-(2,6-dimethy!phenyl)oxazole gave thecompound 5-(2-{(c/'s-3-[5-ethyl-2-(2,6-dimethylphenyl)oxazol-4- ylmethoxy]cyclohexyI}ethyl)thiazolidine-2,4-dione.

cis/racemate C25H32N2O4S (456.64), MS(ESI): 457 (M+H+).

Example XL 5-(2-{(c/s-3-[5-methyl-2-(2-trifluoromethylpheny!)oxazol-4-ylmethoxy]- cyclohexyl}ethyl)thiazolidine-2,4-dione 73 013036

Analogously to Example XXVIII and Example XXXI, c/s-3-allylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-methyl-2-(2-trifluoromethylphenyl)oxazolegave the compound 5-(2-{(czs-3-[5-methyl-2-(2-trifIuoromethylphenyl)oxazol-4- 5 ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

10 C23H25F3N2O4S (482.53), MS(ESI): 483 (M+H+).

Example XLI 5-(2-{(cz's-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]-15 cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, c/s-3-allylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-ethyl-2-(3-methoxyphenyl)oxazole gave thecompound 5-(2-{(c/s-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4- 20 ylmethoxy3cyclohexyI}ethyl)thiazolidine-2,4-dione.

cis/racemate 74 013036 C24H30N2O5S (458.58), MS(ESI): 459 (M+H+).

Example XLII 5 5-(2-{(c/s-3-[5-ethyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy]- cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, c/s-3-alIylcyclohexanol, 10 thiazolidinedione and 4-iodomethyl-5-ethyl-2-(2-trifluorophenyl)oxazole gave the compound 5-(2-{(c/s-3-[5-ethyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyI)thiazolidine-2,4-dione.

15 cis/racemate C24H27F3N2O4S (496.55), MS(ESI): 497 (M+H+).

Example XLIII 20 5-{2-[3-(5-ethyl-2-p-tolyloxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, c/s-3-alIylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-ethyl-2-(4-methylphenyl)oxazole gave the 25 compound 5-{2-[c/s-3-(5-ethyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}-thiazolidine-2,4-dione. 75 013036

cis/racemate C24H30N2O4S (442.58), MS(ESI): 443 (M+H+).

Example XL1V 5-(2-{(c/s-3-[5-ethy!-2-(4-isopropyIphenyl)oxazol-4-ylmethoxy]- cyclohexyl}ethyl)thiazoIidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, c/s-3-allylcyclohexanoI,thiazolidinedione and 4-iodomethyl-5-ethyl-2-(4-isopropylphenyl)oxazole gave thecompound 5-(2-{c/'s-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4- ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

C26H34N2O4S (470.64), MS(ESI): 471 (M+H+).

Example XLV 20 76 013036 5-(2-{(c/s-3-[5-isopropyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]- cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, c/s-3-allylcyciohexanol, 5 thiazolidinedione and 4-iodomethyl-5-ethyl-2-(4-isopropylphenyl)oxazole gave the compound 5-(2-{c/'s-3-[5-isopropyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

io cis/racemate C25H32N2O4S (456.61), MS(ESI): 457 (M+H+).

Example XLVI 15 5-(2-{(c/s-3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]- cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, c/s-3-allylcycIohexanol, 20 thiazolidinedione and 4-iodomethyl-5-methyl-2-(3-trifluoromethylphenyl)oxazole gave the compound 5-(2-{(c/s-3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol-4-. ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

25 77 013036 C23H25F3N2O4S (482.53), MS(ESI): 483 (M+H+).

Example XLV1I 5 The compound 5-{2-[c/s-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclo- hexyl]ethylidene}thiazolidine-2,4-dione from Example XXXI was separated bychromatography on a chiral phase into the compounds 5-{2-[(7S,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyIidene}thiazolidine-2,4-dione and 5-{2[(7R,3R)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclo- io hexyl]ethylidene}thiazolidine-2,4-dione. 5-{2-[(7/?,3/:?,)-3-(5-methyl-2-m-tolyIoxazol-4-ylmethoxy)cyclohexyl]- ethylidene}thiazolidine-2,4-dione: chiral o o 15 C23H28N2O4S (428.55), MS(ESI): 429 (M+H+). 5-{2-[(7S,3S)-3-(5-methy!-2-m-tolyloxazol-4-y!methoxy)cyclohexyl]- ethylidene}thiazolidine-2,4-dione: 20 78 013036

C23H28N2O4S (428.55), MS(ESI): 429 (M+H+).

5 Example XLVIII

The compound 5-(2-{c/s-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione from Example XLIV wasseparated by chromatography on a chiral phase into the compounds 5-(2-((is,3S)- 10 3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine- 2,4-dione and 5-(2-((1 R,3R)-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione. 5-(2-(( 1 s, 3S)-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-y Imethoxyjcyclo- 15 hexyl}ethyl)thiazolidine-2,4-dione:

C26H34N2O4S (470.64), MS(ESI): 471 (M+H+). 79 013036 5-(2-((1 R,3R)-3-(5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclo-hexyl}ethyl)thiazolidine-2,4-dione:

C26H34N2O4S (470.64), MS(ESI): 471 (M+H+).

Example XLIX îo The compound 5-{2-[c/s'-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclo-hexyl]ethyl}thiazolidine-2,4-dione from Example XXXIII was separated bychromatography on a chiral phase into the compounds 5-(2-((1 S, 3S)-3-(5-methyl-2-p-tolyloxazol-4-yImethoxy)cyclohexyI]ethyl}thiazoIidine-2,4-dione and 5-(2-[(1/?,3R>3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl)thiazolidine-2,4- 15 dione. 5-(2-((7 S, 3S)-3-(5-methyl-2-p-tolyloxazol-4-yl methoxy)cyclohexy l]ethyl}-thiazolidine-2,4-dione

C23H28N2O4S (428.55), MS(ESI): 429 (M+H+). 80 013036 5-(2-(( 1 R, 3R)-3-(5-methyl-2-p-tolyioxazol-4-ylmethoxy)cyclohexyl]ethyl}-thiazolidine-2,4-dione

C23H28N2O4S (428.55), MS(ESI): 429 (M+H+).

Example L 5-(2-((1 S,3S)-3-[2-(3,4-dimethylphenyl)-5-ethyloxazol-4-ylmethoxy]cyclo-hexyl}ethyl)thiazolidine-2,4-dione ((1 S, 3S)-3-allylcyclohexanol

lipase vinyl acetate

AJ

50 g of c/s-3-allylcyclohexanol are dissolved in 200 ml vinyl acetate, and 3 g oflipase (Novozym) added. The mixture is stirred at RT until a conversion of 58% isreached (the conversion is monitored by GC). The enzyme is filtered off and the 20 vinyl acetate is removed under reduced pressure. The resulting residue is purifiedchromatographically on silica gel. This gives 17 g of (1S, 3S)-3-allylcyclohexanolas a colorless oil. C8H14O (126.20), Rf (n-heptane:ethyl acetate = 1:1) = 0.46. 25 5-(2-((1 S, 3S)-3-[2-(3,4-dimethylphenyl)-5-ethyloxazo!-4-yImethoxy]cyclo-hexyl}ethyl)thiazolidine-2,4-dione 81 013036

Analogously to Example XXVIII and Example XXXI f7S,3S/3-allylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-ethyl-2-(3,4-dimethylphenyl)oxazol gave thecompound 5-(2-((1 S,3S)-3-[2-(3,4-dimethylphenyl)-5-ethyloxazol-4- 5 ylmethoxy]cyclo hexy IJethy I) th iazolid i ne-2,4-dione

C25H32N2O4S (456.61), MS(ESI): 457 (M+H+). 10

Example LI 5-(2-((1 S,3S)-3-[5-Ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyI)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI, (1S,3SJ-3-allylcyclohexanol, 15 thiazolidinedione and 4-iodomethyl-5-ethyl-2-(4-trifluoromethylphenyl)oxazole gave the compound 5-(2-((1 S,3S)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyi}ethyl)thiazolidine-2,4-dione.

20 C24H27F3N2O4S (496.55), MS(ESI): 497 (M+H+). 82 013036

Example LII 5-{2-[(1S,3S)-3-(5-Ethyl-2-naphthalen-2-y!-oxazol-4-ylmethoxy)cyclohexyl]ethyl}- thiazolidine-2,4-dione

Analogousiy to Example XXVIII and Example XXXI f7S,3S)-3-allyl-cyclohexanol,5 thiazolidinedione and 5-ethyl-4-iodomethyl-2-naphthalen-2-yloxazole gave the compound 5-(2-((1 S,3S)-3-(5-ethyl-2-naphthalen-2-yloxazol-4-ylmethoxy)eyclohexyl]ethyl}thiazolidine-2,4-dione. chiral 10 C27H30N2O4S (478.62), MS(ESI): 479 (M+H+).

Example LUI 5-(2-((1 S,3S)-3-[5-Ethyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]-15 cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogousiy to Example XXVIII and Example XXXI flS^SJ-S-allylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-ethyl-2-(3-trifIuoromethylphenyl)oxazole gavethe compound 5-(2-((1 S,3S)-3-[5-ethyl-2-(3-trifluoromethylphenyl)-oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione. 20 C24H27F3N2O4S (496.55), MS(ESI): 497 (M+H+).

Beispiel LIV 25 5-(2-((1 S, 3S)-3-[5-Ethyl-2-(4-tert-butylphenyl)oxazol-4-ylmethoxy]cyclohexyl}- ethyl)thiazolidine-2,4-dione

Analogousiy to Example XXVII, and Example XXX, (7S,3S)-3-allylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-ethyl-2-(4-tert-butylphenyl)oxazole gave the 83 013036 compound 5-(2-((1 S,3S)-3-[5-ethyl-2-(4-tert-butyiphenyl)oxazol-4-yimethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione.

5 C27H36N2O4S (484.66), MS(ESI): 485 (M+H+).

Example LV 5-(2-((1 S,3S)-3-[5-lsopropyl-2-(3,4-dimethyIphenyl)oxazol-4-ylmethoxy]-io cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI (7S,3S}-3-aIlylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-isopropyl-2-(3,4-dimethylphenyl)oxazolegave the compound 5-(2-((1 S,3S)-3-[5-isopropyl-2-(3,4-dimethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione. 15 chiral

C26H34N2O4S (470.64), MS(ESI): 471(Μ+Ι-Γ).

20 Example LVI 5-(2-((1 S, 3S)-3-[5-Ethyl-2-(4-isobutylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)-thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI (7S,3S>)-3-allylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-ethyl-2-(4-isobutylphenyl)oxazole gave the 25 compound 5-(2-((1 S,3S)-3-[5-ethyl-2-(4-isobutylphenyl)oxazol- 4-ylmethoxy]cyclohexyl}ethy!)thiazolidin-2,4-dione. 84 013036

ο

N C27H36N2O4S (484.66), MS(ESI): 485 (M+H+). 5 Example LVI1 5-(2-((1 S,3S)-3-[5-lsopropyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI (7S,3S)-3-allylcyciohexanol,thiazolidinedione and 4-iodomethyl-5-isopropyl-2-(3-trifluormethylphenyl)oxazole îo gave the compound 5-(2-((1 S,3S)-3-[5-isopropyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyc!ohexyI}ethyl)thiazolidine-2,4-dione. chiral C25H29F3N2O4S (510.58), MS(ESI): 511 (M+H+). 15

Example LVIIi 5-(2-((1 S, 3S)-3-[5-lsopropyl-2-(4-tert-butylpheny!)oxazol-4-ylmethoxy]cyclohexyl}-ethyl)thiazolidine-2,4-dione

Analogously to Example XXVII, and Example XXXI f7S,3S)-3-allylcyclohexanol, 20 thiazolidinedione and 4-iodomethyI-5-isopropyl-2-(4-tert-butylphenyl)oxazol gave the following compound 5-(2-((1 S,3S)-3-[5-isopropyl-2-(4-tert-butylphenyl)oxazol- 4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione. chiral 85 013036

C28H38N2O4S (498.69), MS(ESI): 499 (M+H+).

5 Example LIX 5-(2-((1 S,3S)-3-[5-Isopropyl-2-(4-isobutylphenyl)oxazol-4-ylmethoxy]cyclohexyl}-ethyl)thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI (7S,3S)-3-allylcyclohexanol,thiazolidinedione and 4-iodomethyl-5-isopropyl-2-(4-isobutylphenyl)oxazole gave 10 the compound 5-(2-((1 S,3S)-3-[5-isopropyl-2-(4-isobutylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione. chiral

C28H38N2O4S (498.69), MS(ESI): 499 (M+H+).

Example LX 5-(2-((1 S,3S)-3-[5-lsopropyl-2-(4-trifIuoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyl}ethyl)thiazolidine- 2,4-dione 20 Analogously to Example XXVIII and Example XXXI (7S,3S,)-3-allylcyclohexanol, thiazolidinedione and 4-iodomethyl-5-isopropyl-2-(4-trifluoromethylphenyl)oxazole gave the compound 5-(2-((1 S,3S)-3-[5-isopropyl-2-(4-trifluoromethylphenyi)oxazol- 4-ylmethoxy]cyclohexyl}ethyl)thiazolidine-2,4-dione. chiral 86 013036

C25H29F3N2O4S (510.58), MS(ESI): 511 (M+H+).

5 Example LXI 5-{2-[(1S,3S)-3-(5-lsopropyl-2-naphthalen-2-yloxazol-4-ylmethoxy)cyclohexyl]- ethyl}thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI (YS,3SJ-3-allylcyclohexanol,thiazolidinedione and 5-isopropyl-4-iodomethyl-2-naphthalen-2-yloxazole gave the îo compound 5-{2-[( 1 S,3S)-3-(5-isopropyl-2-naphthalen-2-yloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazoIidine-2,4-dione. chiral

C28H32N2O4S (492.64), MS(ESI): 493 (M+H+).

Example LXII 5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl)ethyl)-20 3-methylthiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI c/s-3-allylcycIohexanol, 3-methylthiazolidinedione and 4-iodomethyl-5-methyl-2-(3-methoxypheny!)oxazoIe gave the compound 5-(2-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4- yImethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione. 87 013036

cis/racemate C24H30N2O5S (458.58), MS(ESI): 459 (M+H+).

Beispiel LXill 5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyI)- 3- pheny!thiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI c/s-3-allylcycIohexanol,îo 3-phenylthiazolidinedione and 4-iodomethyl-5-methyl-2-(3-methoxyphenyl)oxazole gave the compound 5-(2-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol- 4- ylmethoxy]cyclohexyl}ethyl)-3-phenylthiazolidine-2,4-dione.

cis/racemate 15 C29H32N2O5S (520.65), MS(ESI): 521 (M+H+).

Example LXIV 5-(2-{cis-3-[2-(4-MethyIphenyl)-5-methyloxazol-4-yImethoxy]cyclohexyl}ethyl)-20 3-methylthiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI c/s-3-allylcycIohexanol, 3-methylthiazolidinedione and 4-iodomethyl-5-methyl-2-(4-methylphenyl)oxazole 88 013036 gave the compound 5-(2-{cis-3-[2-(4-methylphenyl)-5-methyloxazol- 4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione.

cis/racemate 5 C24H30N2O4S (442.58), MS(ESI): 443 (M+H+).

Example LXV îo 5-(2-{cis-3-[2-(4-Methylphenyl)-5-methyloxazol-4-yImethoxy]cyclohexyl}ethyl)- 3-benzylthiazolidine-2,4-dione

Analogously to Example XXVIII and Example XXXI c/s-3-allyIcyclohexanol, 3-benzylthiazolidinedione and 4-iodomethyl-5-methyl-2-(4-methylphenyl)oxazolegave the compound 5-(2-{cis-3-[2-(4-methylphenyl)-5-methyloxazol- 15 4-ylmethoxy]cyclohexyl}ethyl)-3-benzylthiazolidine-2,4-dione.

cis/racemate C30H34N2O4S (518.58), MS(ESI): 519 (M+H+).

Example LXVI 5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-isopropyloxazol-4-ylmethoxy]cyclohexyl}ethyl)- 3-methylthiazolidine-2,4-dione 89 013036

Anaiogously to Example XXVIII and Example XXXI c/s-3-ailylcyclohexanol, 3-methylthiazolidinedione and 4-iodomethyl-5-isopropyl-2-(3-methoxyphenyl)-oxazole gave the compound 5-(2-{cis-3-[2-(3-methoxyphenyl)-5-isopropyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione. cis/racemate o— 10 10 C26H34N2O5S (486.64), MS(ESI): 487 (M+H+).

Example LXVII 5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-phenyloxazol-4-yImethoxy]cyclohexyl}ethyl)- 3-methylthiazolidine-2,4-dione

Anaiogously to Example XXVIII and Example XXXI c/s-3-allylcyclohexanol, 3- methylthiazolidinedione and 4-iodomethyl-5-phenyl-2-(3-methoxyphenyl)oxazolegave the compound 5-(2-{cis-3-[2-(3-methoxyphenyl)-5-phenyloxazol- 4- ylmethoxy]cyclohexyl}ethyl)-3-methylthiazolidine-2,4-dione. cis/racemate C29H32N2O5S (520.65), MS(ESI): 521 (M+H+). 90 013036

Example LXVIII 5-(2-{cis-3-[2-(3-Methoxyphenyl)-5-phenyloxazol-4-ylmethoxy]cyclohexyl}ethyl)- 3- phenylthiazolidine-2,4-dione

Analogously tô Example XXVIII and Example XXXI c/'s-3-allylcyclohexanol, 5 3-phenylthiazolidinedione and 4-iodomethyl-5-phenyl-2-(3-methoxyphenyl)oxazole gave the compound 5-(2-{cis-3-[2-(3-methoxyphenyl)-5-phenyloxazol- 4- ylmethoxy]cyclohexyI}ethyl)-3-phenylthiazolidine-2,4-dione. cis/racemate C34H34N2O5S (582.72), MS(ESI): 583 (M+H+).

Claims

013036 91 Patent Claims:

1. A compound of the formula I

R2 I in which 10 Ring A is (C3-C8)-cycIoalkanediyl or (C3-C8)-cycloalkenediyI, where in thecycloalkanediyl or cycloalkenediyl rings one or more carbon atomsmay be replaced by oxygen atoms; R1, R2 independently of one another are H, F, Br, CF3i OCF3> (Ci-C6)-alky!, 15 O-(C-i-Cs)-alkyl, SCF3, SF5, OCF2-CHF2, O-phenyl, OH, or NO2; or Ri and R2 in juxtaposition together with the phenyl ring are a fused, unsaturatedor completely or partially saturated bicyclic (C9-C12)-aryl or (Cg-Cn)-heteroaryl ring System; 20 R3 is H, CF3, (Ci-C8)-alkyl, (C-i-C6)-alkoxy, (C3-C8)-cycloalkyI or phenyl; X is (Ci-C6)-alkanediyl, where one or more carbon atoms in the alkanediyl group may be replaced by oxygen atoms; Y is (Ci-C8)-alkanediyl or (Ci-C6)-alkenediyI, where one or more CH2 groups in the alkanediyl or alkenediyl group may be replaced by O,CO, S, SO or SO2 and alkanediyl or alkenediyl may be unsubstitutedor substituted by OH; Ring B is phenyl which may be mono- or disubstituted by NO2, Cl, CN,(Ci-C6)-alkyl, (CrCgj-alkoxy ortetrazole; or 92 013036 pyrrolidin-2-one which additionally contains a nitrogen or sulfur atomin the ring and is substituted by oxo or thioxo and may be substitutedon the nitrogen atom by R4; R4 is (Ci-C6)-alkyl, phenyl, benzyl; and its physiologically acceptable salts.

2. A compound of the formula I as claimed in claim 1, in which Ring A is (C3-C8)-cycloalkanediyl, (C3-C8)-cycloalkenediyl, where in the cycloalkanediyl or cycloalkenediyl rings one or more carbon atom maybe replaced by an oxygen atom; R1, R2 independently of one another are H, F, Br, CF3, OCF3, (Ci-C6)-alkyl,O-fCvCsJ-alkyl, SCF3> SF5> OCF2-CHF2, O-phenyl, OH or NO2; or R1 and R2 in juxtaposition together with the phenyl ring are a fused, unsaturatedor completely or partially saturated bicyclic (Cg-Ci2)-aryl or (Cg-Cn)-heteroaryl ring System; R3 is H, CF3, (Ci-C6)-alkyl, (C3-C8)-cycloalkyl or phenyl; X is (Ci-C6)-alkanediyl, where one carbon atom in the alkanediyl group may be replaced by an oxygen atom; Y is (C-i-C6)-alkanediyl or (Ci-Ce)-alkenediyl, where one or two CH2 groups in the alkanediyl or alkenediyl group may be replaced by O,CO, S, SO or SO2 and alkanediyl or alkenediyl may be unsubstitutedor substituted by OH; Ring B is phenyl which may be mono- or disubstituted by NO2i Cl, CN,(Ci-Cej-alkyl, (Ci-C8)-alkoxy or tetrazole; or pyrrolidin-2-one which additionally contains a nitrogen or sulfur atomin the 4-position and is substituted by oxo or thioxo in the 5-positionand may be substituted on the N1-atom by R4; 93 013036 R4 is (Ci-CeJ-alkyl, phenyl, benzyl; and its physiologically acceptable salts.

3. A compound of the formula I as claimed in claims 1 or 2, in which Ring A is (C3-C8)-cycloalkanediyl in which one carbon atom is replaced byan oxygen atom; R1, R2 independently of one another are H, F, Br, CF3, OCF3, (Ci-C6)-alkyl,O-(Ci-C6)-alkyl, SCF3, SF5, OCF2-CHF2, O-phenyl, OH or NO2; or R1 and R2 in juxtaposition together with the phenyl ring are a fused, unsaturatedor completely or partially saturated bicyclic (C9-C12)-aryl or (C9-Cn)-heteroaryl ring System; R3 is H, CF3, (Ci-C6)-alkyl, (C3-C8)-cycloalkyl or phenyl; X is (Ci-C6)-alkanediyl, where the C1 carbon atom is replaced by an oxygen atom; Y is (Ci-C6)-alkanediyl or (Ci-C6)-alkenediyl, where one or two CH2 groups in the alkanediyl or alkenediyl group may be replaced by O,CO or SO2 and alkanediyl or alkenediyl may be substituted by OH; Ring B is phenyl which may be mono- or disubstituted by NO2, Cl, CN,(Ci-C6)-alkyl, (C-i-C6)-alkoxy or tetrazole; or pyrrolidin-2-one which additionally contains a nitrogen or sulfur atom in the 4-position and is substituted by oxo or thioxo in the 5-positionand may be substituted on the N1-atom by R4; R4 is (Ci-C6)-alkyl, phenyl, benzyl; and its physiologically acceptable salts.

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; 94 013036 R1, R2 are independently of one another H, F, Br, CF3, OCF3, (Ci-C6)-alkyl,O-(Ci-C6)-alkyl, SCF3, SF5, OCF2-CHF2, O-phenyl, OH, NO2; or R1 and R2 in juxtaposition together with the phenyl ring are a fused unsaturatedbicyclic (Cg-Cio)-aryl or (Cg-Cio)-heteroaryl ring System; R3 is H, CF3, (Ci-Ce)-alkyl, (C3-Ce)-cycloalkyl, phenyl; X is CH2-O; Y is (Ci-C4)-alkanediyl, O-(Ci-C4)-alkanediyl, (Ci-C4)-alkenediyl, O-(C1-C4)-alkenediyI, O-SO2 or O-CO, where alkanediyl may besubstituted by OH; Ring B is phenyl which may be mono- or disubstituted by NO2, Cl, CN,(Ci-C6)-alkyl, (Ci-C6)-aIkoxy ortetrazole; orthiazolidine-1,4-dione which may be substituted on the N3-atom byR4; R4 is (Ci-C6)-aIkyl, phenyl, benzyl; and its physiologically acceptable salts.

5. A compound of the formula I as claimed in any of daims 1 to 4, in which Ring A is cyclohexane-1,3-diyl; R1, R2 independently of one another are H, F, Br, CF3, (Ci-C6)-alkyl, O-(Ci-C6)-alkyl; or Ri and R2 together with the phenyl ring are naphthyl; R3 is (Ci-C6)-alkyl, (C5-C6)-cycloalkyl, phenyl; X is CH2-O; 95 013036 Y is (Ci-C4)-alkanediyl, O-(C-i-C4)-alkanediyl, (Ci-C4)-alkenediyl, O- (Ci-C4)-alkenediyl, O-SO2, O-CO, where alkanediyl may besubstituted by OH; Ring B is phenyl which may be mono- or disubstituted by NO2, Cl, CN,(Ci-C6)-alkyl, (Ci-CeJ-alkoxy or tetrazole; or Ring B is thiazolidine-2,4-dione which may be substituted on the N3-atom byR4; R4 is (C-i-C6)-alkyl, phenyl, benzyl; and its physiologically acceptable salts.

6. A compound of the formula I as claimed in any of daims 1 to 5, in which R2 is hydrogen and R1 is attached in the meta- or para-position.

7. A compound of the formula I as claimed in any of claims 1 to 6, in which Y is -CH2-CH2-.

8. A pharmaceutical comprising one or more compounds of the formula I asclaimed in one or more of claims 1 to 7.

9. A pharmaceutical comprising one or more compounds of the formula I as claimed in one or more of claims 1 to 7 and one or more active compounds whichact favorably on metabolic disorders or diseases associated with them.

10. A pharmaceutical comprising one or more compounds of the formula I asclaimed in one or more of claims 1 to 7 and one or more antidiabetics.

11. A pharmaceutical comprising one or more compounds of the formula I asclaimed in one or more of claims 1 to 7 and one or more lipid modulators. 96 013036

12. The use of the compounds of the formula I as claimed in one or more of daims 1 to 7 for the treatment and/or prévention of disorders of fatty acidmetabolism and disorders of glucose utilization.

13. The use of the compounds of the formula I as claimed in one or more of daims 1 to 7 for the treatment and/or prévention of disorders in which insulinrésistance plays a rôle.

14. The use of the compounds of the formula I as claimed in one or more of îo daims 1 to 7 for the treatment and/or prévention of diabètes mellitus and sequelaeassociated therewith.

15. The use of the compounds of the formula I as claimed in one or more ofdaims 1 to 7 for the treatment and/or prévention of dyslipidemias and their 15 sequelae.

16. The use of the compounds of the formula I as claimed in one or more ofdaims 1 to 7 for the treatment and/or prévention of conditions associated withmetabolic syndrome. 20

17. The use of the compounds as claimed in one or more of daims 1 to 7 incombination with at least one further active compound for the treatment and/orprévention of disorders of the fatty acid metabolism and disorders of glucoseutilization. 25

18. The use of the compounds as claimed in one or more of daims 1 to 7 incombination with at least one further active compound for the treatment and/orprévention of disorders in which insulin résistance plays a rôle. 30

19. A process for preparing a pharmaceutical cômprising one or more of the compounds as claimed in one or more of daims 1 to 7, which comprises mixingthe active compound with a pharmaceutically suitable carrier and bringing thismixture into a form suitable for administration.