CA2517381A1 - 3-(2-phenyl-oxazol-4-yl methoxy) cyclohexylmethoxy acetic acid derivatives and related compounds used as ppar modulators for treating type 2 diabetes and arteriosclerosis - Google Patents

3-(2-phenyl-oxazol-4-yl methoxy) cyclohexylmethoxy acetic acid derivatives and related compounds used as ppar modulators for treating type 2 diabetes and arteriosclerosis

Info

Publication number
CA2517381A1
CA2517381A1 CA 2517381 CA2517381A CA2517381A1 CA 2517381 A1 CA2517381 A1 CA 2517381A1 CA 2517381 CA2517381 CA 2517381 CA 2517381 A CA2517381 A CA 2517381A CA 2517381 A1 CA2517381 A1 CA 2517381A1
Authority
CA
Grant status
Application
Patent type
Prior art keywords
cis
methyl
ml
tert
example
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA 2517381
Other languages
French (fr)
Inventor
Christian Stapper
Dirk Gretzke
Heiner Glombik
Eugen Falk
Jochen Goerlitzer
Stefanie Keil
Hans-Ludwig Schaefer
Wolfgang Wendler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi-Aventis Deutschland GmbH
Original Assignee
Aventis Pharma Deutschland Gmbh
Christian Stapper
Dirk Gretzke
Heiner Glombik
Eugen Falk
Jochen Goerlitzer
Stefanie Keil
Hans-Ludwig Schaefer
Wolfgang Wendler
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings

Abstract

The invention relates to cycloalkyl methoxy substituted acetic acid derivatives, in addition to their physiologically compatible salts and physiologically functional derivatives. The invention relates to compounds of formula (I), in which the groups are defined as cited in the description, in addition to their physiologically compatible salts and to a method for their production. The compounds are suitable e.g. for treating and/or preventing disorders of the fatty acid metabolism and disorders of glucose utilisation in addition to disorders, in which insulin resistance plays a part.

Description

Description 3-(2-Phenyl-oxazol-4-ylmethoxy)cyclohexylmethoxy acetic acid derivatives and related compounds used as PPAR modulators for treating type 2 diabetes and arteriosclerosis The invention relates to cycloalkylmethoxy-substituted acetic acid derivatives, to processes for their preparation and to their use as pharmaceuticals, and to their physiologically acceptable salts and physiologically functional derivatives.
Compounds of a similar structure have already been described in the prior art for the treatment of hyperlipidemia and diabetes (WO 2000/64876).
It was an object of the invention to provide compounds which permit a therapeutically exploitable modulation of the lipid and/or carbohydrate metabolism and are thus suitable for the prevention and/or treatment of disorders such as type 2 diabetes and atherosclerosis and their multifarious sequelae.
Surprisingly, we have found a number of compounds which modulate the activity of PPAR receptors. The compounds are particularly suitable for activating PPARalpha and PPARgamma, where the extent of the relative activation may vary, depending on the compounds.
The invention thus relates to compounds of the formula I

R2~~ \ \ Ring A
( )o N X Y~ ~ )n R8 RS R~ O
in which:
Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, where in the cycloalkanediyl or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms;
R1, R2 independently of one another are H, F, CI, Br, CF3, OCF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, SCF3, SFS, OCF2-CHF2, (C6-C10)-aryl, (C6-C10)-aryloxy, OH, N02; or R1 and R2 together with the phenyl, pyridine, 1 H-pyrrole, thiophene or furan ring form fused, partially or unsaturated bicyclic (C6-C10)-aryl, (C5-C11)-heteroaryl;
R3 is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C1-C3)-alkyl-(C3-C8)-cycloalkyl, phenyl, (C1-C3)-alkyl-phenyl, (C5-C6)-heteroaryl, (C1-C3)-alkyl-(C5-C6)-heteroaryl or (C1-C3)-alkyl which is fully or partially substituted by F;
W is CHorNifo=1;
W is O, S or NR10 if o = 0;
X is (C1-C6)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms;
Y1 is (CR13R14)p;
p is 1 or 2;
Y2 is CH2, O, S, SO, S02 or NR9;
n is 0-2;
R4 is H, (C1-C6)-alkyl; or F if Y2 is not O, NR9;
R5 is H, (C1-C6)-alkyl; or F if Y2 is not O, NR9;
R6 is H, (C1-C6)-alkyl; or F if n is not 0;

R7 is H, F (if n is not 0), (C1-C6)-alkyl, (C1-C6)-alkoxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl, where alkyl may be unsubstituted or substituted by one or more radicals selected from the group consisting of hydroxyl, phenyl, (C5-C11)-heteroaryl, (C1-C6)-alkoxy and NR11R12, and phenyl may be unsubstituted or substituted by one or more radicals from the group consisting of hydroxy, (C1-C6)-alkoxy, F and CF3; with the proviso that R7 is not NR11 R12 or (C1-C6)-alkoxy if R6 = F;
R6 and R7 together with the carbon atom that carries them are (C3-C8)-cycloalkyl;
R8 is H, (C1-C6)-alkyl;
R9 is H, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, aryl-(C1-C4)-alkyl, CO-(C1-C6)-alkyl, CO-(C6-C10)-aryl, CO-(C1-C6)-alkyl-(C6-C10)-aryl, CO-(C5-C11)-heteroaryl, C(O)-O-(C1-C6)-alkyl, C(O)-O-(C1-C6)-alkyl-(C6-C10)-aryl, C(O)-O-(C6-C10)-aryl, C(O)-O-(C5-C11)-heteroaryl, S02-(C1-C6)-alkyl, S02-(C1-C6)-alkyl-(C6-C10)-aryl, S02-(C1-C6)-alkyl-S02-(C1-C6)-alkyl, S02-(C6-C10)-aryl, S02-(C5-C11)-heteroaryl, where aryl and heteroaryl may be unsubstituted or substituted by (C1-C6)-alkyl, O-(C1-C6)-alkyl, F, CI, CO-(C1-C6)-alkyl;
R10 is H, (C1-C6)-alkyl, (C1-C6)-alkyl-phenyl;
R11 is H, (C1-C6)-alkyl, (C1-C6)-alkyl-phenyl;
R12 is H, (C1-C6)-alkyl, (C1-C6)-alkyl-phenyl;
R13 is H, (C1-C6)-alkyl;
R14 is H, (C1-C6)-alkyl;

and their physiologically acceptable salts.
Preference is given to compounds of the formula I in which Ring A is (C3-Cg)-cycloalkanediyl or (C3-Cg)-cycloalkenediyl, where in the cycloalkanediyl or cycloalkenediyl rings one carbon atom may be replaced by an oxygen atom;
X is (C1-C6)-alkanediyl, where in the alkanediyl group the C1 or C2 carbon atom (to Ring A) may be replaced by an oxygen atom.
Particular preference is given to the compounds of the formula I in which one or more radicals are as defined below:
Ring A is cyclohexane-1,3-diyl; or R1 is F, Br, CF3, OCF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl; or R1 and R2 together with the phenyl ring = naphthyl; or R1 is in the meta- or in the para-position; or R2 is hydrogen; or R3 is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C1-C3)-alkyl-(C5-C6)-cycloalkyl, phenyl, (C1-C3)-alkyl-phenyl; or W is CHifo=1; or X is CH2-O or CH2-O-CH2; or n is 0; or R6 is H, (C1-C6)-alkyl; or R6 and R7 together with the carbon atom that carries them are (C3-C6)-cycloalkyl, in particular cyclopentyl; or R7 is (C1-C6)-alkyl, where alkyl may be unsubstituted or substituted by one or more radicals selected from the group 5 consisting of hydroxyl, phenyl, (C5-C11)-heteroaryl, (C1-C6)-alkoxy and NR11 R12, where R11 and R12 are H, (C1-C6)-alkyl; or R13 and R14 are hydrogen.
Particular preference is furthermore given to the compounds of the formula I in which R7 is (C1-C4)-alkyl, (C1-C4)-alkyl-O-(C1-C4)-alkyl or benzyl;
very particularly preferably R7 is (C1-C4)-alkyl or benzyl.
Very particular preference is furthermore given to the compounds of the formula I
in which Ring A is cis-cyclohexane-1,3-diyl R1, R2 independently of one another are H, F, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl, or R1 and R2 together with the phenyl ring = naphthyl;
R3 is (C1-C6)-alkyl, (C3-C8)-cycloalkyl, phenyl;
W is CH if o = 1;

W is O, S, if o = 0;
X is CH2-O, CH2-O-CH2;
Y1 is CH2;
Y2 is CH2, O, S, SO, S02, NR9;
n is 0;
R4 is H;
R5 is H;
R6 is H, (C1-C6)-alkyl, benzyl;
R7 is H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl, benzyl, R6 and R7 together with the carbon atom that carries them are (C3-C6)-cycloalkyl;
R8 is H;
R9 is H; (C1-C6)-alkyl which may be unsubstituted or substituted by (C3-C6)-cycloalkyl, phenyl, (C5-C6)-heteroaryl;
CO-(C1-C6)-alkyl, CO-(C1-C6)-alkyl-phenyl, CO-phenyl, C(O)-O-(C1-C6)-alkyl, CO-NH-phenyl, S02-(C1-C4)-alkyl, S02-(C1-C4)-alkyl-S02-(C1-C4)-alkyl, S02-tolyl, where phenyl for its part may be substituted by O-(C1-C3)-alkyl;

and their physiologically acceptable salts.
The alkyl radicals in the substituents R1, R2, R3, R4, R5 , R6, R7, R8, R9, R10, R11, R12, R13 and R14 may be either straight-chain or branched.
Aryl means an aromatic carbocyclic mono- or bicyclic ring system which comprises 6 to 10 atoms in the ring or rings.
Heteroaryl is a mono- or bicyclic aromatic ring system having 4 to 11 ring members, in which at least one atom in the ring system is a heteroatom from the series N, O and S.
The compounds of the formula I comprise at least two centers of asymmetry and may comprise more in addition. The compounds of the formula I may therefore exist in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and mixtures of diastereomers.
The present invention encompasses all these isomeric forms of the compounds of the formula I. These isomeric forms can be obtained by known methods even if not specifically described in some cases.
Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, malefic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.
Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.
The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.
All references to "compound(s) of formula I" hereinafter refer to compounds) of the formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein.
Use This invention relates further to the use of compounds of the formula I and their pharmaceutical compositions as PPAR ligands. The PPAR ligands of the invention are suitable as modulators of PPAR activity.
Peroxisome proliferator-activated receptors (PPAR) are transcription factors which can be activated by ligands and belong to the class of nuclear hormone receptors. There are three PPAR isoforms, PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes (Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Motojima K, Cell Struct Funct. 1993 Oct; 18(5): 267-77).
Two variants of PPARgamma exist, PPARgamma~ and gamma2, which are the result of alternative use of promoters and differential mRNA splicing (Vidal-Puig et al. J. Clin. Invest., 97:2553-2561, 1996). Different PPARs have different tissue distribution and modulate different physiological functions. The PPARs play a key role in various aspects of the regulation of a large number of genes, the products of which genes are directly or indirectly crucially involved in lipid and carbohydrate metabolism. Thus, for example, PPARalpha receptors play an important part in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARgamma is crucially involved for example in regulating adipose cell differentiation. In addition, however, PPARs are also involved in the regulation of many other physiological processes, including those which are not directly connected with carbohydrate or lipid metabolism. The activity of different PPARs can be modulated by various fatty acids, fatty acid derivatives and synthetic compounds to varying extents. For relevant reviews about functions, physiological effect and pathophysiology, see:
Joel Berger et al., Annu. Rev. Med. 2002, 53, 409 - 435; Timothy Wilson et al. J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al., Recent Prog Horm Res. 2001; 56: 239-63.
The present invention relates to compounds of the formula I suitable for modulating the activity of PPARs, especially the activity of PPARalpha and PPARgamma. Depending on the modulation profile, the compounds of the formula I are suitable for the treatment, control and prophylaxis of the indications described hereinafter, and for a number of other pharmaceutical applications connected thereto (see, for example, Joel Berger et al., Annu.
Rev. Med. 2002, 53, 409 - 435; Timothy Wilson et al. J. Med. Chem., 2000, Vol. 43, No. 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 and Arteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52; 2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARs in health and disease, NATURE, VOL 405, 25 MAY 2000; 421-4; Ines Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staels:
Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001, 245-254).
Compounds of this type are particularly suitable for the treatment and/or prevention of 1. - disorders of fatty acid metabolism and glucose utilization disorders - disorders in which insulin resistance is involved 2. Diabetes mellitus, especially type 2 diabetes, including the prevention of 10 the sequelae associated therewith.
Particular aspects in this connection are - hyperglycemia, - improvement in insulin resistance, - improvement in glucose tolerance, - protection of the pancreatic f3 cells - prevention of macro- and microvascular disorders 3. Dyslipidemias and their sequelae such as, for example, atherosclerosis, coronary heart disease, cerebrovascular disorders etc, especially those (but not restricted thereto) which are characterized by one or more of the following factors:
- high plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations, - low HDL cholesterol concentrations - low ApoA lipoprotein concentrations - high LDL cholesterol concentrations - small dense LDL cholesterol particles - high ApoB lipoprotein concentrations 4. Various other conditions which may be associated with the metabolic syndrome, such as:
- obesity (excess weight), including central obesity - thromboses, hypercoagulable and prothrombotic states (arterial and venous) - high blood pressure - heart failure such as, for example (but not restricted thereto), following myocardial infarction, hypertensive heart disease or cardiomyopathy 5. Other disorders or conditions in which inflammatory reactions or cell differentiation may for example be involved are:
- atherosclerosis such as, for example (but not restricted thereto), coronary sclerosis including angina pectoris or myocardial infarction, stroke - vascular restenosis or reocclusion - chronic inflammatory bowel diseases such as, for example, Crohn's disease and ulcerative colitis - pancreatitis - other inflammatory states - retinopathy - adipose cell tumors - lipomatous carcinomas such as, for example, liposarcomas - solid tumors and neoplasms such as, for example (but not restricted thereto), carcinomas of the gastrointestinal tract, of the liver, of the biliary tract and of the pancreas, endocrine tumors, carcinomas of the lungs, of the kidneys and the urinary tract, of the genital tract, prostate carcinomas etc - acute and chronic myeloproliferative disorders and lymphomas - angiogenesis - neurodegenerative disorders - Alzheimer's disease - multiple sclerosis - Parkinson's disease - erythemato-squamous dermatoses such as, for example, psoriasis - acne vulgaris - other skin disorders and dermatological conditions which are modulated by PPAR
- eczemas and neurodermitis - dermatitis such as, for example, seborrheic dermatitis or photodermatitis - keratitis and keratoses such as, for example, seborrheic keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or keratosis follicularis - keloids and keloid prophylaxis - warts, including condylomata or condylomata acuminata - human papilloma viral (HPV) infections such as, for example, venereal papillomata, viral warts such as, for example, molluscum contagiosum, leukoplakia - papular dermatoses such as, for example, Lichen planus - skin cancer such as, for example, basal-cell carcinomas, melanomas or cutaneous T-cell lymphomas - localized benign epidermal tumors such as, for example, keratoderma, epidermal naevi - chilblains - high blood pressure - syndrome X
- polycystic ovary syndrome (PCOS) - asthma - osteoarthritis - lupus erythematosus (LE) or inflammatory rheumatic disorders such as, for example, rheumatoid arthritis - vasculitis - wasting (cachexia) - gout - ischemia/reperfusion syndrome - acute respiratory distress syndrome CARDS) Formulations The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg) per day and per kilogram of bodyweight, for example 0.1-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.001 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health.
The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical preparations for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients.
Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one (or more) surface-active/dispersing agents) in a suitable machine. Molded tablets can be produced by molding the compound, which is in powder form and is moistened with an inert liquid diluent, in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient.

These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile 5 and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.
Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced 10 by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or 15 oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances.
The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1 % to 35%, preferably about 3% to 15%. A particular possibility is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).
The compounds of the formula I are distinguished by favorable effects on metabolic disorders. They beneficially influence lipid and sugar metabolism, in particular they lower the triglyceride level and are suitable for the prevention and treatment of type II diabetes and arteriosclerosis and the diverse sequalae thereof.
Combinations with other medicaments The compounds of the invention can be administered alone or in combination with one or more further pharmacologically active substances which have, for example, favorable effects on metabolic disturbances or disorders frequently associated therewith. Examples of such medicaments a re 1. medicaments which lower blood glucose, antidiabetics, 2. active ingredients for the treatment of dyslipidemias, 3. antiatherosclerotic medicaments, 4. antiobesity agents, 5. antiinflammatory active ingredients 6. active ingredients for the treatment of malignant tumors 7. antithrombotic active ingredients 8. active ingredients for the treatment of high blood pressure 9. active ingredients for the treatment of heart failure and 10. active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.
They can be combined with the compounds of the invention of the formula I
in particular for a synergistic improvement in the effect. Administration of the active ingredient combination can take place either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.
Examples which may be mentioned are:
Antidiabetics Suitable antidiabetics are disclosed for example in the Rote Liste 2001, chapter 12 or in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. Antidiabetics include all insulins and insulin derivatives such as, for example, Lantus~ (see www.lantus.com) or Apidra~, and other fast-acting insulins (see US 6,221,633), GLP-1 receptor modulators as described in WO 01/04146 or else, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S.
The orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones', thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, DPP-IV inhibitors, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which alter lipid metabolism and lead to a change in the blood lipid composition, compounds which reduce food intake, PPAR and PXR
modulators and active ingredients which act on the ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with substances which influence hepatic glucose production such as, for example, glycogen phosphorylase inhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO
03/084922, WO 03/104188) In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.
In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compounds of the formula I are administered in combination with a biguanide such as, for example, metformin.
In a further embodiment, the compounds of the formula I are administered in combination with a meglitinide such as, for example, repaglinide.
In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione such as, for example, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxyJphenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in combination with a DPPIV inhibitor as described, for example, in W098/19998, W099/61431, W099/67278, W099/67279, W001 /72290, WO 02/38541, W003/040174, in particular P 93/01 (1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-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)aminoJ-acetyl]pyrrolidine-2-carbonitrile monobenzenesulfonate).
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARgamma agonist such as, for example, rosiglitazone, pioglitazone.
In one embodiment, the compounds of the formula I are administered in combination with compounds with an inhibitory effect on SGLT-1 and/or 2, as disclosed directly or indirectly for example in PCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455.
In one embodiment, the compounds of the formula I are administered in combination with an - glucosidase inhibitor such as, for example, miglitol or acarbose.

In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
Lipid modulators In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid reabsorption inhibitor (see, for example, US 6,245,744, US 6,221,897, US 6,277,831, EP 0683 773, EP
0683 774).
In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor as described for example in WO 0250027, or ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see, for example, US 6,342,512).
In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax, (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hoechst, 65926 Frankfurt/Main)). Combination with Caromax, is possible in 5 one preparation or by separate administration of compounds of the formula I and Caromax,. Caromax, can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.
10 In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARalpha agonist.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist such as, for example, AZ 242 (Tesaglitazar, (S)-3-(4-[2-(4-15 methanesulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionic acid), BMS
298585 (N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine) or as described in WO 99/62872, WO 99/62871, WO 01 /40171, WO 01 /40169, W096/38428, WO 01 /81327, WO 01 /21602, WO 03/020269, WO 00/64888 or WO 00/64876.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I are administered in combination with nicotinic acid or niacin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, e.g. CP- 529, 414 (torcetrapib).
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, implitapide.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist.
Antiobesity agents In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor such as, for example, orlistat.
In one embodiment, the further active ingredient is fenfluramine or dexfenfluramine.
In another embodiment, the further active ingredient is sibutramine.
In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.: Hormone and Metabolic Research (2001 ), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}amide hydrochloride (CGP 71683A)), MC4 agonists (e.g.
1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexin antagonists (e.g.
1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, (33 agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-yloxy)ethylamino]-ethanol hydrochloride (WO 01/83451)), MSH
(melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tertiary butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), uncoupling 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 (bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO
00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-[i agonists.
In one embodiment of the invention, the further active ingredient is leptin.
In one embodiment, the further active ingredient is dexamphetamine, amphetamine, mazindole or phentermine.
In one embodiment, the compounds of the formula I are administered in combination with medicaments having effects on the coronary circulation and the vascular system, such as, for example, ACE inhibitors (e.g.
ramipril), medicaments which act on the angiotensin-renine system, calcium antagonists, beta blockers etc.
In one embodiment, the compounds of the formula I are administered in combination with medicaments having an antiinflammatory effect.

In one embodiment, the compounds of the formula I are administered in combination with medicaments which are employed for cancer therapy and cancer prevention.
It will be appreciated that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is regarded as falling within the protection conferred by the present invention.
The activity of the compounds was tested as follows:
Determination of EC50 values of PPAR agonists in the cellular PPARalpha assay Principle The potency of substances which bind to human PPARa and activate in an agonistic manner is analyzed using a stably transfected HEK cell line (HEK= human embryo kidney) which is referred to here as PPARalpha reporter cell line. It contains two genetic elements, a luciferase reporter element (pOM-GAL4-Luc-Zeo) and a PPARalpha fusion protein (GR-GAL4-humanPPARa-LBD) which mediates expression of the luciferase reporter element depending on a PPARalpha ligand. The stably and constitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD binds in the cell nucleus of the PPARalpha reporter cell line via the GAL4 protein portion to the GAL4 DNA binding motifs 5'-upstream of the luciferase reporter element which is integrated in the genome of the cell line. There is only little expression of the luciferase reporter gene without addition of a PPARalpha ligand if fatty acid-depleted fetal calf serum (cs-FCS) is used in the assay. PPARa ligands bind and activate the PPARa fusion protein and thereby bring about expression of the luciferase reporter gene. The luciferase which is formed can be detected by means of chemiluminescence via an appropriate substrate.
Construction of the cell line The PPARalpha reporter cell line was prepared in 2 stages. Firstly, the luciferase reporter element was constructed and stably transfected into HEK cells. For this purpose, five binding sites of the yeast transcription factor GAL4 (each 5'-CGGAGTACTGTCCTCCGAG-3') were cloned in 5'-upstream of a 68 bp-long minimal MMTV promoter (Genbank Accession #
V01175). The minimal MMTV promoter section contains a CCAAT box and a TATA element in order to enable efficient transcription by RNA
polymerase II. The cloning and sequencing of the GAL4-MMTV construct took place in analogy to the description of Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Then the complete Photinus pyralis gene (Genbank Accession # M15077) was cloned in 3'-downstream of the GAL4-MMTV element. After sequencing, the luceriferase reporter element consisting of five GAL4 binding sites, MMTV
promoter and luciferase gene was recloned into a plasmid which confers zeocin resistance in order to obtain the plasmid p~M-GAL4-Luc-Zeo. This vector was transfected into HEK cells in accordance with the statements in Ausubel, F.M. et al. (Current protocols in molecular biology, Vol. 1-3, John ~ley & Sons, Inc., 1995). Then zeocin-containing medium (0.5 mg/ml) was used to select a suitable stable cell clone which showed very low basal expression of the luceriferase gene.
In a second step, the PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) was introduced into the stable cell clone described. For this purpose, initially the cDNA coding for the N-terminal 76 amino acids of the glucocorticoid receptor (Genbank Accession #
P04150) was linked to the cDNA section coding for amino acids 1-147 of the yeast transcription factor GAL4 (Genbank Accession # P04386). The cDNA of the ligand-binding domain of the human PPARalpha receptor (amino acids S167-Y468; Genbank Accession # S74349) was cloned in at the 3'-end of this GR-GAL4 construct. The fusion construct prepared in this way (GR-GAL4-humanPPARalpha-LBD) was recloned into the plasmid pcDNA3 (from Invitrogen) in order to enable constitutive expression therein by the cytomegalovirus promoter. This plasmid was linearized with a restriction endonuclease and stably transfected into the previously described cell clone containing the luciferase reporter element. The finished PPARalpha reporter cell line which contains a luciferase reporter element and constitutively expresses the PPARalpha fusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by selection with zeocin (0.5 mg/ml) and 6418 (0.5 mg/ml).

Assay procedure The activity of PPARalpha agonists is determined in a 3-day assay which is described below:
Day 1 The PPARa reporter cell line is cultivated to 80% confluence in DMEM
(# 41965-039, Invitrogen) which is mixed with the following additions: 10%
cs-FCS (fetal calf serum; #SH-30068.03, Hyclone), 0.5 mg/ml zeocin (#R250-01, Invitrogen), 0.5 mg/ml 6418 (#10131-027, Invitrogen), 1%
penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). The cultivation takes place in standard cell culture bottles (# 353112, Becton Dickinson) in a cell culture incubator at 37°C in the presence of 5% C02. The 80%-confluent cells are washed once with 15 ml of PBS (#14190-094, Invitrogen), treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C for 2 min, taken up in 5 ml of the DMEM described and counted in a cell counter. After dilution to 500.000 cells/ml, 35,000 cells are seeded in each well of a 96 well microtiter plate with a clear plastic base (#3610, Corning Costar). The plates are incubated in the cell culture incubator at 37°C and 5% C02 for 24 h.
Day 2 PPARalpha agonists to be tested are dissolved in DMSO in a concentration of 10 mM. This stock solution is diluted in DMEM (#41965-039, Invitrogen) which is mixed with 5% cs-FCS (#SH-30068.03, Hyclone), 2 mM L-glutamine (#25030-024, Invitrogen) and the previously described antibiotics (zeocin, 6418, penicillin and streptomycin).

Test substances are tested in 11 different concentrations in the range from 10 NM to 100 pM. More potent compounds are tested in concentration ranges from 1 pM to 10 pM or between 100 nM and 1 pM.
The medium of the PPARalpha reporter cell line seeded on day 1 is completely removed by aspiration, and the test substances diluted in medium are immediately added to the cells. The dilution and addition of the substances is carried out by a robot (Beckman FX). The final volume of the test substances diluted in medium is 100 pl per well of a 96 well microtiter plate. The DMSO concentration in the assay is less than 0.1 v/v in order to avoid cytotoxic effects of the solvent.
Each plate was charged with a standard PPARalpha agonist, which was likewise diluted in 11 different concentrations, in order to demonstrate the functioning of the assay in each individual plate. The assay plates are incubated in an incubator at 37°C and 5% C02 for 24 h.
Day 33 The PPARa~,~rla reporter cells treated with the test substances are removed from the incubator, and the medium is aspirated off. The cells are lyzed by pipetting 50 pl of Bright Glo reagent (from Promega) into each well of a 96 well microtiter plate. After incubation at room temperature in the dark for 10 minutes, the microtiter plates are measured in the luminometer (Trilux from Wallac). The measuring time for each well of a microtiter plate is 1 sec.
Evaluation The raw data from the luminometer are transferred into a Microsoft Excel file. Dose-effect plots and EC50 values of PPAR agonists are calculated using the XL.Fit program as specified by the manufacturer (IDBS).
The PPARalpha EC50 values for the compounds of Examples 1 to ... in this assay are in the range from 0.07nm to >10 NM.
The results for the activity of some compounds of the invention of the formula I are indicated in Table I below:
Table 1 Example No. EC50 PPARalpha [nM]

8a 1.8 9 4.3 16 4.0 22 0.07 24 0.3 38 8.5 64 0.4 74 0.4 It is evident from Table I that the compounds of the invention of the formula I activate the PPARalpha receptor and thus bring about for example in analogy to fibrates in clinical use a lowering of triglycerides in the body (see, for example, J.-Ch. Fruchard et al.: PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52, 2001;
S. Kersten et al.: Roles of PPARs in health and disease, NATURE, VOL
405, 25 MAY 2000, 421-4; I. Pineda et al.: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001, 245-254).

Determination of EC50 values of PPAR aaonists in the cellular PPARaamma assay Principle A transient transfection system is employed to determine the cellular PPARgamma activity of PPAR agonists. It is based on the use of a luciferase reporter plasmid (pGL3basic-SxGAL4-TK) and of a PPARgamma expression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids are transiently transfected into human embryonic kidney cells (HEK cells). There is then expression in these cells of the fusion protein GAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of the reporter plasmid. In the presence of a PPARgamma-active ligand, the activated fusion protein GAL4-humanPPARgammaLBD induces expression of the luciferase reporter gene, which can be detected in the form of a chemiluminescence signal after addition of a luciferase substrate. As a difference from the stably transfected PPARalpha reporter cell line, in the cellular PPARy assay the two components (luciferase reporter plasmid and PPARgamma expression plasmid) are transiently transfected into HEK
cells because stable and permanent expression of the PPARgamma fusion protein is cytotoxic.
Construction of the plasmids The luciferase reporter plasmid pGL3basic-SxGAL4-TK is based on the vector pGL3basic from Promega. The reporter plasmid is prepared by cloning five binding sites of the yeast transcription factor GAL4 (each binding site with the sequence 5'-CTCGGAGGACAGTACTCCG-3'), together with a 160 bp-long thymidine kinase promoter section (Genbank Accession # AF027128) 5'-upstream into pGL3basic. 3'-downstream of the thymidine kinase promoter is the complete luciferase gene from Photinus pyralis (Genbank Accession # M15077) which is already a constituent of the plasmid pGL3basic used. The cloning and sequencing of the reporter plasmid pGL3basic-5xGAL4-TK took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989).
The PPARgamma expression plasmid pcDNA3-GAL4-humanPPARyLBD
was prepared by first cloning the cDNA coding for amino acids 1-147 of the yeast transcription factor GAL4 (Genbank Accession # P04386) into the plasmid pcDNA3 (from Invitrogen) 3'-downstream of the cytomegalovirus promoter. Subsequently, the cDNA of the ligand-binding domain (LBD) of the human PPARy receptor (amino acids 1152-Y475; Accession #
g1480099) 3'-downstream of the GAL4 DNA binding domain. Cloning and sequencing of the PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD again took place in analogy to the description in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Besides the luciferase reporter plasmid pGL3basic-SxGAL4-TK and the PPAR~y expression plasmid pcDNA3-GAL4-humanPPARgammaLBD, also used for the cellular PPARgamma assay are the reference plasmid pRL-CMV (from Promega) and the plasmid pBluescript SK(+) from Stratagene. All four plasmids were prepared using a plasmid preparation kit from Qiagen, which ensured a plasmid quality with a minimal endotoxin content, before transfection into HEK cells.
Assay procedure The activity of PPARgamma agonists is determined in a 4-day assay which is described below. Before the transfection, HEK cells are cultivated in DMEM (# 41965-039, Invitrogen) which is mixed with the following additions: 10% FCS (#16000-044, Invitrogen), 1 % penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen).

Dav 1 Firstly, solution A, a transfection mixture which contains all four plasmids previously described in addition to DMEM, is prepared. The following amounts are used to make up 3 ml of solution A for each 96 well microtiter 5 plate for an assay: 2622 pl of antibiotic- and serum-free DMEM (# 41965-039, Invitrogen), 100 NI of reference plasmid pRL-CMV (1 ng/pl), 100 pl of luciferase reporter plasmid pGL3basic-5xGAL4-TK (10 ng/NI), 100 NI of PPAR~y expression plasmid pcDNA3-GAL4-humanPPAR~yLBD (100 ng/pl) and 78 pl of plasmid pBluescript SK(+) (500 ng/pl). Then 2 ml of solution B
10 are prepared by mixing 1.9 ml of DMEM (# 41965-039, Invitrogen) with 100 pl of PolyFect transfection reagent (from Qiagen) for each 96 well microtiter plate. Subsequently, 3 ml of solution A are mixed with 2 ml of solution B to give 5 ml of solution C, which is thoroughly mixed by multiple pipetting and incubated at room temperature for 10 min.
15 80%-confluent HEK cells from a cell culture bottle with a capacity of 175 cm2 are washed once with 15 ml of PBS (#14190-094, Invitrogen) and treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37°C
for 2 min. The cells are then taken up in 15 ml of DMEM (# 41965-039, Invitrogen) which is mixed with 10% FCS (# 16000-044, Invitrogen), 1 20 penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). After the cell suspension has been counted in a cell counter, the suspension is diluted to 250,000 cells/ml. 15 ml of this cell suspension are mixed with 5 ml of solution C for one microtiter plate. 200 NI of the suspension are seeded in each well of a 96 25 well microtiter plate with a clear plastic base (#3610, Corning Costar).
The plates are incubated in a cell culture incubator at 37°C and 5% C02 for h.
Day 2 30 PPAR agonists to be tested are dissolved in DMSO in a concentration of 10 mM. This stock solution is diluted in DMEM (# 41965-039, Invitrogen) which is mixed with 2% Ultroser (#12039-012, Biosepra), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Test substances are tested in a total of 11 different concentrations in the range from 10 pM to 100 pM. More potent compounds are tested in concentration ranges from 1 NM to 10 pM.
The medium of the HEK cells transfected and seeded on day 1 is completely removed by aspiration, and the test substances diluted in medium are immediately added to the cells. The dilution and addition of the substances is carried out by a robot (Beckman FX). The final volume of the test substances diluted in medium is 100 pl per well of a 96 well microtiter plate. Each plate is charged with a standard PPAR~y agonist, which is likewise diluted in 11 different concentrations, in order to demonstrate the functioning of the assay in each individual plate. The assay plates are incubated in an incubator at 37°C and 5% C02.
D~a-4 After removal of the medium by aspiration, 50 pl of Dual-GIoT"" reagent (Dual-GIoT"" Luciferase Assay System; Promega) are added to each well in accordance with the manufacturer's instructions in order to lyze the cells and provide the substrate for the firefly luciferase (Photinus pyralis) formed in the cells. After incubation at room temperature in the dark for 10 minutes, the firefly luciferase-mediated chemiluminescence is measured in a measuring instrument (measuring time/well 1 sec; Trilux from Wallac).
Then 50 pl of the Dual-GIoT"" Stop & Glo reagent (Dual-GIoT"" Luciferase Assay System; Promega) is added to each well in order to stop the activity of the firefly luciferase and provide the substrate for the Renilla luciferase expressed by the reference plasmid pRL-CMV. After incubation at room temperature in the dark for a further 10 minutes, a chemiluminescence mediated by the Renilla luciferase is again measured for 1 sec/well in the measuring instrument.
Evaluation The crude data from the luminometer are transferred into a Microsoft Excel file. The firefly/Renilla luciferase activity ratio is determined for each measurement derived from one well of the microtiter plate. The dose-effect plots and EC50 values of PPAR agonists are calculated from the ratios by the XL.Fit program as specified by the manufacturer (IDBS).
PPARgamma EC50 values in the range from 0.08nM to >10 NM were measured for the PPAR agonists described in this application.

I I I I I

N

Z

M
s Z

c U U a U

co = Z = Z Z

c o 0 0 0 0 O O O O O

= N N N N N

m >- U U U U U

E

~

_ O O O O O

% II N

O ap = Z Z Z Z

>C U U U U U
c O

c ~ ~
~

Z I Z I Z

_ ~ U U U U U
c ~- V -2~'' II M M M M M

U U U U

U

Q >, ._ _o = M
~

u~ ~ Z Z = Z Z
- ~

X c c~

O ~ M

O /Z ~ 2 cn ~' ~ U U U U

~ Q ~ Q E

~

U

II

a v LIJ r- N M

I I I I I I I I I I I I I I I I

M M M M M M M M M M M M M M M
Z = Z Z ~ = = Z = _ = Z = = Z Z
U U U U U U U U U U U U U U U

c a~

a M M ~ M M M M M M M M M M M
t0 Z Z = _ ~ Z = = Z Z Z I = = 2 =
U U v U U U U U U U U U U U

c o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O O O O O O O O O O O O O O O O

N N N N N N N N N N N N N N N N
Z Z Z = Z Z Z = _ _ = Z Z

>- U U U U U U U U U U U U U U U U
M

O O O O O O O O O O O O O O O O
N N N N N N N N N N N N N N N N
X Z = _ _ = Z Z = Z Z Z = = Z
U U U U U U U U U U U U U U U U

I I Z I Z Z I Z I Z I Z I Z
U U U U U U U U O U U U U cn U U

M M M M M M M M M M M M M M M
M = _ = Z Z = = Z Z Z L Z = = I =
U U U U U U U U U U a. U U U U U

M

Z

Z = Z = _ = Z 2 Z E O Z Z 2 = Z =

M M M LL Z
~ 2 = M
U U ~ U U M
U U U U U ~ Z O
Q U U O U U O U
E E ~ a Q ~ ;
E E a ~ Q a Q E ~a O r- N M Wit' In CflI~ CO O O
W CO f~ COCO D7 ~- r- r- r- r- c- c- r- ~ r- N

I I I I I I I I I I I I I I I I I

Z
Z Z N U V I s ~ M ~ = = M
I ~ V Z U V U I
U U U c ~ U a v c c U ~ c >, M M ~ M
= = Z Z = Z Z = U Z = = = Z
U U v U

c o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 N

N N N N N N N N N N N N N N N N N
Z Z = = 2 Z = = Z = Z Z Z Z

U U U U U U U U U U U U U U U U U

M

N N N N N N N N N N N N N N N N N

Z Z Z Z

X U U U U U U U U U U U U U U U U U

Z I I Z I I I Z Z I I I Z Z I I Z
U U U U U U U U U U U U U U U U U

M M M M M M M M M M M M M M M M M
M 2 Z Z = Z = _ _ _ = Z = Z Z
U U U U U U U U U U U U U U U U U

N

Z = 2 = = Z = Z = Z = Z Z Z Z

M M M M M M M M M M M M M M M M M
2 2 2 Z = Z = _ = Z = Z Z Z
U U U U U U U U U U U U U U U U U
E Q ~ Q ~ Q ~ Q a a ~ Q ~ a Q n. a L1J N N N N N N N N N ~M M M M M M M M

O
L
~' N

I O
M N ~ O L
c~ O O M N
N N M N O N
O O = O O Z

I I I I I U U cA c~ c!~U Z U U U c~
U

Z Z I I I Z I Z I

r- f~ M M M M M M M M M
= ~''~ U U U U U U U U U
U U =
c U U c ~ c~ c~ c~ c~ c~ c!~ cO c~

M

ca =

Z U Z = = Z = Z Z = = Z = _ = Z

c o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 N N N N O O O O O O O O O O O
N O O O O

(n fn (n cn Z Z Z Z Z Z Z Z Z Z Z Z

N N N N N N N N N N N N N N N N
e- Z = _ _ = Z = Z 2 Z = _ _ = Z =

o ~ U U U U U U U U U U U U U U U U
M

O O O O O O O O O O O O O O O O
N N N N N N N N N N N N N N N N
)C Z Z Z Z = _ _ _ = Z
U U U U U U U U U U U U U U U U

Z I Z I I I I Z I I Z I Z I I Z
U U U U U U U U U U U U U U U U

M M M M M M M M M M M M M M M M
M = _ = Z = _ _ = Z = Z Z = Z
U U U U U U U U U U U U U U U U

N

Z = = Z = Z = Z Z = Z 2 Z = 2 =

M M M M M M M M M M M M M M M M
2 Z Z = Z = Z Z = Z = = Z Z
U U U U U U U U U U U U U U U U
n Q a n.~ a a ~ Q a ~ ~ a a Q

00 O O r- N M '~tIn Cfl f~ 00 O O c- N M
LJJ M M '~t~t ~ ~ ~ ~' ~ ~ ~ '~i'lf~lf~lf~~

CO

U

N

U I I I I I I I I I I I I I I I

M = M M M M M M M M M M M =
1~ Z Z N Z Z = = Z 2 Z = Z 2 Z Z N
U U U U U U U U U U U U U U

M M M M M M M M M M M M

to = Z Z = Z Z = Z = Z Z =

U U U U U U U U U U U U I Z Z

c o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O N N N
Z O O O O O O O O O O O O U U U

N N

U U

O O

N N N N N N N N N N N N N N N N
2 = = Z = _ = Z Z = Z = Z = Z Z

U U U U U U U U U U U U U U U U

M

N N N N N N N N N N N N

Z 2 2 = Z Z Z Z Z

U U U U U U U U U U U U
O O O O O O O O O O O O O O O O

Z = = Z Z Z = Z = _ = Z Z
U U U U U U U U U U U U U U U U

U U U U U U U U U U U U U U U U

u7 M M M M M M M N = ~, N N M = = Z
= _ = Z Z = N
U U U U U U U U U U U U .~ U U U
U

N

Z Z Z = Z Z Z Z = 2 = = 2 =

s M M M
M M M ~ Q ~ M M M Q M M = Z Z
Z Z Z = ~ U = U ~ Z ti U U U
U U U d c Q _ U ~ c U U O O O
Q ~ a N E ~Q ~ ~~~..N ~ E E E E

~ COf~ 00 O O r- N M ~ lf~C~ f~ 00 O
W LO lf~~ 87 ~ ~ CO O CO CflO CO C~ O CD O

_-~O
O
.__ I I I I I I I I I

I~ f~ N O f~ M
c U U U
~ ~ d ~ c c c Z = = I = c U U Z U
U U v v c o 0 0 0 0 0 0 0 0 0 0 N N N N N N N N N O O
N Z = Z Z = Z =
U U U U U U U U U Z Z

N N N N N N N N N
>- 2 = _ = Z = Z Z Z N N
M U U U U U U U U U U U

N N N N N N N N N N N
)C Z Z Z = _ _ = Z Z
U U U U U U U U U U U

Z I Z I Z Z I I I I I
U U U U U U U U U U U

M M M M M M M M M M M
M = = Z 2 Z 2 =
U U U U U U U U U U U

N
2' 2 Z = Z = Z = = 2 Z =

M M
M M M = M M M M V U
E U ~ V V U V
E

n. Q a E ~ E E

O r- N M '~'In CO f~ 00 O O
M

O
O , ~ ~ _ O
~O , ~ \ ~ , b N
Q I
o U
~

ca ~, t U ~ a Z Z

O O O O

O O O O

U U U U

M

O O O O
X U U U U

U U U U

M M M M
U U U U

N
I Z Z Z

M M M M
E E E
E

tillo O
.__ _ Z \

I

t0 Z

C O

O
N
Z

I
o e- N
Y~ U

O
N

U

c U E

U
M
Z o U
....

c 'o I n.

a~
c~
U_ M
.C
U a~

c a~

W ~ H

Processes The compounds of the formula I according to the invention can be obtained according to the reaction schemes below:
Process A:
1. NaOMe 2. protection of LiAIH4 the OH group SG~ ~ ---t SG~O~OH
" O COZMe 1. LDA, Rfi-i NaOH 0 2. optionally LDA, R7-I
3. deprotection O SG~O O~O~ --r Br~ ~ A-4 O
R3 O O~O
O NaH, DMF
HO~O O ~N R6 R7 ~0~
Rfi R7 R3, ,..._I
A- ~5 W \
O /N ~()~ A'7 W \

~~ )o O

~0 OOH

TFA O i N
yi \
A-S
)o The compound A-1 is reacted in an alcohol R-80H. The resulting product is protected on the secondary hydroxyl group (for example by stirring with TBDPSCI and imidazole in DMF at room tempearture), giving the compound A-2, where R8 has the meaning described above. A-2 is, in an ethereal solvent and using lithium aluminum hydride, reduced to give compound A-3. Compound A-3 is reacted in a two-phase system of toluene and 50% strength sodium hydroxide solution at 10°C with tert-butyl bromoacetate and tetrabutylammonium hydrogensulfate to give compound A-4.

Compound A-4 is, in tetrahydrofuran, reacted with lithium diisopropylamide and an alkyl iodide of the formula R6-I, where R6 has the meaning described above. In some examples, the compound obtained in this manner is, in tetrahydrofuran, reacted with lithium diisopropylamide and a further alkyl iodide of the formula R7-I, where R7 has the meaning described above. The protective group is removed, giving the compound of the formula A-5.
Compound A-5 is, in methyl tert-butyl ether or dimethylformamide, converted into compound A-7 using sodium hydride and the compound A-6 (see process A) where R1, R2, R3 and W have the meanings described above.
The product A-7 is stirred in trifluoroacetic acid or HCI/dioxane for a number of hours. This yields the compound of the formula A-8.
According to this process, it is possible to synthesize examples 31 to 51.

Process B:

~~\
R1" ~ N
( )°

W C02Me SG~O C02Me BiBr3, HSiEt3 A-2 R 1 ( B-2 LiAIH4 OH Iz, PPh3 O ~ I

R1'~( )°Kl B-4 KOtBu, DMF R3 Rg KOH
S MeOH R3 O S R6 N O
%~R~ ~ Et0 O ~N HO O
O OEt ~ W \
B-5 W ~R2 B
R1~ R1 TFA TFA
HzOz HZOz O O,, .O

~O ~O
~R~ R7 O ~N HO O O ~N HO O
W \
R2 B-8 ~( ) R2 B-9 )° R1 Compound A-2 where SG = tert-butyldimethylsilyl is, in acetonitrile and at room temperature, converted into compound B-2 using bismuth tribromide, triethylsilane and a compound of the formula B-1 in which R1, R2, W and R3 have the meanings described above.

Using lithium aluminum hydride in diethyl ether or THF, the compound B-2 is reduced to give compound B-3. Compound B-3 is reacted at room temperature with triphenylphosphine and iodine in toluene to give compound B-4.
Using the compound of the formula B-5 where R6 and R7 have the meanings described above, the compound B-4 is converted into compound B-6. The ester is hydrolyzed by stirring compound B-6 in a mixture of methanol and concentrated aqueous potassium hydroxide solution or lithium hydroxide in THF/methanol/water for a number of hours.
This gives the compound B-7.
In some examples, the compound B-7 is oxidized at room temperature using one equivalent of hydrogen peroxide in trifluoroacetic acid to give the compound of the formula B-8 in which R1, R2, R3, R6, W and R7 have the meanings described above.
In some examples, the compound B-7 is oxidized at room temperature with three equivalents of hydrogen peroxide in trifluoroacetic acid to give the compound of the formula B-9 in which R1, R2, R3, R6, W and R7 have the meanings described above.
According to this process, it is possible to synthesize examples 52 to 71.

Process C:
R3 (COCI)2 R3 DMSO
N Et3 O
W ~N O OH CH2CIz W ~N O i O
R1~ ~ R1 R2 ( )° B-3 R2 ( )° C-1 NaBH(OAc)3 CHZCIZ R3 R3\ /~
~O O TFA ~O O
R6 NHZ O ~-1N N~O ~ O' i 1N N~OH
R7~
O O ~ VV \ ~ ~/~/ \

R1~( )° C-3 ~( )° C-4 Rg-CI

~O O TFA ~O O
O ~N Rg~N\~'~O O ~N Rg~N~OH
W \ ~ W \
~( ) R2 The compound B-3 (see process B) is oxidized at -78°C with oxalyl 5 chloride, triethylamine and dimethyl sulfoxide in dichloromethane to give aldehyde C-1. This compound is, using sodium triacetoxyborohydride and the compound of the formula C-2 where R6 and R7 have the meanings described above, converted into compound C-3.
Compound C-3 is converted into compound C-4 by stirring in trifluoroacetic 10 acid for a number of hours.
In some examples, the compound C-3 is reacted with acyl chlorides, sulfonyl chlorides or chloroformic esters of the formula R9-CI where R9 has the meaning described above in dichloromethane in the presence of pyridine to give the compound C-5.

By stirring in trifluoroacetic acid for a number of hours, the compound C-5 is converted into compound C-6.
According to this process, it is possible to synthesize examples 72 to 78.
Process D:
1. protection 2. LiAIH4 NaOH
COZMe ' OH
OH O O ~SG O
D-1 ~SG O

1. deprotection 1. LDA, R6-I
2. TBDMSCI 2. LDA, R7-I
O O ~ O R6 O

O ~ O

Et3SiH
BiBr3 R3~o _N

( )° TFA
R1 ~
R7 ~ p R7 KOtBu O
PhCI R6 R3 p R6 R3 O=
R3~~ ~~ N O ~ V H
~N
R2 s ( )° R1 R2 R1 R2 D_6 D_7 The compound D-1 is protected on the hydroxyl group with a suitable protective group, for example with the methoxymethyl protective group. The carboxyl group is then converted with lithium aluminum hydride in diethyl ether into compound D-2. This compound is reacted with tert-butyl bromoacetate and tetrabutylammonium hydrogensulfate in a two-phase system of toluene/50% strength aqueous sodium hydroxide solution to give compound D-3.
Compound D-3 is deprotected (using, for example, concentrated hydrochloric acid in tetrahydrofuran in the case of the methoxymethyl protective group) and then converted with tert-butyldimethylsilyl chloride and imidazole in dimethylformamide into compound D-4.
Compound D-4 is deprotonated at 0°C using lithium diisopropylamide in tetrahydrofuran and reacted with an alkyl iodide of the formula R6-I, where R6 has the meaning described above. The resulting compound is then deprotonated at 0°C using lithium diisopropylamide in tetrahydrofuran and reacted with an alkyl iodide of the formula R7-I, where R7 has the meaning described above, to give the compound D-5.
Compound D-5 is reacted with bismuth tribromide, triethylsilane and the compound B-1 (see process B) in acetonitrile at room temperature or - after removal of the silyl protective group using TBAF in THF - with potassium tert-butoxide and the compound A-6 (see process A) to give the compound D-6.
By stirring in trifluoroacetic acid, the compound D-6 is converted into compound D-7.
Using this process, it is possible to synthesize examples 79 and 80.

Process E:

iPrOH NaH
O
O O ~ R3 I O
J ~ ~ _N
E-2 O ~ N W-~ R2 R2 R1~( )o ( )o O O~

Os04 a Na104 O ~ O v ~ R6 P(O)(OEt)2 O ~ O
~N ~ 'N R6 /

W- W-R2 ~ R2 ~ O O
R1 ( )o E-4 R1 ( )a H2/Pd O~O O \ O
'N R6 _LiOH~ _N R6 R1 ( )o R1 ( )o E_7 E_8 Using diisobutylaluminum hydride and isopropanol in diethyl ether, the compound E-1 is reduced to give compound E-2.This is reacted with the compound of the formula A-6 and sodium hydride in dimethylformamide to give compound E-3.
Using osmium tetroxide and sodium periodate in diethyl ether, compound E-3 is converted into aldehyde E-4. In a Horner-Emmons-Wadsworth reaction, using a triethyl phosphonoacetate of the formula E-5 in which R6 is as defined above, this compound is converted into compound E-6.
Using hydrogen, the compound E-6 is hydrogenated over palladium/carbon to give compound E-7, and the ester is then hydrolyzed using lithium hydroxide to give the acid E-8.

According to this process, it is possible to synthesize examples 81 to 84.
Process F:
1. TBDPSCI
2. Os04 / Na104 COZtBu O \ SI-O
3. Ph3P~C02tBu E-2 ~ ~ F-1 4. H2/Pd 1. LDA, R6-I ~ ~ 1. TBAF R3 2. LDA, R7-I S~~O 2. NaH O~O

R7 ~ I W- R7 C02tBu O ,N ~ R2 O O

F-2 ~ ~ R2 F-3 °

TFA O

W-~c R2 O O
R1~~ )°

Using tert-butyldiphenylsilyl chloride and imidazole as base in dimethylformamide, the compound E-2 is reacted, worked up and then reacted with osmium tetroxide and sodium periodate in diethyl ether. The resulting compound is reacted with tert-butyl triphenylphosphoranylidene-acetate and n-butyllithium in a Wittig reaction and then hydrogenated with hydrogen over palladium/carbon to give compound F-1.
At 0°C, the compound F-1 is deprotonated using lithium diisopropylamide in tetrahydrofuran and reacted with an alkyl iodide of the formula R6-I, where R6 is as defined above. The resulting compound is then deprotonated using lithium diisopropylamide in tetrahydrofuran at 0°C and reacted with an alkyl iodide of the formula R7-I where R7 is as defined above to give the compound F-2.

For deprotection, the compound F-2 is reacted with tetrabutylammonium fluoride in tetrahydrofuran. The resulting alcohol is then reacted with sodium hydride and the compound A-6 in dimethylformamide to give compound F-3.
5 The tert-butyl ester is cleaved by stirring compound F-3 for a number of hours in trifluoroacetic acid, giving the compound F-4.
Examples 85 to 92 were synthesized according to this process.
Process G:

Os04 N~O\R8 Na104 O~O O O~O
N O~ G-~ ' N
N
W- W- R7~ ' R2 ~( R2 R6~O~R8 R1 ( )o E-4 R1 '-( )o I IO

or O
R12 O~O O
~N LiOH' ~N R12~N
W- R7~ 'O
R2 R2 R6~
R1 ( )o R1 '-( )o IIO

Using an amino acid ester of the formula G-1 in which R6, R7 and R8 are as defined above in the presence of a borohydride reagent (for example sodium triacetoxyborohydride), the compound E-4 is converted into compound G-2.
Using a chloride R12-CI in which R12 is as defined above, compound G-2 is converted into compound G-3 (R12 may also be isocyanate or isothiocyanate). Compound G-3 is then hydrolyzed with LiOH to give compound G-4.

Process H:
This process is used for the synthesis of building blocks A-6 and B-2 in which R1, R2, W and R3 are as defined above.
O O NaN02 O O HZ/Pd O O
R3~0~ R3~0~ ' R3~0~
O~N N HCI

R~\WYCOCI O O R3 O \ O
( )o W ~ POCI3 W~ ~N LiAIH4 R2 R1 ~N C02Et R1 ~ O
H-4 ~( )o ~( )o O ~ 12, PPh3, ImH
R1 W~N O ~ R1 W~N I
( )o ~( )o (COCI)2, DMSO, NEt3, CH2CI2 O
W~N ~O

( )o s_2 Using sodium nitrite and hydrochloric acid, the ester H-1 in which R3 is as defined above is converted into oxime H-2 which is reduced by hydrogenation with hydrogen over palladium/carbon to give amine H-3.
Using acid chlorides of the formula H-4 in which R1, W and R2 are as defined above and base (for example triethylamine), the compound H-3 is converted into compound H-5.
By heating in phosphoryl chloride, the compound H-5 is converted into compound H-6.

The ester H-6 is reduced with lithium aluminum hydride in diethyl ether to give alcohol H-7. This is converted into the iodide A-6 using iodine, imidazole (ImH) and triphenylphosphine.
Alternatively, the compound H-7 is oxidized using oxalyl chloride, dimethyl sulfoxide and triethylamine in dichloromethane at -78°C to give aldehyde B-1.
Process J:
This process is used for synthesizing the building block A-6 in which R1, R2, W and R3 are as defined above.

W CHO HCI 0~ POC13 O
~R3 + R1 ~ W ~
,N ~~ ) ~R2 R1 \ N - ~ ~ N CI
O ° ~ ~- p R 1-jt-C )°~R2 C )° R2 Nal aceton ' \e W ~N I
R1~ , R2 In ethanol and using hydrogen chloride, the compound J-1 is reacted with the aldehyde J-2 in which R1, R2, W and R3 are as defined above, to give the compound J-3.
The compound J-3 is heated to the boil in phosphoryl chloride, giving the compound J-4. This is heated to the boil with sodium iodide in acetone.
This gives the compound A-6.
The abbreviations used denote:
Ac Acetyl Bn Benzyl iBu Isobutyl tBu tert-Butyl BuLi n-Butyllithium Bz Benzoyl Cy Cyclohexyl TLC Thin-layer chromatography DCI Direct chemical ionization (in MS) DCM Dichloromethane DMAP 4-N,N-Dimethylaminopyridine DMF N, N-Dimethylformamide DMSO Dimethyl sulfoxide EA Ethyl acetate EDC N'-(3-Dimethylaminopropyl)-N-ethylcarbodiimide x HCI

EI Electron impact ionization (in MS) eq Equivalent ESI Electrospray ionization (in MS) Et Ethyl sat. Saturated h Hour HATU O-(7-Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate HOBt 1-Hydroxy-1 H-benzotriazole x H20 HPLC High pressure, high performance liquid chromatography LC-MS Liquid chromatography-coupled mass spectroscopy Me Methyl MS Mass spectroscopy MsCI Methanesulfonyl chloride NMR Nuclear magnetic resonance spectroscopy Pd/C Palladium on carbon iPr Isopropyl nPr n-Propyl Rf Retention time (in TLC) RT Room temperature TBAF Tetrabutylammonium fluoride TBAI Tetrabutylammonium iodide TBDPSCI tent-Butyldiphenylsilyl chloride TBDMSCI tert-Butyldimethylsilyl chloride THF Tetrahydrofuran Tr Trityl It is possible to prepare other compounds by the processes mentioned above.

Building block synthesis according to process H:

NaN02 H2lPd I O~ ~ O
'N N HCI
O
/coci i' O ~ POCI3 ~ ~ LiAlH4 --~. -.~ w ~ ~N COZEt I ~ ~N O
12. PPh3. ImH O
w ~..
'N O I ~ \N I
/ /
5 Ethyl2-hydroxyimino-4-methyl-3-oxopentanoate NaN02 O
,N
O
42.4 g of ethyl 4-methyl-3-oxopentanoate are dissolved in 100 ml of glacial 10 acetic acid, and 21 g of sodium nitrite, dissolved in 100 ml of water, are added at 5°C. Over a period of one hour, the mixture is allowed to warm to room temperature, 100 ml of water are added and the mixture is stirred at room temperature for another hour. The mixture is extracted three times with in each case 150 ml of methyl tert-butyl ether, 200 ml of water are 15 added to the combined organic phases and the mixture is neutralized by addition of solid NaHC03. The organic phase is removed, washed with saturated NaCI solution and dried over MgS04, and the solvent is removed under reduced pressure. This gives 46 g of ethyl 2-hydroxyimino-4-methyl-3-oxopentanoate as an oil. C8H13N04 (187.20), MS (ESI) = 188 (M+H+).

Ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride o~ ---~. o E
HCI
10 g of HCI are introduced into 200 ml of ethanol. 46 g of ethyl 2-hydroxy-imino-4-methyl-3-oxopentanoate are dissolved in this mixture, 5 g of Pd (10% on carbon) are added and the mixture is stirred under atmosphere of hydrogen (5 bar) for 8 hours. The reaction mixture is filtered through Celite and the solvent is removed under reduced pressure. This gives 45 g of ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride as a white solid.
C8H15N03*HCI (209.5), MS(ESI) = 188 (M+H+).
Ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate cool o 0 o~

HCI N O
10 g of ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride and 7.4 g of 4-methylbenzoyl chloride are dissolved in 250 ml of dichloromethane, and 13.3 ml of triethylamine are slowly added dropwise at 0°C. The mixture is stirred at room temperature for one hour and then washed with water, the organic phase is separated off and dried over MgS04 and the solvent is then removed under reduced pressure. This gives 13 g of ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate as an oil.
C16H21 N04 (291.35), MS(ESI) = 292 (M+H+).

Ethyl 5-isopropyl-2-p-tolyloxazole-4-carboxylate o \ o N O '' \ \N
O
/
13 g of ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate in 80 ml of phosphorus oxychloride are heated to the boil under reflux for 2 h. The phosphorus oxychloride is removed under reduced pressure and the resulting residue is dissolved in 200 ml of dichloromethane, washed three times with saturated NaHC03 solution and dried over MgS04, and the solvent is then removed under reduced pressure. This gives 11 g of ethyl 5-isopropyl-2-p-tolyloxazole-4-carboxylate as a brownish sold. C16H19N03 (273.33), MS(ESI) = 292 (M+H+), Rf(n-heptane:ethyl acetate) = 2:1) = 0.43.
(5-Isopropyl-2-p-tolyloxazol-4-yl)methanol \ ,N O -~ I \ . ,N O
11 g of ethyl 5-isopropyl-2-p-tolyloxazole-4-carboxylate are dissolved in 100 ml of tetrahydrofuran, and 40 ml of a 1 molar solution of lithium aluminum hydride in tetrahydrofuran are added at 0°C. After 30 min, 1 N
of HCI are added to the reaction mixture, and the mixture is extracted five times with ethyl acetate. The combined organic phases are dried over MgS04 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 6:1 => 1:1. This gives 4.3 g of (5-isopropyl-2-p-tolyloxazol-4-yl)methanol as a light-yellow solid.
C14H17N02 (231.30), MS(ESI) = 232 (M+H+), Rf(n-heptane:ethyl acetate) = 1:1 ) = 0.17.

4-lodomethyl-5-isopropyl-2-p-tolyloxazole 500 mg of (5-isopropyl-2-p-tolyloxazol-4-yl)methanol, together with 690 mg of triphenylphosphine and 600 mg of imidazole, are dissolved in 20 m1 of toluene. 715 mg of iodine are added, and the mixture is stirred at room temperature for 1 hour. 10 ml of saturated sodium carbonate solution and 500 mg of iodine are then added. After 10 minutes, the organic phase is separated off, washed twice with saturated Na2S2O3 solution and dried over MgS04, and the solvents are then removed under reduced pressure.
The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 400 mg of 4-iodomethyl-5-isopropyl-2-p-tolyl-oxazole as a white solid. C14H161N0 (341.19), MS(ESI): 342 (M+H+), Rf(n-heptane:ethyl acetate = 1:1 ) = 0.75.
Analogously to the building block synthesis according to process K, ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride and 3-methoxybenzoyl chloride gave 4-iodomethyl-2-(3-methoxyphenyl)-5-isopropyloxazole.
O
C14H161N02 (357.19), MS(ESI): 358 (M+H+), Rf(n-heptane:ethyl acetate =
1:1) = 0.60.
Analogously to the building block synthesis of 4-iodomethyl-5-isopropyl-2-p-tolyloxazole, ethyl 4,4,4-trifluoro-3-oxobutyrate and 3-methoxybenzoyl chloride gave 4-iodomethyl-2-(3-methoxyphenyl)-5-trifluoromethyloxazole.

,O
C12H9F31N02 (383.11), MS(ESI): 384 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-isopropyl-2-p-tolyloxazole, ethyl 4,4,4-trifluoro-3-oxobutyrate and 3-trifluoromethyl-benzoyl chloride gave 4-iodomethyl-2-(3-trifluoromethylphenyl)-5-trifluoro-methyloxazole.
F F
C12H6F61N0 (421.08), MS(ESI): 422 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-isopropyl-2-p-tolyloxazole, ethyl 4,4,4-trifluoro-3-oxobutyrate and 4-methylbenzoyl chloride gave 4-iodomethyl-5-trifluoromethyl-2-p-tolyloxazole.

C12H9F31N0 (367.11), MS(ESI): 368 (M+H+) Building block synthesis according to process J:

+ ~ cHO Hcl ° \
_.~.. \ ~N+
.N ~ / ~ /
D
10_ ppC~3 O \ Nal~ tone O \
~N
~N CI ~ I
4-Methyl-5-phenyl-2-p-tolyloxazole 3-oxide / \

cwo wc~
+ ( ~ _~ ~ wN.
O ! o-12.5 g of 1-phenyl-1,2-propanedione-2-oxime and 10 ml of p-tolualdehyde are added to 50 ml of glacial acetic acid, and HCI gas is introduced for 30 minutes, with ice-cooling. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether and filtered off with suction, and the precipitate is washed with methyl tert-butyl ether. The precipitate is suspended in water and the pH is made alkaline using ammonia. The mixture is extracted three times with in each case 200 ml of dichloromethane, the combined organic phases are dried over MgS04 and the solvent is then removed under reduced pressure. This gives 6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide as a white solid. C17H15N02 (265.31), MS(ESI) = 266 (M+H+).
4-Chloromethyl-5-phenyl-2-p-tolyloxazole / \ / \
O \ POC13 --'---~ O
O ~ ~ \N CI
6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide are dissolved in 50 ml of chloroform, 2.4 ml of phosphorus oxychloride are added and the mixture is, under reflux, heated at the boil for 30 minutes. The reaction mixture is cooled to 0°C, the pH is made slightly alkaline using ammonia and the mixture is extracted three times with in each case 100 ml of ethyl acetate.
The combined organic phases are washed with water and dried over MgS04, and the solvent then removed under reduced pressure. This gives 5.4 g of 4-chloromethyl-5-phenyl-2-p-tolyloxazole as a yellow solid.
C17H14CIN0 (283.76), MS(ESI) = 284 (M+H+), Rf(n-heptane:ethyl acetate) = 7:1 ) = 0.41 4-lodomethyl-5-phenyl-2-p-tolyloxazole Together with 3 g of sodium iodide, 1.8 g of 4-chloromethyl-5-phenyl-2-p-tolyloxazole are, in 150 ml of acetone, heated at the boil under reflux for 2 hours. After cooling of the reaction mixture, 300 ml of methyl tent-butyl ether are added, the mixture is washed three times with saturated Na2S203 solution and dried over MgS04 and the solvents are then removed under reduced pressure. This gives 2.7 g of 4-iodomethyl-5-phenyl-2-p-tolyloxazole as a light-yellow solid.
C17H141N0 (375.21), MS(ESI): 376 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-phenyl-1,2-propanedione-2-oxime and m-anisaldehyde gave 4-iodomethyl-2-(3-methoxyphenyl)-5-phenyloxazole.
C17H141N02 (391.21), MS(ESI): 392 (M+H+) Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-ethyl-1,2-propanedione-2-oxime and m-anisaldehyde gave 4-iodomethyl-5-ethyl-2-(3-methoxyphenyl)oxazole.
C13H141N02 (343.17), MS(ESI): 344 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-ethyl-1,2-propanedione-2-oxime and p-tolualdehyde gave 4-iodomethyl-5-ethyl-2-p-tolylazole.

C13H141N0 (327.17), MS(ESI): 328 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-cyclohexyl-1,2-propanedione-2-oxime and m-anis-aldehyde gave 4-iodomethyl-5-cyclohexyl-2-(3-methoxyphenyl)oxazole.
C17H201N02 (397.26), MS(ESI): 398 (M+H+) Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-cyclohexyl-1,2-propanedione-2-oxime and p-tolu-aldehyde gave 4-iodomethyl-5-cyclohexyl-2-p-tolyloxazole.
C17H201N0 (381.26), MS(ESI): 382 (M+H+) Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and p-tolualdehyde gave 4-iodomethyl-5-methyl-2-p-tolyloxazole.

C12H121N0 (313.14), MS(ESI): 314 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and m-anisaldehyde gave 4-iodo-methyl-2-(3-methoxyphenyl)-5-methyloxazole.
O
w 'N I
~O
C12H121N02 (329.14), MS(ESI): 330 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3-bromobenzaldehyde gave 2-(3-bromophenyl)-4-iodomethyl-5-methyloxazole.
O
w 'N I
Br C11H9BrIN0 (377.01/379.01), MS(ESI): 378/380 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-methyl-2-(3-trifluoromethylphenyl)oxazole.

O
w 'N I
F F
F
C12H9F31N0 (367.11), MS(ESI): 368 (M+H+).
5 Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-fluorobenzaldehyde gave 2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole.
O
'N I
F
CH11H9FIN0 (317.10), MS(ESI): 318 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-methoxybenzaldehyde gave 4-iodomethyl-2-(4-methoxyphenyl)-5-methyloxazole.
O
'N I
O
C12H121N02 (329.14), MS(ESI): 330 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-methyl-2-(4-trifluoromethylphenyl)oxazole.

O
\ 'N I
FF
F
C12H9F31N0 (367.11), MS(ESI): 368 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and m-tolualdehyde gave 4-iodomethyl-5-methyl-2-m-tolyloxazole.
\ N
C12H121N0 (313.14), MS(ESI): 314 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and benzaldehyde gave 4-chloro-methyl-5-methyl-2-phenyloxazole.
~I
C 11 H 1 OCINO (299.15), MS(ESI): 300 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and p-phenylbenzaldehyde gave 4-iodomethyl-5-methyl-2-p-biphenyloxazole.
O
\ N I
\ /
/
C18H131N0 (375.21), MS(ESI):376 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3-trifluoromethoxybenzaldehyde gave 4-iodomethyl-5-methyl-2-(3-trifluoromethoxyphenyl)oxazole.
F\ /O
-~F
F
C12H9F31N02 (383.11), MS(ESI): 384 (M+H+) Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 5-methylfuran-2-carbaldehyde gave 4-iodomethyl-5-methyl-2-(5-methylfuran-2-yl)oxazole.
O
O wN
I
C10H101N02 (303.11), MS(ESI): 304 (M+H+) Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and thiophene-2-carbaldehyde gave 4-iodomethyl-5-methyl-2-thiophen-2-yloxazole.
O
~N

C9H81NOS (305.14), MS(ESI): 306 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl 2-p-tolyloxazole, diacetylmonoxime and 4-isopropylbenzaldehyde gave 4-iodomethyl-2-(4-isopropylphenyl)-5-methyloxazole.
C14H161N0 (341.19), MS(ESI): 342 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and 3-trifluoromethyl-benzaldehyde gave 5-ethyl-4-iodomethyl-2-(3-trifluoromethylphenyl)-oxazole.
N I
F F
F
C13H11F31N0 (381.14), MS(ESI):382 (M+H+).

Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and naphthalene-2-carbaldehyde gave 5-ethyl-4-iodomethyl-2-naphthalen-2-yloxazole.
O
N I
/
C16H141N0 (363.20), MS(ESI):364 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, butane-2,3-dione-2-oxime and naphthalene-2-carbaldehyde gave 5-methyl-4-iodomethyl-2-naphthalen-2-yloxazole.
O
N I
/
C15H121N0 (349.20), MS(ESI):350 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and 4-isopropylbenzaldehyde gave 5-ethyl-4-iodomethyl-2-(4-isopropylphenyl)oxazole.
O
'N I

C15H181N0 (355.22), MS(ESI):356 (M+H+).
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3,4-dimethoxybenzaldehyde gave 5 4-iodomethyl-5-methyl-2-(3,4-dimethoxyphenyl)oxazole.
O
N I
\O
/O
C13H141N03 (359.17), MS(ESI): 360 (M+H+).
10 All substances described below have the cis-configuration on the cyclohex-1,3-ylene.

Example 1:
2-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-pentanoic acid:
1. NaOMe 2. MOM-CI LiAIH4 NaOH
----~ ---~ O O H
O- ~ O COZMe ~o J
cislracemate cis/racemate cislracemate O
O. /
1. LDA, Prl O 2. HCI, THF O
O O v _O HO O O
~oJ
cis/racemate cis/diastereomer mixture O
NaH, DMF \ ~O O O
O~i N
~I
O ~N
/ cis/diastereomer mixture O
TFA ~O O OH
O iN
cis/diastereomer mixture Methyl cis-3-(methoxymethoxy)cyclohexanecarboxylate:
1. NaOMe 2. MOM-CI
p--~ O C02Me p ~J
O
cis/racemate cis/racemate 15 g of 6-oxabicyclo[3.2.1 ]octan-7-one are dissolved in 150 ml of methanol, 13 g of sodium methoxide are added and the mixture is stirred at room temperature for 2 h. 13.7 ml of glacial acetic acid are then added, and most of the solvent is distilled off under reduced pressure. The residue is taken up in water and extracted three times with in each case 100 ml of ethyl acetate. The organic phases are dried over MgS04 and then concentrated under reduced pressure. This gives 18.8 g of the methyl ester as a colorless oil. This is dissolved in 150 ml of dichloromethane, 19.2 g of methoxymethyl chloride and 23.2 g of diisopropylethylamine are added and the mixture is stirred at room temperature for 15 h. 250 mf of saturated NH4C1 solution and 200 ml of water are added to the solution, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate and concentrated. This gives 22.2 g of methyl cis-3-(methoxymethoxy)cyclohexanecarboxylate as a yellow oil. C10H18O4 (202), MS(ESI): 203 (MH+).
cis-(3-Methoxymethoxycyclohexyl)methanol:
LiAIH4 OH
O C02Me O
J ~pJ
O
cis/racemate cis/racemate 9.0 g of methyl cis-3-methoxymethoxycyclohexanecarboxylate are dissolved in 280 ml of diethyl ether, 2.2 g of LiAIH4 are added and the mixture is stirred at room temperature. After 4 h, at 0°C, 10 ml of ethyl acetate and then 15 ml of 10N NaOH are added dropwise. The suspension is stirred for 1 h, MgS04 is added, the mixture is filtered through Celite and the filtrate is concentrated, giving 7.0 g of (cis-3-methoxymethoxycyclo-hexyl)methanol as a colorless oil. C9H1803 (174), MS(ESI): 175 (MH+).
tert-Butyl (cis-3-methoxymethoxycyclohexylmethoxy)acetate:
NaOH O
O OH ' ~
Br O O ~O
pJ ~ J
O O
cis/racemate O
cis/racemate 1.0 g of (cis-3-methoxymethoxycyclohexyl)methanol and 3.3 g of tert-butylbromoacetate are dissolved in 30 ml of toluene, and 0.50 g of tetrabutylammonium hydrogensulfate is added. The suspension is cooled to 10°C. 10 ml of 50% strength NaOH are added to the suspension. The mixture is allowed to warm to room temperature, and after 3 h the aqueous phase is removed and extracted with methyl tert-butyl ether. The combined organic phases are dried over MgS04 and concentrated. Flash column chromatography on silica gel (heptane/ethyl acetate 10/1 -> 2/1) gives 1.10 g of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy)acetate as a colorless oil. C15H28O5 (288), LCMS(ESI): 306 (M++H20).
tert-Butyl2-(cis-3-hydroxycyclohexylmethoxy)pentanoate:
1. LDA, Prl O 2. HCI, THF O
O " O HO O O
O
cis/racemate cis/diastereomer mixture 200 mg of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy)acetate are dissolved in 5 ml of abs. tetrahydrofuran and cooled to -78°C (dry ice/acetone bath). 0.7 ml of a 2M lithium diisopropylamide solution in tetrahydrofuran/hexane is then added dropwise. The solution is initially stirred at -78°C and then warmed to 0°C (ice bath) and stirred at this temperature for 20 min. 600 mg of propyl iodide in 2 ml of tetrahydrofuran are then added, and the solution is stirred at 0°C for a further 2.5 h.
15 ml of a saturated ammonium chloride solution are added, and the phases are separated. The aqueous phase is extracted with methyl tert-butyl ether.
The combined organic phases are dried over MgS04 and concentrated (yield: 240 mg of crude product). The residue is taken up in 2 ml of tetrahydrofuran, 0.5 ml of conc. HCI is added and the mixture is stirred at room temperature for 18 h. The mixture is diluted with water and methyl tert-butyl ether, the phases are separated and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic phases are washed with saturated NaCI solution, dried over MgS04 and concentrated.
This gives 130 mg of tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-pentanoate as a yellow oil. NMR (CDC13) diastereomer mixture: 3.55-3.67 (m, 2H), 3.41-3.48 (m, 1 H), 3.07-3.18 (m, 1 H), 1.91-2.13 (m, 2H), 1.11-1.82 (m, 14H), 1.48 (s, 9H).
tert-Butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methoxy]pentanoate HO O O NaH, DMF \ ~O O O
i O iN
O\/ N I \
cis/diastereomer mixture ~' ~ cisldiastereomer mixture 130 mg of tert-butyl 2-(cis-3-hdyroxycyclohexylmethoxy)pentanoate are dissolved in 3 ml of dimethylformamide, and 20 mg of NaH (95%) are added. After 60 min of stirring, 350 mg of 5-methyl-2-p-tolyloxazol-4-yl-methyl iodide in 1 ml of dimethylformamide are added at 0°C. The mixture is stirred at room temperature for 2 h. 10 ml of methyl tert-butyl ether, 5 ml of water and 10 ml of saturated NaCI solution are then added. The phases are separated, the aqueous phase is extracted once with methyl tert-butyl ether and the organic phases are dried over MgS04 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 99/1 -> 10/1 ). This gives 20 mg of the crude tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]pentanoate as a yellow oil.
C28H41N05 (471), LCMS (ESI): 472 (MH+).
2-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-5 pentanoic acid:

TFA ~O O OH
O/~i~N/ \ O i N
\ \
/ ~/
cis/diastereomer mixture cis/diastereomer mixture 10 20 mg of tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclo-hexylmethoxy]pentanoate are stirred in 1 ml of trifluoroacetic acid overnight. The solution is concentrated completely and purified by HPLC, giving 15 mg of 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-methoxy)cyclohexyl-methoxy]pentanoic acid 7. C24H33N05 (415), MS(ES+) 416 (MH+).
Example 2 Analogously to Example 1, tert-butyl (cis-3-methoxymethoxycyclohexyl-methoxy)acetate, methyl iodide and 5-methyl-2-p-tolyloxazol-4-ylmethyl iodide give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methoxy]propionic acid. C22H29N05 (387), LCMS(ES+) 388 (MH+).
O
O
-O -OH
O iN
cis/diastereomer mixture Example 3 Analogously to Example 1, tert-butyl (cis-3-methoxymethoxycyclohexyl-methoxy)acetate, ethyl iodide and 5-methyl-2-p-tolyloxazol-4-ylmethyl iodide give 2-[3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-butyric acid.
C23H31N05 (401), LCMS(ES+) 402 (MH+) O
O
'O ~OH
O iN
cis/diastereomer mixture Example 4 Analogously to Example 1, tert-butyl (cis-3-methoxymethoxycyclohexyl-methoxy)acetate, benzyl bromide and 5-methyl-2-p-tolyloxazol-4-ylmethyl iodide give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methoxy]-3-phenylpropionic acid. C28H33N05 (463), LCMS(ES+) 464 (MH+).
O
O
~O ~OH
O iN ~ \
cis/diastereomer mixture Example 5 Analogously to Example 1, tert-butyl (cis-3-methoxymethoxycyclohexyl-methoxy)acetate, methyl iodide and 5-methyl-2-(3-methoxyphenyl)oxazol-4-ylmethyl iodide give 2-[cis-3-(5-methyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy)cyclohexylmethoxy]propionic acid. C22H29N06 (403), LCMS(ES+) 404(MH+).
O
O
~O -OH
O iN
cis/diastereomer mixture /
Example 6 Analogously to Example 1, tert-butyl cis-(3-methoxymethoxycyclohexyl-methoxy)acetate, methyl iodide and 5-methyl-2-m-tolyloxazol-4-ylmethyl iodide give 2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl-methoxy]propionic acid. C23H31 N05 (401 ), LCMS(ES+) 402 (MH+).
O
O
~O ~OH
O iN
cis/diastereomer mixture Example 7 Analogously to Example 1, tert-butyl cis-(3-methoxymethoxycyclohexyl-methoxy)acetate, methyl iodide and 5-methyl-2-(3-trifluoromethylphenyl)-oxazol-4-ylmethyl iodide give 2-[cis-3-(5-methyl-2-(3-trifluoromethylphenyl)-oxazol-4-ylmethyl)cyclohexylmethoxy]propionic acid. C22H26F3N05 (441 ), LCMS(ES+) 442 (MH+).

Example 8 2-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionic acid:
1. LDA, Mel O 2. LDA, Mel O
3. HCI, THF
O O v _O HO O O
J
\o cis/racemate cis/racemate O
NaH ~O O O
I O /N
O~)-~--~(N \
\ ~ cis/racemate O
TFA ~O O OH
O iN
\
cis/racemate tert-Butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate:
1. LDA, Mel 2. LDA, Mel O 3. HCI, THF O
O v 0 HO O O
O
cis/racemate cis/racemate 300 mg of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy)acetate are dissolved in 5 ml of abs. tetrahydrofuran and cooled to -78°C (dry ice/acetone bath). 1.5 ml of a 2M lithium diisopropyl amide solution in tetrahydrofuran/hexane are then added dropwise. The solution is initially stirred at -78°C for 90 min and then warmed to 0°C (ice bath), 1.41 g of methyl iodide and 1.5 ml of tetrahydrofuran are added and the solution is stirred at 0°C for 1 h. 1 ml of HCI (cone) is added, and the phases are separated. The aqueous phase is extracted with ethyl acetate. The 5 combined organic phases are dried over MgS04 and concentrated (yield:
320 mg of crude product). The crude product is dissolved in 5 ml of abs.
tetrahydrofuran and cooled to -78°C (dry ice/acetone bath). 1.5 ml of a lithium diisopropylamide solution in tetrahydrofuran/hexane are then added dropwise. The solution is initially stirred at -78°C for 90 min and then 10 warmed to 0°C (ice bath), 1.41 g of methyl iodide and 1.5 ml of tetrahydrofuran are added and the solution is stirred at 0°C for 1 h. 1 ml of HCI (cone) is added, and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgS04 and concentrated (yield: 350 mg of crude product). The residue is 15 taken up in 1 ml of tetrahydrofuran, 1 ml of conc. HCI is added and the mixture is stirred at room temperature for 3 d. The mixture is diluted with water and ethyl acetate, the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated NaCI solution, dried over MgS04 and concentrated. The 20 residue is chromatographed on silica gel (heptane/ethyl acetate 2/1), giving 200 mg of tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methyl-propionate as a yellow oil. C15H2804 (272.20), MS(ESI): 273.4 (MH+).
tert-Butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-25 methoxy]-2-methylpropionate:

HO O O NaH, DMF O O/~O
i O ~N
~N
cis/racemate O ~ I \ cis/racemate 200 mg of tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methyl-30 propionate are dissolved in 5 ml of dimethylformamide, and 20 mg of NaH
(95%) are added. After 60 min of stirring at room temperature, 460 mg of 5-methyl-2-p-tolyloxazol-4-ylmethyl iodide in 1.5 ml of dimethylformamide are added at 0°C. The mixture is stirred at room temperature for 2 h.
10 ml of methyl tert-butyl ether and 10 ml of saturated NH4C1 solution are then added. The phases are separated, the aqueous phase is extracted once with methyl tert-butyl ether and the organic phases are dried over MgS04 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 5/1 -> 1/1). 200 mg of the crude tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionate are obtained as a yellow oil. C27H39N05 (457), LCMS
(ESI): 458 (MH+) Improved synthesis of tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexylmethoxy]-2-methylpropionate:

HO O O NaH, MTBE \ ~O O O
O iN
I
cis/racemate O i N ~ \ cis/racemate \
50 mg of tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate are dissolved in 0.5 ml of dimethylformamide and 22 mg of NaH (60%) are added. After 30 min of stirring, 112 mg of 5-methyl-2-p-tolyloxazol-4-yl-methyl iodide are added at room temperature. The mixture is placed in an ultrasonic bath for 10 min and then stirred at room temperature for 3 h.
10 ml of methyl tert-butyl ether and 10 ml of water are then added. The phases are separated, the aqueous phase is extracted once with methyl tert-butyl ether and the organic phases are dried over MgS04 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 5/1 -> 1 /1 ). 60 mg of the crude tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionate are obtained as a yellow oil. C27H39N05 (457), LCMS(ESI): 458 (MH+).

2-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionic acid:

O p O _TFA ~O O OH
O /N
O /N
/ ~ /
cis/racemate cis/racemate 200 mg of tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclo-hexylmethoxy]-2-methylpropionate are stirred in 2 ml of trifluoroacetic acid for 1 h. The solution is concentrated completely and purified by flash chromatography (heptane/ethyl acetate 5/1 ) giving 66 mg of 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionic acid.
C23H31 N05 (401.51 ), MS(ES+) 402.29 (MH+).
Example 8a:
2-[(1 R,3S)-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionic acid O
~~O O OH
~/ -i 1N
Starting with an enantiomerically pure tert-butyl 2-[(1 R,3S)-cis-3-hydroxy-cyclohexylmethoxy]-2-methylpropionate, 2-[(1 R,3S)-cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionic acid is obtained. C23H31N05 (401.51), MS(ES+) 402.29 (MH+).

Example 9:
1-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]cyclo-pentanecarboxylic acid:
O 1. LDA, allyl iodide O
2. LDA, allyl iodide O O~O O O O
\OJ \oJ
cis/racemate cis/racemate 1. [CIz(Cy3P)2Ru=CHPh]
CHZCIZ O
2. Hz,Pd/C (10%) 3. HCI, THF HO O O
cis/racemate O
NaH, DMF \ ~O O O
~I O i N
O ~N \
\ / cis/racemate TFA ~O O OH
O iN
\
cis/racemate tert-Butyl 2-allyl-2-(cis-3-methoxymethoxycyclohexylmethoxy)pent-4-enoate:
1. LDA, allyl iodide 2. LDA, allyl iodide O
O O O O O O
~oJ ~oJ
cis/racemate cis/racemate 200 mg of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy)acetate are dissolved in 6 ml of abs. tetrahydrofuran and cooled to -78°C (dry ice/acetone bath). 1.05 ml of a 2M lithium diisopropylamide solution in tetrahydrofuran/hexane are then added dropwise. The solution is initially stirred at -78°C and then at 0°C, in each case for 20 min, and 0.85 g of allyl bromide in 1.5 ml of tetrahydrofuran is added at 0°C. The solution is stirred at 0°C for 30 min. 1 ml of a saturated NH4C1 solution and 5 ml of ethyl acetate are added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgS04 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 10/1 ), giving 160 mg of monoallylated product. This is dissolved in 6 ml of abs. tetrahydrofuran and cooled to -78°C (dry ice/acetone bath). 1.05 ml of a 2M lithium diisopropylamide solution in tetrahydrofuran/hexane are then added dropwise. The solution is initially stirred at -78°C and then at 0°C, in each case for 20 min, and 0.85 g of allyl bromide in 1.5 ml of tetrahydrofuran is added at 0°C. The solution is stirred at 0°C for 2 h. 1 ml of a saturated NH4C1 solution and 5 ml of ethyl acetate are added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgS04 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 5/1), giving 140 mg of tert-butyl 2-allyl-2-(cis-3-methoxymethoxycyclohexylmethoxy)pent-4-enoate as a yellow oil.
C21 H3605 (368.52), MS(ESI): 296.25 (MH+-C4H90).

tert-Butyl (cis-3-hydroxycyclohexylmethoxy)cyclopentanecarboxylate:
O 1. [CIZ(PCy3)ZRu=CHPh]

O O 2. H2,Pd/C (10%) O
3. HCI, THF HO'~~O O
\O~
cis/racemate cis/racemate 140 mg of tert-butyl 2-allyl-2-(cis-3-methoxymethoxycyclohexylmethoxy)pent-4-enoate are dissolved in 5 ml of dichloromethane, 10 mg of Grubbs catalyst (C12(Cy3P)2Ru=CHPh) are added under an Ar atmosphere and the mixture is stirred at 40°C for 48 h.
10 10 ml of heptane/ethyl acetate (3/1 ) are added and the solution is filtered through silica gel. This gives 100 mg of tert-butyl 1-(cis-3-methoxymethoxy-cyclohexylmethoxy)cyclopent-3-enecarboxylate as a brown oil. This is dissolved in 2 ml of MeOH, degassed and saturated with Ar. 30 mg of Pd/C
(10%) are then added, and the mixture is degassed again. The solution is 15 saturated with hydrogen and stirred at room temperature overnight. Dilution with 20 ml of ethyl acetate and filtration through Celite give 100 mg of crude tert-butyl 1-(cis-3-methoxymethoxycyclohexylmethoxy)cyclopentane-carboxylate. This is taken up in 2 ml of tetrahydrofuran, 0.5 ml of HCI
(cone) is added and the mixture is stirred at room temperature overnight.
20 The solution is neutralized with saturated NaHC03 solution and extracted three times with ethyl acetate. The organic phases are dried over MgS04 and concentrated. Chromatography of the residue on silica gel (heptane/ethyl acetate 10/1 -> 1/1) gives 57 mg oftert-butyl 1-(cis-3-hydroxycyclohexylmethoxy)cyclopentanecarboxylate as a yellow 25 oil. For the next step, this is used in crude form.

tert-Butyl 1-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methoxy]cyclopentanecarboxylate:

NaH, DMF
O _ O O O
HO O
I
~N
O ~N
/
cis/racemate / cis/racemate 57 mg of tert-butyl 1-(cis-3-hydroxycyclohexylmethoxy)cyclopentane-carboxylate are dissolved in 3 ml of dimethylformamide, and 10 mg of NaH
are added. The suspension is stirred at room temperature for 30 min and then cooled to 0°C, and 150 mg of methyl 2-p-tolyloxazol-4-ylmethyl iodide in 1 ml of dimethylformamide are added dropwise. The suspension is stirred at room temperature for 2 h and diluted with methyl tert-butyl ether and saturated NaCI solution. The aqueous phase is removed and extracted with methyl tert-butyl ether. The combined organic phases are washed with saturated NaCI solution, dried over MgS04 and concentrated. Chromato-graphy of the residue on silica gel (heptane/ethyl acetate 99/ -> 10/1 ) gives mg of a product mixture which, according to LCMS, contains the desired tert-butyl 1-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methoxy]cyclopentanecarboxylate. This mixture is used for the next step, without further purification. C29H41 N05 (483.65), LCMS (ESI): 484.2 20 (MH+).
1-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]cyclo-pentanecarboxylic acid:
o ~ o O O O~ TFA O O OH
iN O iN
/ I/
cis/racemate cis/racemate 20 mg of impure tert-butyl 1-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexylmethoxy]cyclopentanecarboxylate is stirred in 1 ml of trifluoroacetic acid at room temperature overnight. The solution is concentrated completely and the residue is chromatographed on silica gel (heptane/ethyl acetate 10/1 -> 1/1 -> methyl tert-butyl ether), giving 7.5 mg of 1-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]cyclo-pentanecarboxylic acid. C25H33N05 (427.55); LCMS 428.2 (MH+).
Example 10:
\ /
O O TBAHS04lNaOH \ / O
.O
si + s~'° o~
~o~
/ \ Br / \
a cis/racemate cis/racemate o r~l LDA/Mel \ / .O O O Tg~ ~O O
Si O' v v O
/ \
cis/racemate cis/racemate NaH/MTBE ~ O TFA O
--.~ O O~O~ ~ O O
O iN O iN
F F CIS/raCemate emate tert-Butyl cis-3-(tert-butyldiphenylsilanyloxy)cyclohexylmethoxy]acetate Br / /
\1 \ + o~ \\ \
~~si, o -~si, ~o 0 0 ~ / o cislracemate cis/racemate 25 g of [cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]methanol, together with 40 g of tert-butyl bromoacetate and 6.9 g of tetrabutylammonium hydrogensulfate, are dissolved in 300 ml of toluene, and 200 ml of NaOH
(50% strength) are then added dropwise at 0°C. The mixture is stirred at 0°C for 1 h and then warmed to room temperature. The solvent is removed and the mixture is extracted with 3 x 100 ml of methyl tert-butyl ether. After the third extraction, the aqueous phase is acidified and once more extracted with 200 ml of methyl tert-butyl ether. The combined organic phases are extracted with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is removed under reduced pressure. This gives 27.8 g of tert-butyl cis-3-(tert-butyldiphenylsilanyloxy)-cyclohexylmethoxy]acetate as a yellow oil.
C2gH4204S1 (482.74), MS(ESI): 483 (M+H+) tert-Butyl 2-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexylmethoxy]-2-methylpropionate /
~\ /
s~, ~o ° ~ o o ~ s.. %~o / ~ o o /

cis/racemate cis/racemate 20.0 g of tert-butyl cis-3-(tert-butyldiphenylsilanyloxy)cyclohexylmethoxy]-acetate are initially charged in a 1 I three-necked flask, which had been dried by heating, dissolved in 200 ml of dry tetrahydrofuran and cooled to -78°C, and 83 ml of lithium diisopropylamide (2N in tetrahydrofuran) are slowly added dropwise such that the internal temperature does not exceed -65°C. The mixture is then warmed to 0°C and stirred for 1 h, during which the color of the solution turns to yellow. The mixture is cooled again to -70°C, 35.27 g of methyl iodide are then added dropwise and the mixture is stirred at 0°C for 3 h. The reaction is checked (TLC and LCMS), showing the formation of a new product (monomethyl compound).
200 ml of saturated ammonium chloride solution are added to the reaction mixture, and the mixture is extracted with water/methyl tent-butyl ether. This gives the crude product as a dark-red oil which, without purification, is converted in the same reaction sequence into the geminal dimethyl compound. The crude product is purified on silica gel (heptane/ethyl acetate 50:1 -~ 10:1 ). This gives 16 g of tert-butyl 2-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexylmethoxy]-2-methylpropionate as a light-yellow oil.
C31 H46~4Si (510.80), MS(ESI): 511 (M+H+) tert-Butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate ~~s~ ~ o ° o~o o/vv ° ~ o cis/racemate cis/racemate 16 g of tert-butyl 2-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexylmethoxy]-2-methylpropionate are dissolved in 100 ml of acetonitrile, and 62 ml of tetrabutylammonium fluoride (1 N solution in tetrahydrofuran) are added.
After 2 h of stirring at 60°C, the reaction has ended and the mixture is concentrated under reduced pressure. The residue is extracted from water/ethyl acetate. The combined org. phases are extracted with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is removed under reduced pressure. The crude product is purified on silica gel (heptane/ethyl acetate 15:1 ~ 1:1). This gives 16 g of the product tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate as a colorless oil.
C~ 5H2g04 (272.39), MS(ESI): 273 (M+H+) tert-Butyl 2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclo-hexylmethoxy~-2-methylpropionate N + O ~ O ~ F ~ ~ N~O~~ O
F.
5 cis/racemate cis/racemate 0.05 g of the alcohol tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate is dissolved in methyl tert-butyl ether, and 15 mg of sodium hydride are added. After 15 minutes of stirring at room temperature, 10 0.12 g of 2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole is added, and the mixture is stirred at room temperature for 12 h. Following addition of 2 ml of 1 N HCI, the product is extracted with ethyl acetate (2 x 5 ml), the solvent is removed under reduced pressure and the crude product is then purified by HPLC. This gives 0.08 g of the compound tert-butyl 15 2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-methoxy}-2-methylpropionate as a colorless oil.
C2gH3gFN05 (461.58), MS(ESI): 462 (M+H+) 2-{cis-3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-20 methoxy~-2-methylpropionic acid F ~ ~ N~O~O~O~ --~ F I ~ N~O~O~O
cis/racemate cis/racemate 25 0.07 g of tert-butyl 2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-yl-methoxy]cyclohexylmethoxy}-2-methylpropionate is dissolved in 1 ml of dichloromethane, 1 ml of trifluoroacetic acid is added and the mixture is stirred at room temperature. The reaction is monitored (LCMS), showing complete conversion after 30 minutes. The reaction mixture is extracted 30 with water/dichloromethane and, after removal of the solvent under reduced pressure, purified by preparative HPLC. This gives 0.06 g of the carboxylic acid 2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexylmethoxy}-2-methylpropionic acid as a colorless oil.
C22H2gFN05 (405.47), MS(ESI): 406 (M+H+) Example 11:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethyl iodide give 2-{(1S,3R)-cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexylmethoxy}-2-methylpropionic acid.

N~ o 0 0 o~
cis/racemate C23H31 N06 (417.50) MS(ESI): 418 (M+H+) Example 12:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 2-(3-trifluoromethylphenyl)-5-methyloxazol-4-yl-methyl iodide give 2-{(1S,3R)-3-[2-(cis-3-trifluoromethylphenyl)-5-methyl-oxazol-4-ylmethoxy]cyclohexylmethoxy)-2-methylpropionic acid.
F
F
F ~ O
O O O
O
cis/racemate C23H2gF3N05 (455.47) MS(ESI): 456 (M+H+) Example 13:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 5-methyl-2-(5-methylfuran-2-yl)oxazol-4-ylmethyl iodide give 2-methyl-2-{(1 R,3S)-cis-3-[5-methyl-2-(5-methylfuran-2-yl)-oxazol-4-ylmethoxy]cyclohexylmethoxy}propionic acid.

cis/racemate O O
O
O O
cis/racemate C2~ H2gNOg (391.46) MS(ESI): 392 (M+H+) Example 14:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 2-(3,4-dimethoxyphenyl)-5-methyloxazol-4-yl-methyl iodide give 2-{(1 R,3S)-cis-3-[2-(3,4-dimethoxyphenyl)-5-methyl-oxazol-4-ylmethoxy]cyclohexylmethoxy}-2-methylpropionic acid.

O N ~O O
/ ~ ~ / ~ 'O
O
cis/racemate C24H33N07 (447.53) MS(ESI): 448 (M+H+) Example 15:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 5-phenyl-2-p-tolyloxazol-4-ylmethyl iodide give 2-methyl-2-[(1 R,3S)-cis-3-(5-phenyl-2-p-tolyloxazol-4-ylmethoxy)cyclo-hexylmethoxy]propionic acid.

O O
O ~ _O
C2gH33N05 (463.57) MS(ESI): 464 (M+H+) Example 16:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl-methyl iodide give 2-methyl-2-{(1 R,3S)-cis-3-[5-methyl-2-(4-trifluoromethyl-phenyl)oxazol-4-ylmethoxy]cyclohexylmethoxy}propionic acid F F ~ O
_ N ~ O O O
F
O
cis/racemate C23H2gF3N05 (455.47) MS(ESI): 456 (M+H+) Example 17:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 2-(4-methoxyphenyl)-5-methyloxazol-4-ylmethyl iodide give 2-{(1 R,3S)-cis-3-[2-(4-methoxyphenyl)-5-methyloxazol-4-yl-methoxy]cyclohexylmethoxy}-2-methylpropionic acid ~O~N' O O O
\\ /~O
cis/racemate C23H31 N06 (417.50) MS(ESI): 418 (M+H+) Example 18:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 5-methyl-2-thiophen-2-yloxazol-4-methyl iodide give 2-methyl-2-[(1 R,3S)-cis-3-(5-methyl-2-thiophen-2-yloxazol-4-yl-methoxy)cyclohexylmethoxy]propionic acid N ~ O
O~ O
O
cis/racemate C2pH27N05S (393.50) MS(ESI): 394 (M+H+) Example 19:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and -methyl-2-(3-trifluoromethoxyphenyl)oxazol-4-ylmethyl iodide give 2-methyl-2-[(1 R,3S)-cis-3-[5-methyl-2-(3-trifluoro-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexylmethoxy]propionic acid N ~O O
O
O
F~F
F
cis/racemate C23H2gF3NOg (471.47) MS(ESI): 472 (M+H+) Example 20:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 5-methyl-2-(4-isopropylphenyl)oxazol-4-ylmethyl iodide give 2-methyl-2-[(1 R,3S)-cis-3-(5-methyl-2-(4-isopropylphenyl)-oxazol-4-ylmethoxy)cyclohexylmethoxy]propionic acid.
/ ~ N ~O
.O O
O
cis/racemate C25H35N05 (429.56) MS(ESI): 430 (M+H+) Example 21:
Analogously to Example 10, tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate and 5-methyl-2-m-tolyloxazol-4-ylmethyl iodide give 2-methyl-2-[(1 R,3S)-cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclo-hexylmethoxy]propionic acid.

N ~O O
~O
O
cis/racemate C25H31 N~5 (401.50) MS(ESI): 402 (M+H+) Example 22:
cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]acetic acid:
Et0 ~~O ~O
1. LiAIH j~'~4 O ~ N 2. (COCI)2, DMSO, NEt3 O ~ N
1. NaOMe 2. TBSCI
_ ~ ~O COZMe O--~ TBSO COzMe gigr3, HSiEt3 O/ -~1N

cis/racemate cis/racemate I ~ cis/racemate LiAIH4 ~O OH 12, PPh3 I
~O
O iN O/ -i1N
cis/racemate ~ cis/racemate /
KOH
KOtBu, D~ ~O S MeOH ~O S
HS ~N O ,N
Et0 O HO O
O OEt / /
cis/racemate cis/racemate 5-Methyl-2-p-tolyloxazole-4-carboxaldehyde:
EtO

1. LiAIH j~'~(4 O ~ N 2. (COCI)2, DMSO, NEt3 O ~ N
/ /
In a dry four-necked flask with stirrer motor, internal thermometer, dropping funnel with pressure equalizer and reflux condenser with argon inlet (aspirator with tap), 9.3 g of LiAIH4 are covered with 600 ml of diethyl ether.
The suspension is cooled to 0°C. 30 g of ethyl 5-methyl-2-p-tolyloxazole-4-carboxylate are dissolved in 100 ml of diethyl ether and added dropwise to the suspension. After one hour of stirring at room temperature, the reaction has ended (TLC (heptane/ethyl acetate 1:1 ): Rf, starting material =
0.66, Rf, product = 0.18). 80 g of MgS04, 300 ml of methyl tert-butyl ether and 30 ml of ethyl acetate are added successively, and the suspension is stirred at room temperature. The mixture is then cooled to 0°C, 90 ml of 10N KOH are added dropwise and the mixture is stirred for another 60 min.
The solids are filtered off, the residue is washed three times with ethyl acetate and the filtrate is concentrated, giving 24 g of 5-methyl-2-p-tolyl-oxazole-4-methanol as a yellow solid. C12H13N02 (203.24), LCMS(ESI):
204.1 (MH+).
At -78°C, 22.2 ml of DMSO in 30 ml of dichloromethane are added dropwise to a solution of 12 ml of oxalyl chloride in 150 ml of dichloromethane such that the temperature does not exceed -70°C. The solution is then stirred at this temperature for 30 min. 24 g of 5-methyl-2-p-tolyloxazole-4-methanol in 120 ml of dichloromethane/chloroform (2/1 ) are then added dropwise, the temperature not exceeding -70°C. The solution is stirred at this temperature for 30 min. 80 ml of NEt3 are then added dropwise such that the temperature does not exceed -70°C. After the addition has ended, the cooling bath is removed and the solution is, with stirring, warmed to 0°C. At this temperature, 100 ml of water are added and the mixture is stirred vigorously at room temperature. The aqueous phase is separated off and extracted with chloroform. The combined organic phases are washed with saturated NH4C1 solution, dried over MgS04 and concentrated, giving 23.8 g of 5-methyl-2-p-tolyloxazole-4-carbaldehyde as a yellow solid. C12H11N02 (201.23), LCMS(ESI): 202.1 (MH+).
Methyl [cis-3-(tert-butyldimethylsilanyloxy)cyclohexyl]carboxylate:
1. NaOMe 2. TBSCI
a O-~ TBSO C02Me O
cis/racemate cis/racemate 47 g of 6-oxabicyclo[3.2.1 ]octan-7-one are dissolved in 500 ml of MeOH, and 40.5 g of NaOMe are added. After 2.5 hours of stirring at room temperature, 135 ml of acetic acid are added and most of the methanol is distilled off. The residue is taken up in ethyl acetate/water and the phases are separated. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over MgS04 and concentrated, the residue being the methyl ester in quantitative yield.
10.7 g of the residue are dissolved in 100 ml of dimethylformamide, and 11.2 g of tert-.butyldimethylsilyl chloride are added. At 0°C, 11.5 g of imidazole are added, and the solution is stirred at room temperature overnight. 200 ml of saturated NaCI solution are added and the solution is extracted three times with methyl tert-butyl ether. The combined organic phases are washed with saturated NaCI solution, dried over MgS04 and concentrated. This gives 16.4 g of methyl [cis-3-(tert-butyldimethylsilanyl-oxy)cyclohexyl]carboxylate as a colorless oil. C14H2803Si (272.46), MS(ESI): 273.13 (MH+).

Methyl cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexane-carboxylate:
\ /=o BiBr3, HSiEt3 ~O COZMe O ~ N CH3C /-1N
O ,N
TBSO COzMe cis/racemate cis/racemate At room temperature, 1.35 g of methyl [cis-3-(tert-butyldimethylsilanyloxy)-cyclohexyl]acetate are added dropwise to a mixture of 4.0 ml of HSiEt3 and 1.50 g of BiBr3 in 20 ml of acetonitrile. 1.51 g of 5-methyl-2-p-tolyloxazole-4-carbaldehyde in 5 ml of acetonitrile are then added, and the mixture is stirred at room temperature for 4 h. The suspension is filtered and concentrated. The residue is chromatographed on silica gel (dichloro-methane/methanol 100/1 ), giving 1.20 g of methyl cis-3-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)cyclohexanecarboxylate as a light-yellow oil.
C20H25N04 (343.43), LCMS(ESI): 344.1 (MH+).
cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]methanol:
OH
O C02Me _ ~O
O / N LiAIH4 O ~ N
/ /
cis/racemate cis/racemate At 0°C, 1.70 g of methyl cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclo-hexanecarboxylate in 5 ml of tetrahydrofuran are added dropwise to a suspension of 380 mg of LiAIH4 in 50 ml of diethyl ether, and the mixture is stirred at room temperature for 2 h. 3 g of MgS04, 30 ml of methyl tert-butyl ether and 3 ml of ethyl acetate are added successively, and the suspension is stirred at room temperature. The mixture is then cooled to 0°C, 1 ml of 10N KOH is added dropwise and the mixture is stirred for another 60 min.
The solids are filtered off, the residue is washed three times with ethyl acetate and the filtrate is concentrated, giving 1.55 g of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]methanol as a yellow oil.
C19H25N03 (315.42), MS(EI): 315.4 (M+) 4-(cis-3-lodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole:
\~O OH Iz~~ O I

iN
O iN
/ cis/racemate cis/racemate 1.56 g of PPh3, 0.87 g of imidazole and 1.64 g of iodine are added to 1.55 g of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]methanol in 20 ml of toluene, and the mixture is stirred at room temperature for 2 h.
10 ml of dichloromethane are then added, and the mixture is stirred for another 60 min. The solution is diluted with 50 ml of water and 50 ml of methyl tert-butyl ether, the phases are separated and the organic phase is dried over MgS04 and concentrated. Filtration of the residue through silica gel using dichloromethane gives 1.12 g of 4-(cis-3-iodomethylcyclohexyl-oxymethyl)-5-methyl-2-p-tolyloxazole as a yellow solid.
C19H241N02 (425.31); LCMS (ESI): 426.0 (MH+).

Ethyl cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl-sulfanyl]acetate:
I KOtBu, DMF ~ S
O O
O~~''~'~N HS O ~N Et0 O
\ O OEt ~ \
/ /
cis/racemate cis/racemate 50 mg of KOtBu are added to 68 mg of ethyl mercaptoacetate in 1.5 ml of dimethylformamide, and the mixture is stirred at room temperature for 1 h.
120 mg of 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyl-oxazole are then added, and the solution is stirred at room temperature.
After 1 h, 20 ml of methyl tert-butyl ether, 15 ml of saturated NaCI solution and 15 ml of water are added and the phases are separated. The aqueous phase is extracted with methyl tert-butyl ether and the combined organic phases are washed with saturated NaCI solution, dried over MgS04 and concentrated, giving 117 mg of ethyl cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]acetate. C23H31 N04S (417.57);
LCMS (ESI): 418.1 (MH+).
cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]acetic acid:
KOH
S MeOH S
O ---~ O
O ~ N Et0 O O ~ N HO O
\ ~\
/ /
cis/racemate cis/racemate 117 mg of ethyl cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methylsulfanyl]acetate are dissolved in 3 ml of methanol, 1 ml of 2N KOH is added and the mixture is stirred at room temperature overnight. 2 ml of 2N
HCI, 10 ml of saturated NaCI solution, 5 ml of water and 20 ml of dichloromethane are then added, and the phases are separated. The organic phase is dried over MgS04 and concentrated, giving 100 mg of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]acetic acid. C21 H27N04S (389.52); LCMS (ESI): 390.1 (MH+).
Example 23:
Analogously to Example 22, 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole and ethyl 2-mercaptopropionate give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]propionic acid as a mixture of diastereomers. C22H29N04S (403.54), LCMS(ESI):
404.1 (MH+).
O
S
-O ~OH
O iN
/ cis/diastereomer mixture Example 24:
Analogously to Example 22, 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole and methyl 2-mercaptobutyrate give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]butyric acid as a mixture of diastereomers. C23H31 N04S (417.57), LCMS(ESI):
418.1 (MH+).

O
\~O S OH
O/ -i 1N
/ cis/diastereomer mixture Example 25:
Analogously to Example 22, 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole and ethyl 2-mercaptoheptanoate give 2-(cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]-heptanoic acid as a mixture of diastereomers. C26H37N04S (459.65), MS(ESI): 460.41 (MH+) O
S
'O 'OH
O ~N
cis/diastereomer mixture Example 26:
Analogously to Example 22, 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole and ethyl 2-mercapto-3-methylbutyrate acid give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]
3-methylbutyric acid as a mixture of diastereomers. C24H33N04S
(431.60), LCMS(ESI): 432.2 (MH+) O
S
~O ~OH
O iN
cis/diastereomer mixture Example 27:
Analogously to Example 22, 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole and ethyl 2-mercapto-2-methylpropionate give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]-2-methylpropionic acid. C23H31 N045 (417.57), LCMS(ESI): 418.1 (MH+) O
S
~O OH
O iN
cis/racemate Example 28:
Analogously to Example 22, 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole and ethyl 2-mercapto-2-phenylacetate give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]-2-phenylacetic acid as a mixture of diastereomers. C27H31 N04S (465.62), MS(ESI): 466.39 (MH+) O
S
~O ~OH
O iN /
cis/diastereomer mixture Example 29:
Analogously to Example 22, 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole and ethyl 2-mercapto-2-cyclohexylacetate give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]-2-cyclohexylacetic acid as a mixture of diastereomers. C27H37N04S
(471.66), LCMS(ESI): 472.2 (MH+) O
S
_O ~OH
O iN
/ cis/diastereomer mixture Example 30:
Analogously to Example 22, 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole and ethyl 2-mercaptovalerate give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]valeric acid as a mixture of diastereomers. C24H33N04S (431.60), MS(ESI):
432.39 (MH+) O
S
~O ~OH
O iN
cis/diastereomer mixture Example 31:
Analogously to Example 22, 4-(cis-3-iodomethylcyclohexyloxymethyl)-5-methyl-2-p-tolyloxazole and ethyl 1-mercaptocyclobutanecarboxylate give 1-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]-cyclobutanecarboxylic acid. C24H31 N04S (429.58), MS(ESI): 430.35 (MH+) O
S
-O -O H
O iN
cis/racemate Building block synthesis of the methyl 2-mercaptobutyrates Methyl 2-mercaptobutyrate O
Br KSAc S/ \ NaSMe SH
OMe ~MF MeOH pMe ---~ OMe --,.
O O O
racemate racemate racemate 1.43 g of KSAc are added to 1.81 g of methyl 2-bromobutyrate in 5ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h.
ml of methyl tert-butyl ether, 10 ml of water and 15 ml of saturated NaCI

solution are then added, and the phases are separated. The aqueous phase is extracted with methyl tert-butyl ether and the combined organic phases are washed with saturated NaCI solution, dried over MgS04 and concentrated, giving methyl 2-acetylsulfanylbutyrate as a yellow oil. This is taken up in 10 ml of methanol, 11 ml of a 1 M NaSMe solution in methanol are added and the mixture is stirred at room temperature overnight. The solvent is distilled off completely under reduced pressure, the residue is taken up in 15 ml of methyl tert-butyl ether and 20 ml of water, the phases are separated and the organic phase is washed with saturated NaCI
solution and dried over MgS04. The solution is concentrated under reduced pressure, giving 1.30 g of methyl 2-mercaptobutyrate as a yellow oil.
Analogously to the building block synthesis of the methyl 2-mercaptobutyrates, ethyl 2-bromoheptanoate gives ethyl 2-mercapto-heptanoate.
SH
oEt racemate Analogously to the building block synthesis of the methyl 2-mercaptobutyrates, ethyl 2-bromo-3-methylbutyrate acid gives ethyl 2-mercapto-3-methylbutyrate acid.
SH
OEt racemate Analogously to the building block synthesis of the methyl 2-mercaptobutyrates, ethyl 2-bromo-2-methylpropionate acid gives ethyl 2-mercapto-2-methylpropionate acid.
SH
OEt O

Analogously to the building block synthesis of the methyl 2-mercaptobutyrates, ethyl 2-bromo-2-phenylacetate gives ethyl 2-mercapto-2-phenylacetate.
SH
OEt O
racemate Analogously to the building block synthesis of the methyl 2-mercaptobutyrates, methyl 2-bromo-2-cyclohexylacetate gives methyl 2-mercapto-2-cyclohexylacetate.
SH
OMe O
racemate Analogously to the building block synthesis of the methyl 2-mercaptobutyrates, ethyl 2-bromovalerate gives ethyl 2-mercapto-valerate.
SH
OEt O
racemate Analogously to the building block synthesis of the methyl 2-mercaptobutyrates, ethyl 1-bromocyclobutanecarboxylate gives ethyl 1-mercaptocyclobutanecarboxylate.
SH
OEt O

Example 32:

ii o s H2o2 ~o s J-~ _TF j~(A
0 -' N O iN

/ /
cislracemate cis/diastereomer mixture cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfinyl]acetic acid:
65 mg of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl-sulfanyl]acetic acid are dissolved in 1.5 ml of trifluoroacetic acid, 6.3 NI
of 35% H202 are added at 0°C and the mixture is stirred overnight at room temperature. Saturated NH4C1 solution and methyl tert-butyl ether are added, the phases are separated, the aqueous phase is extracted with methyl tert-butyl ether and the combined organic phases are washed with saturated NaCI solution, dried over MgS04 and concentrated. The residue is purified by HPLC, which gave 6.6 mg of a colorless solid. C21 H27N05S
(405.52), LCMS(ESI): 406.1 (MH+).
Example 33:
Analogously to Example 32, 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]heptanoic acid gives 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfinyl]heptanoic acid as a mixture of diastereomers.
C26H37N05S (475.65), MS(ESI): 476.18 (MH+) O O
I I
S
~O ~OH
O ,N
cis/diastereomer mixture Example 34:
Analogously to Example 32, 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]-2-methylpropionic acid gives 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfinyl]-2-methylpropionic acid. C23H31 N05S (433.57), LCMS(ESI): 434.1 (MH+).
O O
I I
S
-O OH
O iN
cis/diastereomer mixture Example 35:
Analogously to Example 32, 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexylmethylsulfanyl]-3-methylbutyric acid gives 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfinyl]-3-methylbutyric acid as a mixture of diastereomers. C24H33N05S (447.60), MS(ESI): 448.43 (MH+) O O
I I
S
~O -OH
iN
/ cis/diastereomer mixture Example 36:
Analogously to Example 32, 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfanyl]valeric acid gives 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfinyl]valeric acid as a mixture of diastereomers. C24H33N05S (447.60), MS(ESI): 448.14 (MH+).
O O
I I
S
~O ~OH
O iN
/ cis/diastereomer mixture Example 37:
cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfonyl]acetic acid:
q s Hzoz 1~
TFA ~O O
O ~ O N
~ N HO O ~ HO O
cis/racemate ~ cis/racemate 65 mg of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl-sulfanyl]acetic acid are dissolved in 1.5 ml of trifluoroacetic acid, 21.5 NI
of 35% H2O2 are added at 0°C and the mixture is stirred at room temperature overnight. Saturated NH4C1 solution and methyl tent-butyl ether are added, the phases are separated, the aqueous phase is extracted with methyl tert-butyl ether and the combined organic phases are washed with saturated NaCI solution, dried over MgS04 and concentrated. The residue is purified by HPLC, which gave 6.6 mg of a colorless solid. C21 H27N06S (421.52), LCMS(ESI): 422.1 (MH+) Example 38:
Analogously to Example 37, 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexylmethylsulfanyl]heptanoic acid gives 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfonyl]heptanoic acid as a mixture of diastereomers. C26H37N06S (491.65), MS(ESI): 492.42 (MH+).
O O
I I
S
-O II ~OH
O
O iN
cis/diastereomer mixture Example 39:
Analogously to Example 37, 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexylmethylsulfanyl]-2-methylbutyric acid gives 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfonyl]-2-methylbutyric acid. C23H31 N06S (449.57), LCMS(ESI): 450.1 (MH+).
O
O\~O
\~O S OH
~/ -r 1N
cis/racemate Example 40:
Analogously to Example 37, 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexylmethylsulfanyl]-3-methylbutyric acid gives 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfonyl]-3-methyl butyric acid as a mixture of diastereomers. C24H33N06S (463.60), LCMS(ESI): 464.1 (MH+).
O O
I I
S
_O II -OH
O
O iN
/ cis/diastereomer mixture Example 41:
Analogously to Example 37, 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexylmethylsulfanyl]valeric acid gives 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethylsulfonyl]valeric acid as a mixture of diastereomers. C24H33N06S (463.60), MS(ESI): 464.14 (MH+).
O O
I I
S
~O I I ~OH
O
O iN
cis/diastereomer mixture Example 42:
(S)-3-Methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methyl]amino}butyric acid (COCI)2, DMSO
\ ~O OH NEt3, CHzCIz i O
\~O
O iN
O ~N
/ cis/racemate I ~ cis/racemate tert-butyl (S)-valinate O
NaBH(OAc)3 N' ~
CH2CIz O v _O
O iN
cis/diastereomer mixture O
O N v _O
TFA
O iN
cis/diastereomer mixture cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbaldehyde (COCI)2, DMSO
\~O OH NEt3, CH2CI2 \~ O
O iN
O iN
\
cis/racemate cis/racemate At -78°C, 089 ml of DMSO in 1 ml of dichloromethane are added dropwise to 0.48 ml of oxalyl chloride in 15 ml of dichloromethane such that the temperature does not exceed -70°C. After the end of the addition, the solution is stirred at this temperature for 30 min. 1.5 g of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]methanol in 2 ml of dichloromethane are then added dropwise such that the temperature remains below -78°C.
The solution is stirred at this temperature for 30 min. 3.2 ml of NEt3 are then added dropwise, the cooling bath is removed and the solution is warmed to 0°C. At this temperature, 10 ml of water are added, and the mixture is stirred vigorously at room temperature. The aqueous phase is removed and extracted with dichloromethane. The combined organic phases are washed with saturated NH4C1 solution, dried over MgS04 and concentrated, giving 1.50 g of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexanecarbaldehyde. C19H23N03 (313.40); LCMS (ESI): 314.1 (MH+) tert-Butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexylmethyl]amino}butyrate _ 0 ~ 0 tent-butyl (S)-valinate 0 N ~0 NaBH(OAc)3 0 ~N CHZCI2 0 iN
\ ~\
/ /
cislracemate cis/diastereomer mixture 511 mg of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarb-aldehyde, 0.9 ml of HOAc and 310 mg of tert-butyl (S)-valinate are dissolved in 5 ml of abs. dichloromethane. 500 mg of molecular sieve 4 A
are then added, and the suspension is cooled to 0°C. 414 mg of sodium triacetoxyborohydride are added a little at a time. This suspension is stirred at 0°C for 2 h, 3 ml of saturated NH4C1 solution are then added and the suspension is stirred for a further 10 min. In each case 10 ml of water and dichloromethane are added, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried over MgS04 and concentrated, which gives 760 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]-amino}butyrate. C28H42N204 (470.66); MS (ESI): 471.50 (MH+).
(S)-3-Methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methyl]amino}butyric acid O O
'~N' ~ HCO H ~N~
O ~O~ 2 O OH
TFA
~N ~ ~ iN
cis/diastereomer mixture cis/diastereomer mixture 40 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate are dissolved in 1 ml of formic acid, and 0.5 ml of trifluoroacetic acid is added. The solution is stirred at room temperature for 18 and then concentrated completely. The residue is purified by HPLC, which gives 28.2 mg of (S)-3-methyl-2-{(cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyric acid trifluoroacetic acid salt as a colorless solid. C24H34N202.C2HF302 (414.55); MS(ES-): 413.28 (M+-H).
Example 43:
(S)-2-{Acetyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methyl]amino}-3-methylbutyric acid 0 ~0 0 0 N~0 AcCI, pyridine 0 CHZCIZ
0 ~ N ~ .
cisldiastereomer mixture I \ cis/diastereomer mixture / /
0\ /

0 N~0 TFA
0 ~N
cis/diastereomer mixture (S)-2-{Acetyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methyl]amino}-3-methylbutyric acid 1. AcCI ~O
O pyridine ~N~ CHZCl2 ~N~
O O~ 2. TFA O 0 ~N ~ iN
/ /
cis/diastereomer mixture cis/diastereomer mixture 12 NI of acetyl chloride and 22 NI of pyridine are added to 40 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate in 0.5 ml of dichloromethane, and the mixture is stirred at room temperature for 18 h. The solution is then diluted with water and dichloromethane, the aqueous phase is removed and extracted with dichloromethane and the combined phases are dried over MgS04 and concentrated. The residue is taken up in 0.5 ml of trifluoroacetic acid and allowed to stand at room temperature overnight.
The solvent is distilled off completely and the residue is purified by HPLC, which gives 17 mg of (S)-2-{acetyl-(cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methylbutyric acid. C26H36N205 (456.59); LCMS (ESI): 457.36 (MH+).
Example 44:
Analogously to Example 43, tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate and benzoyl chloride give (S)-2-{benzoyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexylmethyl]amino}-3-methylbutyric acid. C31 H38N205 (518.29);
LCMS (ESI): 519.54 (MH+) O
O
O N v _O
O iN
cis/diastereomer mixture Example 45:
Analogously to Example 43, tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate and methyl-sulfonyl chloride give (S)-2-{methylsulfonyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methylbutyric acid. C25H36N206S
(492.23); LCMS (ESI): 493.26 (MH+).
O_S:O O
O N~o o ~N
\
/
cis/diastereomer mixture Example 46:
Analogously to Example 43, tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate and methyl-sulfonyl chloride in triethylamine give (S)-2-{methylsulfonylmethylsulfonyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methylbutyric acid. C26H38N208S2 (570.21 ); LCMS (ES-): 569.23 (M+-H).

I I, ~S~ O
O~S~O O
I
O N v _O
O ,N
cis/diastereomer mixture Example 47:
Analogously to Example 43, tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate and p-toluenesulfonyl chloride give (S)-2-{p-toluenesulfonyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methylbutyric acid.
C31 H40N206S (568.26); LCMS (ESI): 569.35 (MH+) O~S:O O
I
O N~O
0 , N /\
cis/diastereomer mixture Example 48:
Analogously to Example 43, tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate and methyl chloroformate give (S)-2-~methoxycarbonyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methylbutyric acid.
C26H36N206 (472.26), LCMS (ESI): 473.37 (MH+).
O\ /O O
O N v 'O
O iN
cis/diastereomer mixture Example 49:
Analogously to 42, cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexanecarbaldehyde and isopropyl glycinate hydrochloride give 2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-acetic acid trifluoroacetic acid salt. C21 H28N204 (486.49), MS (ESI): 487 (MH+).
O
O N v 'O
O ,N F O
F
O
F
cis/racemate Example 50:
(S)-2-{Methyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-methyl]amino}-3-methylbutyric acid trifluoroacetic acid salt 0 1. Mel 0 N ~0 K2C03 0 N ~0 DMF
0 rN ~ 0 iN F 0 2. TFA F

F
cis/diastereomer mixture cis/diastereomer mixture 60 mg of methyl iodide and 12 mg of potassium carbonate are added to 40 mg of tert-butyl (S)-3-methyl-2-f [cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexylmethyl]amino}butyrate (see Example 42) in 0.5 ml of DMF, and the mixture is stirred at RT overnight. 1 ml of TFA is added to the reaction solution, and the mixture is stirred for a further 1 h. The solution is purified by preparative HPLC, yielding 6.4 mg of (S)-2-(methyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methyl-butyric acid trifluoroacetic acid salt. C25H36N2O4 (542.60); MS (ESI): 543 (MH+).
Example 51:
Analogously to Example 50, tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate and benzyl bromide give (S)-2-~benzyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexylmethyl]amino}-3-methylbutyric acid trifluoroacetic acid salt.
C31 H40N2O4 (618.70), MS(ESI): 619 (MH+) O
_ O N~O
O iN
cis/diastereomer mixture Example 52:
2-{Benzyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]-amino}acetic acid O 1. Benzaldehyde O N~O~ CH2C12 ~ O
NaHB(OAc)3 2. LiOH O N ~O
O ~N
O ~N
O
/ I \ FF O
/ F
cis/racemate cis/racemate 120 mg of isopropyl 2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexylmethyl]amino}acetate are dissolved in 1.5 ml of dichloromethane, and 62 mg of benzaldehyde, a spatula tip of MgS04 and 68 mg of sodium triacetoxyborohyride are added successively. The suspension is stirred at RT overnight, and water is then added. The oraganic phase is separated off, washed with Na2C03 solution, dried over MgS04 and concentrated. The residue is dissolved in 0.7 ml of methanol and 0.23 ml of water, 20 mg of LiOH are added and the mixture is stirred at RT overnight. The solution is concentrated and the residue is purified by preparative HPLC, yielding 15 mg of 2-{benzyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}acetic acid. C28H34N2O4 (462.59); MS(ESI): 463 (MH+).
Example 53:
Analogously to Example 52, mg isopropyl 2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}acetate and thiophene-2-carbaldehyde give 2-{2-thienylmethyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}acetic acid trifluoroacetic acid salt.
C26H32N2O4 (468.62), MS(ESI): 469 (MH+).

/ ~S
O
O N v _O
O iN
cis/racemate Example 54:
Analogously to Example 52, mg isopropyl 2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}acetate and cyclohexanecarbaldehyde give 2-{cyclohexylmethyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}acetic acid trifluoroacetic acid salt. C28H40N2O4 (468.64), MS(ESI): 469 (MH+).
O
O N v _O
O rN
cis/racemate Example 55:
2-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid:

1. MOMCI
2. LiAIH4 NaOH
CO2Me OH
OH O\ O
O ~O 1~
O
O ~O O O
cis/racemate cis/racemate cis/racemate 1. HCI (aq) 1. LDA, Mel 2. TBDMSCI ~ 2. LDA, Mel ~
\ 'O O \ 'O O
iii iii O ~ O
cis/racemate cis/racemate Et3SiH
BiBr3 O O O O
O
o O
O
O ~N OH
i/ N O O
cis/racemate cis/racemate (cis-3-Methoxymethoxymethylcyclohexylmethyl)methanol:
1. MOMCI
2. LiAIH4 OH
~COZMe OH O~O
cis/racemate cis/racemate 1.70 g of methyl cis-3-hydroxymethylcyclohexanecarboxylate are dissolved in 20 ml of dichloromethane, 1.60 g of methoxymethyl chloride and 2.60 g of diisopropylamine are added and the mixture is stirred at room temperature for 15 h. 50 ml of saturated NH4C1 solution and 50 ml of water are added to the solution, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate and concentrated. This gives 2.0 g of methyl cis-3-methoxymethoxymethylcyclohexanecarboxylate as a yellow oil. This is dissolved in 50 ml of diethyl ether, 350 mg of LiAIH4 are added and the mixture is stirred at room temperature. After 2 h at 0°C, 5 ml of ethyl acetate, 40 ml of methyl tert-butyl ether and 3 g of MgS04 are added. 15 ml of 10N KOH are then added dropwise. The suspension is stirred for 3 h and filtered through Celite and the filtrate is concentrated, which gives 1.65 g of (cis-3-methoxymethoxymethylcyclohexyl)methanol as a colorless oil.
C10H20O3 (188.27), MS(ESI): 189.2 (MH+) tert-Butyl [cis-3-(methoxymethoxymethyl)cyclohexylmethoxy]acetate:
NaOH O
OH O O
v v ~Br O~O ~ IOI O~O
cis/racemate cis/racemate 1.65 g of (cis-3-methoxymethoxymethylcyclohexyl)methanol and 5.1 g of tert-butyl bromoacetate are dissolved in 20 ml of toluene, and 1.50 g of tetrabutylammonium hydrogensulfate are added. The suspension is cooled to 10°C. 20 ml of 50% NaOH are added to the suspension. The mixture is stirred at 10°C for 6 h and the aqueous phase is then removed and extracted with methyl tert-butyl ether. The combined organic phases are dried over MgS04 and concentrated. Flash column chromatography on silica gel (heptane/ethyl acetate 10/1 ~ 2/1 ) gives 2.23 g of tert-butyl [cis-3-(methoxymethoxymethyl)cyclohexylmethoxy]acetate as a colorless oil.
C16H30O5 (302.41), MS(ESI): 320.30 (M+NH4+).
tert-Butyl [cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexylmethoxy]-acetate:

1. HCI (aq) O
O 2. TBDMSCI O
O~ ~ O
\ 'O
Ou0 ~ ~ i cis/racemate cis/racemate 1.9 g of tert-butyl [cis-3-(methoxymethoxymethyl)cyclohexylmethoxy]-acetate are dissolved in 10 ml of tetrahydrofuran, 5 ml of conc. HCI are added and the mixture is stirred at room temperature for 2 h. 10 ml of sat.
NaCI solution, 10 ml of water and 30 ml of methyl tert-butyl ether are then added, the phases are separated and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic phases are dried over MgS04 and concentrated. Flash chromatography on silica gel (heptane/ethyl acetate 3/1) gives 600 mg of tert-butyl (cis-3-hydroxymethyl-cyclohexylmethoxy)acetate as a colorless oil (TLC (heptane/ethyl acetate 2/1 ): Rf, starting material = 0.68, Rf, product = 0.18). 260 mg of this are dissolved in 5 ml of dimethylformamide, and 170 mg of tert-butyldimethylsilyl chloride are added. The solution is then cooled to 0°C, and 160 mg of imidazole are added. The solution is stirred at room temperature for 15 h, and 20 ml of sat. NaCI solution, 10 ml of water and 30 ml of methyl tert-butyl ether are then added. The phases are separated and the organic phase is washed with sat. NaCI solution, dried over MgS04 and concentrated. This gives 350 mg of tert-butyl [cis-3-(tert-butyldimethyl-silanyloxymethyl)cyclohexylmethoxy]acetate as a colorless oil.
C20H4004Si (372.36); LCMS (ESI): 390.3 (M+NH4+).
tert-Butyl 2-[cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexylmethoxy]-2-methylpropionate:
1. LDA, Mel O
O 2. LDA, Mel O
\ 'O O \ 'O O
~Si ~Si cis/racemate cis/racemate 250 mg of tert-butyl [cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexyl-methoxy]acetate are dissolved in 10 ml of abs. tetrahydrofuran and cooled to -78°C (dry ice/acetone bath). 1.70 ml of a 2M lithium diisopropylamide solution in tetrahydrofuran/hexane are then added dropwise. The solution is initially stirred at -78°C for 20 min and then warmed to 0°C
(ice bath), and 950 mg of methyl iodide are added. The solution is stirred at 0°C for 1 h.
1 ml of sat. NH4C1 solution and 10 ml of water are added, and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgS04 and concentrated. The crude product is dissolved in 10 ml of abs. tetrahydrofuran and cooled to -78°C (dry ice/acetone bath). 1.70 ml of a 2M lithium diisopropylamide solution in tetrahydrofuran/hexane are then added dropwise. The solution is initially stirred at -78°C for 20 min and then warmed to 0°C
(ice bath), and 950 mg of methyl iodide are added. The solution is stirred at 0°C for 1 h.
1 ml of sat. NH4C1 solution and 10 ml of water are added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgS04 and concentrated. This gives 220 mg of tert-butyl 2-[cis-3-(tert-butyldimethylsilanyloxymethyl)cyclo-hexylmethoxy]-2-methylpropionate as a light-yellow oil. TLC (heptane/ethyl acetate 4/1): Rf, starting material = 0.66, Rf, product = 0.80.
2-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid:
Et3SiH
BiBr3 O O
'O O O O
~~i O
O
O
O O ~ O %N O O ~N OH
/ \ / \
cis/racemate cislracemate cis/racemate 50 mg of tert-butyl 2-[cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexyl methoxy]-2-methylpropionate are added to a mixture of 20 mg of BiBr3 and 30 mg of HSiEt3 in 0.5 ml of acetonitrile. 38 mg of 5-methyl-2-p-tolyloxazole-4-carbaldehyde in 0.2 ml of acetonitrile are added dropwise, and the mixture is stirred at room temperature overnight. The resulting black solid is filtered and the filtrate is concentrated and taken up in 1 ml of trifluoroacetic acid. The solution is stirred at room temperature overnight.
The solvent is distilled off under reduced pressure and the residue is purified by HPLC. This gives 3.4 mg of 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid as a colorless oil. C24H33N05 (415.24); MS(ES-): 414.25 (M-H+) Example 56:
Analogously to Example 55, tert-butyl (cis-3-(methoxymethoxymethyl)cyclo-hexylmethoxy)acetate, methyl iodide, ethyl iodide and 5-methyl-2-p-tolyloxazole-4-carbaldehyde give 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-3-methylbutyric acid. C25H35N05 (429.25); MS (ES-): 428.22 (M-H+).
O O
O ' ~~ N OH
O
cis/diastereomer mixture Example 57:
TBAF KOtBu THF ~~ PhCI
~O O O O
\ si w ~ ~ w I~
cis/racemate cis/racemate TFA
O O ~ O O
_ O O
O ~N O ~~N OH
O
cis/racemate cis/racemate tert-Butyl 2-[cis-3-hydroxymethylcyclohexylmethoxy]-2-methylpropionate TBAF
THF
.O O O O
\ si cis/racemate cis/racemate 4.5 g of tert-butyl 2-[cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexyl-methoxy]-2-methylpropionate (synthesis analogously to tert-butyl 2-[cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexylmethoxy]-2-methylpropionate in Example 55) are dissolved in 85 ml of THF, 2.24 g of TBAF trihydrate are added and the mixture is stirred at 60°C for 90 min. Water and MTBE are added, the phases are separated and the organic phase is dried over MgS04 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 1:1), which gives 1.45 g of tert-butyl 2-[cis-3-hydroxymethylcyclohexylmethoxy]-2-methylpropionate. C16H3004 (286.42), MS(ESI): 287 (MH+).
2-[cis-3-(5-Methyl-2-(4-biphenyl)oxazol-4-ylmethoxymethyl)cyclohexyl-methoxy]-2-methylpropionic acid 1. KOtBu PhCI
~~iN
O p o v O w 2. TFA OH
O
cis/racemate cis/racemate 50 mg of tert-butyl 2-[cis-3-hydroxymethylcyclohexylmethoxy]-2-methylpropionate and 200 mg of 5-methyl-2-(4-biphenyl)oxazol-4-yl-methoxymethyl iodide are dissolved in 2 ml of chlorobenzene, and 59 mg of potassium tert-butoxide are added. The suspension is stirred at RT for 24 h, 2.5 ml of TFA are then added and the solution is stirred at RT for another 24 h. The solvent is distilled off under reduced pressure and the residue is purified by preparative HPLC, which gives 20 mg of 2-[cis-3-(5-methyl-2-(4-biphenyl)oxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid. C29H35N05 (477.61), MS(ESI): 478 (MH+).

Example 58:
Analogously to Example 57, tert-butyl 2-(cis-3-hydroxymethylcyclohexyl-methoxy]-2-methylpropionate and 5-methyl-2-phenyloxazol-4-ylmethoxy-methyl chloride give 2-[cis-3-(5-methyl-2-phenyloxazol-4-ylmethoxymethyl)-cyclohexylmethoxy]-2-methylpropionic acid. C23H31 N05 (401.51 ); MS
(ESI): 402 (MH+) O O
O ' ~~ N O H
O
cis/racemate Example 59:
Analogously to Example 57, tert-butyl 2-[cis-3-hydroxymethylcyclohexyl-methoxy]-2-methylpropionate and 5-methyl-2-naphthyloxazol-4-ylmethoxy-methyl chloride give 2-[cis-3-(5-methyl-2-naphthyloxazol-4-ylmethoxy-methyl)cyclohexylmethoxy]-2-methylpropionic acid. C27H33N05 (451.57);
MS (ESI): 458 (MH+).

O O
O ' ~~ N O H
O
cis/racemate Example 60:
Analogously to Example 57, tert-butyl 2-[cis-3-hydroxymethylcyclohexyl-methoxy]-2-methylpropionate and 5-ethyl-2-(3-methoxyphenyl)oxazol-4-yl-methoxymethyl chloride give 2-[cis-3-(5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid.
C25H35N05 (445.56); MS (ESI): 446 (MH+).
n O
OH
O
cis/racemate Example 61:
Analogously to Example 57, tert-butyl 2-[cis-3-hydroxymethylcyclohexyl-methoxy]-2-methylpropionate and 5-methyl-2-(4-isopropylphenyl)-oxazol-4-ylmethoxymethyl chloride give 2-[cis-3-(5-ethyl-2-(4-isopropylphenyl)-oxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid.
C26H37N05 (443.59); MS (ESI): 444 (MH+).
O O
O ' ~~ N OH
O
cis/racemate Example 62:
Analogously to Example 57, tert-butyl 2-[cis-3-hydroxymethylcyclohexyl-methoxy]-2-methylpropionate and 5-cyclohexyl-2-p-tolyloxazol-4-yl-methoxymethyl chloride give 2-[cis-3-(5-ethyl-2-p-tolyloxazol-4-ylmethoxy-methyl)cyclohexylmethoxy]-2-methylpropionic acid. C29H41 N05 (483.65);
MS (ESI): 484 (MH+).
O O
O ' ~~ N O H
O
cis/racemate Example 63:
Analogously to Example 57, tert-butyl 2-[cis-3-hydroxymethylcyclohexyl-methoxy]-2-methylpropionate and 5-ethyl-2-p-isopropyloxazol-4-ylmethoxy-methyl chloride give 2-[cis-3-(5-ethyl-2-p-isopropyloxazol-4-ylmethoxy-methyl)cyclohexylmethoxy]-2-methylpropionic acid. C27H39N05 (457.62);
MS (ESI): 458 (MH+).
n O
OH
cis/racemate Example 64:
Analogously to Example 57, tert-butyl 2-[cis-3-hydroxymethylcyclohexyl-methoxy]-2-methylpropionate and 5-ethyl-2-(2-naphthyl)oxazol-4-yl-methoxymethyl chloride give 2-[cis-3-(5-ethyl-2-(2-naphthyl)oxazol-4-yl-methoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid. C28H35N05 (465.59); MS (ESI): 466 (MH+) O O
OH
cis/racemate Example 65:
Analogously to Example 57, tent-butyl 2-[cis-3-hydroxymethylcyclohexyl-methoxy]-2-methylpropionate and 5-ethyl-2-p-tolyloxazol-4-ylmethoxy-methyl chloride give 2-[cis-3-(5-ethyl-2-p-tolyloxazol-4-ylmethoxy-methyl)cyclohexylmethoxy]-2-methylpropionic acid. C25H35N05 (429.56);
MS (ESI): 430 (MH+).
O O
O
i ~N OH
O
cis/racemate Example 66:
Analogously to Example 57, tert-butyl 2-[cis-3-hydroxymethylcyclohexyl-methoxy]-2-methylpropionate and 5-ethyl-2-(3-trifluoromethyl)oxazol-4-yl-methoxymethyl chloride give 2-[cis-3-(5-ethyl-2-(3-trifluoromethyl)oxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid.
C26H34F3N05 (497.56); MS (ESI): 498 (MH+).

O O
O
OH
O
cis/racemate Example 67 4-{cis-3-[2-(3-Methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}-butyric acid O
n Os04 / Na104 O~O ~O PhsP ~ CO2Et O~O ~ O
-~ ~N ----~ -N
\ cis/racemate \ / cis/racemate O ~ ~ O
O
H2/Pd 1 LiOH ~O O
_~ 'O
-N
\ /
cislracemate O
DIBAIOiPr O~O \
O \ ~ O \ -N
\ cisJracemate racemate cis/racemate O
cis-3-Allylcyclohexanol DIBAIOiPr O \ p \
racemate cis/racemate 87 ml of a 1 molar solution of lithium diisobutylaluminum hydride in n-hexane are dissolved in 100 ml of diethyl ether, and 7 ml of isopropanol are added at 0°C. After the evolution of gas has ceased, 12.4 g of cis-3-allylcylohexanone, dissolved in 50 ml of diethyl ether, are added. The mixture is stirred at room temperature for 48 hours. The reaction mixture is quenched by addition of 1 M HCI and the aqueous phase is saturated with sodium chloride and extracted five times with in each case 200 ml of ethyl acetate. The combined organic phases are washed with 2N NaOH and dried over MgS04, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 15:1 => 5:1. This gives 6.8 g of cis-3-allylcyclohexanol as an oil. C9H160 (140.23), MS(ESI): 141 (M+H+), Rf(n-heptane:ethyl acetate = 2:1 ) = 0.22.
4-(cis-3-Allylcyclohexyloxymethyl)-2-(3-methoxyphenyl)-5-methyloxazole O ~ 'O \
O \ ~N
O
cis/racemate ~ cis/racemate 1.8 g of cis-3-allylcyclohexanol are dissolved in 20 ml of dimethyl-formamide, and 770 mg of sodium hydride (60% strength suspension in paraffin oil) are added. After 30 minutes, 4 g of 4-iodomethyl-5-methyl-2-(3-methoxyphenyl)oxazole, dissolved in 20 ml of dimethylformamide, are added dropwise. The mixture is stirred at room temperature for 1 hour.
200 ml of methy tert-buthyl ether are then added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over MgS04 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 750 mg of 4-(cis-3-allyl-cyclohexyloxymethyl)-2-(3-methoxyphenyl)-5-methyloxazole as an oil.
C21 H27N03 (341.45), MS(ESI): 342 (M+H+), Rf(n-heptane:ethyl acetate =
2:1) = 0.26.

{cis-3-[2-(3-Methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}-acetaldehyde O ~ ~O \ w O
,N Os04 / Nal~
O ~ ~ O
cis/racemate cislracemate 750 mg of 4-(cis-3-allylcyclohexyloxymethyl)-2-(3-methoxyphenyl)-5-methyloxazole are dissolved in 20 ml of diethyl ether, and 1.4 g of sodium periodate, dissolved in 20 ml of water, are added. At 0°C, 1 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) is added, and the mixture is stirred vigorously at room temperature. After 8 hours, 100 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over MgS04 and the solvent is then removed under reduced pressure. This gives 740 mg of {cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyl}acetaldehyde as a yellow-brown oil. C20H25N04 (343.43), MS(ESI): 344 (M+H+), Rf(n-heptane:ethyl acetate = 2:1) = 0.10.
Ethyl 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclo-hexyl}but-2-enoate O
.~ O ~ O Ph3P~CO2Et O~O ~ O
° -N J
'N
O
O
cis/racemate cis/racemate 280 mg of {cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclo-hexyl}acetaldehyde are dissolved in 10 ml of dichloromethane, and 370 mg of ethyl (triphenylphosphoranylidene)acetate are added. The mixture is stirred at room temperature for 3 hours. The mixture is washed with saturated sodium chloride solution and dried over MgS04, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1. This gives 190 mg of ethyl 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}but-2-enoate as an oil. C24H31 N05 (413.52), MS(ESI): 414 (M+H+), Rf(n-heptane:ethyl acetate = 2:1) = 0.30.
Ethyl4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclo-hexyl}butyrate O O
O _I O \ O ~ O O
H2/Pd O
_N J _N J
O O
cis/racemate cis/racemate 190 mg of ethyl 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-yl-methoxy]cyclohexyl}but-2-enoate are dissolved in 25 ml of methanol, and mg of Pd (10% on activated carbon) are added. The mixture is stirred at room temperature and under an atmosphere of hydrogen for 7 hours. The catalyst is filtered off through Celite and the filtrate is concentrated under 20 reduced pressure. This gives 110 mg of ethyl 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}butyrate as an oil.
C24H33N05 (415.53), MS(ESI): 416 (M+H+).
4-{cis-3-[2-(3-Methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}-butyric acid O O
O _I O O~ LiOH ~ O O
O
-N ~ -N
\ / \
O O
cis/racemate / cis/racemate 110 mg of ethyl 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}butyrate are dissolved in 5 ml of a mixture of tetrahydrofuran and water in a ratio of 2:1, and 20 mg of lithium hydroxide are added. The mixture is stirred at room temperature for 12 hours. The mixture is acidified by addition of 1 N HCI and extracted with ethyl acetate.
The organic phase is dried over MgS04, and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. Freeze-drying gives 24 mg of 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}butyric acid as a lyophilizate. C22H29N05 (387.48), MS(ESI): 388 (M+H+).
Example 68:
Analogously to Example 67, {cis-3-(2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}acetaldehyde and ethyl 2-(triphenylphosphoranyl-idene)propionate gave 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}-2-methylbutyric acid.
O
O ~ 'O v v O
-N
O
cis/diastereomer mixture C23H31N05 (401.51), MS(ESI): 402 (M+H+) Example 69 2-Ethyl-4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclo-hexyl}butyric acid Ethyl 2-ethyl-4-~cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyl}but-2-enoate O
O ~O O~O ~ O
° -N J
~N
\ /

cis/racemate / cis/racemate 0.4 ml of triethyl phosphonobutyrate is dissolved in 5 ml of tetrahydrofuran, and 0.5 ml of a 2.5 M n-butyllithium solution in n-hexane is added at -20°C.
The mixture is stirred at -20°C for 1 hour, and 386 mg of {cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}acetaldehyde, dissolved in 4 ml of tetrahydrofuran, are then added. After 30 minutes, the reaction mixture is slowly warmed to room temperature, 0.5 ml of water is added, the residue is diluted with ethyl acetate and dried over MgS04 and the solvent is then removed under reduced pressure. This gives 750 mg of ethyl 2-ethyl-4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyl}but-2-enoate as an oil. C26H35N05 (441.57), MS(ESI): 442 (M+H+).
Analogously to Example 67, ethyl 2-ethyl-4-fcis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}but-2-enoate gave 2-ethyl-4-fcis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}butyric acid.
O y _O ~ ~ ~ _O
-N
\ /
/O
cis/diastereomer mixture C24H33N05 (415.53), MS(ESI): 416 (M+H+).
Example 70:
Analogously to Example 69, ~cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}acetaldehyde and triethyl phosphonopentanoate gave 2-(2-fcis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclo-hexyl}ethyl)pentanoic acid.
O ~~ ~O O
-N
\ /
cis/diastereomer mixture C25H35N05 (429.56), MS(ESI): 430 (M+H+) Example 71:
2,2-Dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]-butyric acid TBDPSCI ~ ~ Os04 / Na104 O ~ Si'O
cis/racemate / ~ cis/racemate Si'O ~O PhsP~COZtBu ~ ~ \ CO tBu Si'O z cis/racemate ~ / ~ cis/racemate H2/Pd COztBu ~ ~ LDA, Mel O O COZtBu Si' Si' 2. LDA, Mel cis/racemate cis/racemate TBAF COZtBu ~ O _I O
-~ O v v -N
cis/racemate ~ ~ cis/racemate O~O O
TFA _N
cis/racemate (cis-3-Allylcyclohexyloxy)-tert-butyldiphenylsilane TBDPSCI
O ~ Si~O
cis/racemate cis/racemate 6.8 g of cis-3-allylcyclohexanol are, together with 15 ml of tert-butyl-diphenylsilyl chloride, 5 g of imidazole and 200 mg of dimethyl-aminopyridine, dissolved in 100 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h. 400 ml of methyl tert-butyl ether are added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over MgS04 and the solvent is then removed under reduced pressure. This gives 20.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenyl-silane as an oil. C25H340Si (378.64), MS(ESI): 379 (M+H+), Rf(n-heptane:ethyl acetate = 2:1) = 0.93.
[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]acetaldehyde Si~O ~ Os04/Na 04 Si~O ~O
cis/racemate cis/racemate 5.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenyl-silane are dissolved in 100 ml of diethyl ether, and 9.4 g of sodium periodate, dissolved in 100 ml of water, are added. At 0°C, 15 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 5 hours, a further 5 g of sodium periodate are added, and the mixture is stirred at room temperature for another 3 hours.
The reaction mixture is then diluted by addition of 300 ml of methyl tert-butyl ether and washed with saturated sodium thiosulfate solution. The organic phase is dried over MgS04 and the solvent is then removed under reduced pressure. This gives 6 g of [cis-3-(tert-butyldiphenylsilanyloxy)-cyclohexyl]acetaldehyde as a yellow-brown oil.
C24H3202Si (380.61), MS(ESI): 381 (M+H+), Rf(n-heptane:ethyl acetate =
5:1) = 0.44.
tert-Butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]but-2-enoate SI~O ~O PhsP~CO2tBu ~ ~ ~ CO tBu Si~~
cis/racemate cis/racemate 3.4 g of [cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]acetaldehyde are dissolved in 100 ml of dichloromethane, and 5 g of tert-butyl (triphenylphosphoranylidene)acetate are added. Under reflux, the mixture is heated at the boil for 1 hour. The mixture is washed with saturated sodium chloride solution and dried over MgS04, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 20:1. This gives 2.4 g of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]but-2-enoate as an oil. C30H4203Si (478.75), MS(ESI): 479 (M+H+), Rf(n-heptane:ethyl acetate = 5:1 ) = 0.56.
tert-Butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]butanoate COZtBu H2/Pd C02tBu Si ~O ----~ Si ~O
cis/racemate cis/racemate 2.4 g of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]but-2-enoate are dissolved in 35 ml of methanol, and 200 mg of PD (10% on activated carbon) are added. At room temperature, the mixture is stirred under an atmosphere of hydrogen for 7 hours. The catalyst is filtered off through Celite and the filtrate is concentrated under reduced pressure. This gives 2.3 g of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-butanoate as an oil. C30H44O3Si (480.75), MS(ESI): 481 (M+H+).
tert-Butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-2,2-dimethyl-butyrate 1. L~el ~ ~ CO tBu CO tBu Si~O Si~O
2. LDA, Mel cis/racemate cis/racemate 2 g of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]butanoate are dissolved in 20 ml of tetrahydrofuran, and 3.1 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to -30°C, and 1.6 ml of methyl iodide are added. Over a period of 12 hours, the mixture is allowed to warm to room temperature. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated NaCI solution. The organic phase is dried over MgS04 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate =
10:1. This gives 2.1 g of the monomethylated product. This product is dissolved in 20 ml of tetrahydrofuran, and 6 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added at -78°C. The reaction mixture is stirred at -78°C for 2 hours and then warmed to 0°C, and, after 10 minutes at 0°C, 2.5 ml of methyl iodide are added. Over a period of 12 hours, the mixture is allowed to warm to room temperature. The reaction mixture is then diluted by addition of 150 ml of methyl tert-buthyl ether and washed with saturated NaCI solution. The organic phase is dried over MgS04 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 10:1. This gives 1.8 g of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate as an oil.
C32H48O3Si (508.82), Rf(n-heptane:ethyl acetate = 5:1) = 0.49.
tert-Butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate O C02tBu TBAF
v v ~ ~ C02tBu Si~ O a a cis/racemate cis/racemate 2 g of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate are dissolved in 10 ml of tetrahydrofuran, and 8 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added.
The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 20:1 => 1:1. This gives 730 mg of tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate as an oil.
C16H30O3 (270.42), Rf(n-heptane:ethyl acetate = 5:1) = 0.22.
tert-Butyl 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclo-hexyl]butyrate O
O C02tBu _~ O ~N 'O ~ ~
cis/racemate cis/racemate 365 mg of tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate are, together with 850 mg of 4-iodomethyl-5-methyl-2-(4 methylphenyl)oxazole, dissolved in 5 ml of dimethylformamide, and 110 mg of sodium hydride (60% strength in paraffin) are added. After 1 hour of stirring at room temperature, 100 ml of methyl tert-butyl ether are added and the reaction mixture is washed three times with water. The organic phase is dried over MgS04 and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 330 mg of tert-butyl 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyrate as a white solid. C28H41 N04 (455.64), MS(ESI): 456 (M+H+).
2,2-Dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]-butyric acid O ~O O ~ O v v ~ -0 ,N ~ ,N
\ / \
cis/racemate cis/racemate 300 mg of tert-butyl 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyrate are dissolved in 20 ml of dichloromethane, and 10 ml of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 1 hour. 200 ml of toluene are added and the solvents are then concentrated under reduced pressure. The residue is purified by RP-HPLC. This gives 180 mg of 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyric acid as an oil. C24H33N04 (399.53), MS(ESI): 400 (M+H+).
Example 72:
Analogously to Example 71, tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate and 4-iodomethyl-5-methyl-2-(3-trifluoromethylphenyl)-oxazole gave 2,2-dimethyl-4-~3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl~butyric acid.

O
O \~ O O
-N
F F
F
cis/racemate C24H30F3N04 (453.50), MS(ESI): 454 (M+H+).
Example 73:
3-Methyl-2-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethyl}butyric acid tert-Butyl 2-(diethoxyphosphoryl)-3-methylbutyrate O NaH, isopropyl iodide ~O\O O
O ~P
\~O O
racemate 5.5 ml of tert-butyl diethylphosphonoacetate are dissolved in 20 ml of dimethylformamide, and 820 mg of sodium hydride (60% strength in paraffin oil) are added a little at a time at 0°C. The suspension is stirred at 0°C for 15 minutes, and 2.4 ml of isopropyl iodide are then added. The mixture is stirred at room temperature for 12 hours. 250 ml of ethyl acetate are then added, and the reaction mixture is washed three times with in each case 150 ml of water. The organic phase is dried over MgS04 and concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 5:1. This gives 4.2 g of tert-butyl 2-(diethoxyphosphoryl)-3-methylbutyrate as an oil. C13H2705P
(294.33), MS(ESI): 239 (M-C4Hg+H+), Rf(n-heptane:ethyl acetate = 1:1) _ 0.34.

tert-Butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-2-isopropylbutyr-2-enoate Si~O O O ~ COztBu Si cis/racemate cis/racemate 770 mg of tert-butyl 2-(diethoxyphosphoryl)-3-methylbutyrate are dissolved in 10 ml of tetrahydrofuran, and 0.73 ml of a 2.7 M solution of n-butyllithium in n-hexane is added at -20°C. After 1 hour of stirring at -20°C, 500 mg of [cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]acetaldehyde, dissolved in 5 ml of tetrahydrofuran, are added dropwise. The reaction mixture is slowly warmed to room temperature. 20 ml of water are then added, and the mixture is extracted three times with in each case 50 ml of ethyl acetate.
The combined organic phases are dried over MgS04 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 30:1. This gives 340 mg of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-2-isopropyl-butyr-2-enoate as an oil. C33H48O3Si (520.83), Rf(n-heptane:ethyl acetate = 5:1 ) = 0.70.
4-[cis-3-(tert-Butyldiphenylsilanyloxy)cyclohexyl]-2-isopropylbutyric acid Si~O ~ COztBu 1.Pd/C COztBu O
2. TBAF
cis/racemate cis/diastereomer mixture 1.5 g of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-2-isopropylbutyr-2-enoate are dissolved in 30 ml of ethyl acetate, and 200 mg of Perlman's catalyst are added. The mixture is stirred under an atmosphere of hydrogen (5 bar) for 5 hours. The catalyst is filtered off through Celite and the filtrate is concentrated under reduced pressure. The residue is dissolved in 15 ml of tetrahydrofuran, and 3 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60°C for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate = 40:1 => 10:1. This gives 400 mg of 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-2-isopropylbutyric acid as an oil.
C17H32O3 (284.44), MS(ESI): 211 (M-C4Hg0-), Rf(n-heptane:ethyl acetate = 10:1) = 0.15.
Analogously to Example 73, 4-iodomethyl-5-methyl-2-(4 methylphenyl)-oxazole and 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-2-isopropyl-butyric acid gave 3-methyl-2-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexyl]ethyl}butyric acid.
~~O O
-N
cis/racemate C25H35N04 (413.56), MS(ESI): 414 (M+H+) Example 74:
Analogously to Example 73, 4-iodomethyl-5-methyl-2-(3 methoxyphenyl)-oxazole and 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-2-isopropyl-butyric acid gave 2-(2-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}ethyl)-3-methylbutyric acid.
~~O O
-N
O
cis/diastereomer mixture C25H35N05 (429.56), MS(ESI): 430 (M+H+) Example 75:
2-Benzyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyric acid Analogously to Example 73, tert-butyl diethylphosphonoacetate and benzyl bromide gave tert-butyl 2-(diethoxyphosphoryl)-3-phenylpropionate.
O O
O," ~
~O.P O' \
i cis/racemate C17H2705P (342.38), Rf(n-heptane:ethyl acetate = 1:1) = 0.53.
Analogously to Example 73, tert-butyl 2-(diethoxyphosphoryl)-3-phenylpropionate, [cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-acetaldehyde and 4-iodomethyl-5-methyl-2-(4 methylphenyl)oxazole gave 2-benzyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyric acid.
_~~ O O
N y i cis/diastereomer mixture C29H35N04 (461.61 ), MS(ESI): 462 (M+H+) Example 76:
4-Methyl-2-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethyl}pentanoic acid Analogously to Example 73, tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]butanoate, 3-bromo-2-methylpropene and 4-iodomethyl-5-methyl-2-(4 methylphenyl)oxazole gave tert-butyl 4-methyl-2-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}pent-4-enoate.
O
O \~O O
-N
I
cis/diastereomer mixture C30H43N04 (481.68), MS(ESI): 482 (M+H+) 4-Methyl-2-{2-[cis.3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclo-hexyl]ethyl}pentanoic acid O 1.H2/Pd ~O O
v v v v \ -N ~ ' -N
2. TFA ~ /
cis/diastereomer mixture cis/diastereomer mixture 500 mg of tert-butyl 4-methyl-2-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}pent-4-enoate are dissolved in 20 ml of ethyl acetate, and 50 mg of palladium (10% on activated carbon) are added. The mixture is stirred under an atmosphere of hydrogen (5 bar) for 5 hours. The catalyst is filtered off through Celite and the filtrate is concentrated under reduced pressure. The residue is dissolved in 20 ml of dichloromethane, and 10 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 1 hour. 100 ml of toluene are added, and the solvents are then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 100 mg of 4-methyl-2-{2-(cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}pentanoic acid as an oil. C26H37N04 (427.59), MS(ESI): 428 (M+H+).
Example 77:

2-(2-{cis-3-(5-Methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclo-hexyl}ethyl)-2-propylpentanoic acid Analogously to Example 71, tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]butanoate and allyl bromide gave tert-butyl 2-allyl-2-~2-[3-(tert-butyldiphenylsilanyloxy)cyclohexyl]ethyl}pent-4-enoate.
/ \
O
~Si-O O
\ / ~/
cis/racemate C36H52O3Si (560.90), Rf(n-heptane:ethyl acetate = 20:1) = 0.60.
Analogously to Example 71 and Example 76, tert-butyl 2-allyl-2-{2-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]ethyl}pent-4-enoate and 4-iodomethyl-5-methyl-2-(3-trifluoromethylphenyl)oxazole gave 2-(2-{cis-3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)-2-propylpentanoic acid.
\~O O
-N
F F
F
cis/racemate C28H38F3N04 (509.61), MS(ESI): 510 (M+H+).
Example 78:
1-{2-[cis-3-(5-Methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}cyclo-pentanecarboxylic acid tert-Butyl 1-{2-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]ethyl}cyclo-pent-3-enecarboxylate P(Cy)3 O P(Cy)3 Ru_ ~SI'O ~ CI~CI
-~ ~SI'O O
\ /
\ /
cis/racemate cis/racemate 2 g of tent-butyl 2-allyl-2-~2-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]
ethyl}pent-4-enoate are dissolved in 100 ml of dichloromethane. For 5 minutes, argon is passed through the solution. 100 mg of Grubbs' catalyst are then added. The mixture is stirred at 40°C for 2 hours.
The solvent is then removed under reduced pressure and the residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate = 40:1. This gives 1.4 g of tert-butyl 1-{2-[cis-3-(tert-butyldiphenylsilanyloxy)cyclo-hexyl]ethyl}cyclopent-3-enecarboxylate as an oil. C34H48O3Si (532.85), Rf(n-heptane:ethyl acetate = 20:1 ) = 0.56.
Analogously to Example 77, tert-butyl 1-{2-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]ethyl~cyclopent-3-enecarboxylate and 4-iodomethyl-5-methyl-2-(4-methylphenyl)oxazole gave 1-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}cyclopentanecarboxylic acid.
O
O ~O O
-N
cis/racemate C26H35N04 (425.57), MS(ESI): 426 (M+H+) Example 79:
2-(4-Methoxyphenoxycarbonyl)-~2-[cis-3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyl]ethyl~amino)-3-methylbutyric acid O Chiral O O 0 ~ O~N O
O
-N -N O
\ /
cis/racemate cis/diastereomer mixture Chiral Chiral 0~ Y
O~O~N~O I / O~O~~O
-~N O CI 0~ ~N 0 O ~~O
\ ~ \ / / I
cis/diastereomer mixture .°
cis/diastereomer mixture Chiral Chiral O \ O~N O ~ ~ O
O O N
-N ~ O
0 O ~ -N O~O O
TFA
\ / ~I ~ \ / ~I
\ \
/o /o cis/diastereomer mixture cis/diastereomer mixture tert-Butyl (S)-3-methyl-2-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]ethylamino}butyrate Chiral O~O ~O ~ O~O N O
-N ~N O
N
cis/diastereomer mixture cis/diastereomer mixture 0.1 g of ~cis-3-[2-(3-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}-acetaldehyde (prepared according to process E4) is initially charged in methylene chloride, and a spatula tip of magnesium sulfate is added. 64 mg of amine are then added, the mixture is cooled to 0°C, 30 mg of sodium acetate are added and the mixture is stirred for 30 min. 84 mg of sodium triacetoxyborohydride are added, and the mixture is stirred at RT overnight.
8 ml of water are added to the reaction and the mixture is filtered through a kieselguhr cartridge, the cartridge is washed with 50 ml of methylene chloride and the solvent is removed under reduced pressure. This gives 0.13 g of tert-butyl (S)-3-methyl-2-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyl]ethylamino}butyrate. C29H44N204 (484), MS (ESI):
485 (M+H).
tert-Butyl (S)-2-((4-methoxyphenoxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-3-methylbutyrate O ~O Chiral Chiral CI \\ ~ N NN~''~0~~'O

/O
cis/diastereomer mixture cisldiastereomer mixture 130 mg of tert-butyl (S)-3-methyl-2-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyl]ethylamino}butyrate are dissolved in 1 ml of methylene chloride, 2 ml of a sat. sodium carbonate solution are added and the mixture is cooled to 0°C, an excess of the acid chloride is then added and the mixture is stirred at RT for 1 h. The entire reaction solution is applied to a kieselguhr cartridge and the cartridge is washed with 20 ml of methylene chloride. The solvent is removed under reduced pressure. This gives 0.1 g of tert-butyl (S)-2-((4-methoxyphenoxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-3-methylbutyrate.
C37H50N207 (635), MS (ESI):636 (M+H) (S)-2-((4-Methoxyphenoxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-3-methylbutyric acid Chiral 0 ~0 Chiral rvrv ~~''0 -N O~O O 0 O~N~O
-N 0~0 O
I -\ ~ ~ /
/o \ I

cis/diastereomer mixture cis/diastereomer mixture 0.10 g of tert-butyl (S)-2-((4-methoxyphenoxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-3-methylbutyrate are dissolved in 2 ml of dichloromethane, and the solution is stirred with 1 ml of trifluoroacetic acid at RT overnight. The solvent is then removed completely and the residue is purified by preparative HPLC. This gives 15.6 mg of (S)-2-((4-methoxyphenoxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-3-methylbutyric acid. C33H42N207 (579), MS (ESI): 580 (M+H) Example 80:
Analogously to Example 79, [cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]acetaldehyde and methyl 1-aminocyclopentanecarboxylate gave 1-(benzyloxycarbonyl-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]ethyl}amino)cyclopentanecarboxylic acid.

O O N
-N ~O O
cis/racemate C34H42N206 (574.7), MS(ESI): 575 (M+H) Example 81:
Analogously to Example 79, cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]acetaldehyde and methyl 1-aminocyclopentanecarboxylate gave 1-((4-methoxybenzyloxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyl]ethyl~amino)cyclopentanecarboxylic acid.

O O N
-N O~O O
~O
cis/racemate C35H44N207 (604.7), MS(ESI): 605 (M+H) Example 82:
Analogously to Example 79, cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]acetaldehyde and methyl (S)-2-amino-2-methyl-3-phenyl-propionate gave (R)-2-((4-methoxybenzyloxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-2-methyl-3-phenylpropionic acid.
i O ~ O N
-N O~O O
~O
cis/diastereomer mixture C39H46N207 (654.8), MS(ESI): 656 (M+H) Example 83:
Analogously to Example 79, cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]acetaldehyde and methyl (S)-2-amino-2-methyl-3-phenylpropionate gave (benzyloxycarbonyl-f2-[cis-3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)acetic acid \ O
p O N
-N O~O IIO
cis/racemate C30H36N207 (520.6), MS(ESI): 521 (M+H) Example 84:
Analogously to Example 79, cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]acetaldehyde and methyl (S)-2-amino-2-methyl-3-phenyl-propionate gave ({2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]ethyl}phenylacetylamino)acetic acid.
O
O \ O N II
-N O
~O
cis/racemate C30H36N205 (504.6), MS(ESI): 505 (M+H) Example 85:
Analogously to Example 79, cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]acetaldehyde and methyl (S)-2-amino-2-methyl-3-phenyl-propionate gave (1-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyl]ethyl}-3-phenylureido)acetic acid.

\ O
O O N
-N N~O I IO
cis/racemate C29H35N205 (505.6), MS(ESI): 506 (M+H)

Claims (15)

1. A compound of the formula I

in which:
Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, where in the cycloalkanediyl or cycloalkenediyl rings one or more carbon atoms may be replaced by oxygen atoms;
R1, R2 independently of one another are H, F, Cl, Br, CF3, OCF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, SCF3, SF5, OCF2-CHF2, (C6-C10)-aryl, (C6-C10)-aryloxy, OH, NO2; or R1 and R2 together with the phenyl, pyridine, 1H-pyrrole, thiophene or furan ring form fused, partially or unsaturated bicyclic (C6-C10)-aryl, (C5-C11)-heteroaryl;
R3 is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C1-C3)-alkyl-(C3-C8)-cycloalkyl, phenyl, (C1-C3)-alkyl-phenyl, (C5-C6)-heteroaryl, (C1-C3)-alkyl-(C5-C6)-heteroaryl or (C1-C3)-alkyl which is fully or partially substituted by F;
W is CH or N if o = 1;
W is O, S or NR10 if o = 0;
X is (C1-C6)-alkanediyl, where in the alkanediyl group one or more carbon atoms may be replaced by oxygen atoms;

Y1 is (CR13R14)p;
p is 1 or 2;
Y2 is CH2, O, S, SO, SO2 or NR9;
n is 0-2;
R4 is H, (C1-C6)-alkyl; or F if Y2 is not O, NR9;
R5 is H, (C1-C6)-alkyl; or F if Y2 is not O, NR9;
R6 is H, (C1-C6)-alkyl; or F if n is not 0;
R7 is H, F (if n is not 0), (C1-C6)-alkyl, (C1-C6)-alkoxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl, where alkyl may be unsubstituted or substituted by one or more radicals selected from the group consisting of hydroxyl, phenyl, (C5-C11)-heteroaryl, (C1-C6)-alkoxy and NR11R12, and phenyl may be unsubstituted or substituted by one or more radicals from the group consisting of hydroxyl, (C1-C6)-alkoxy, F and CF3; with the proviso that R7 is not NR11R12 or (C1-C6)-alkoxy if R6 = F;
R6 and R7 together with the carbon atom that carries them are (C3-C8)-cycloalkyl;
R8 is H, (C1-C6)-alkyl;
R9 is H, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, aryl-(C1-C4)-alkyl, CO-(C1-C6)-alkyl, CO-(C6-C10)-aryl, CO-(C1-C6)-alkyl-(C6-C10)-aryl, CO-(C5-C11)-heteroaryl, C(O)-O-(C1-C6)-alkyl, C(O)-O-(C1-C6)-alkyl-(C6-C10)-aryl, C(O)-O-(C6-C10)-aryl, C(O)-O-(C5-C11)-heteroaryl, SO2-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl-(C6-C10)-aryl, SO2-(C1-C6)-alkyl-SO2-(C1-C6)-alkyl, SO2-(C6-C10)-aryl, SO2-(C5-C11)-heteroaryl, where aryl and heteroaryl may be unsubstituted or substituted by (C1-C6)-alkyl, O-(C1-C6)-alkyl, F, Cl, CO-(C1-C6)-alkyl;
R10 is H, (C1-C6)-alkyl, (C1-C6)-alkyl-phenyl;
R11 is H, (C1-C6)-alkyl, (C1-C6)-alkyl-phenyl;
R12 is H, (C1-C6)-alkyl, (C1-C6)-alkyl-phenyl;
R13 is H, (C1-C6)-alkyl;
R14 is H, (C1-C6)-alkyl;
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 or (C3-C8)-cycloalkenediyl, where in the cycloalkanediyl or cycloalkenediyl rings one carbon atom may be replaced by an oxygen atom;
X is (C1-C6)-alkanediyl, where in the alkanediyl group the C1 or C2 carbon atom (to Ring A) may be replaced by an oxygen atom.
3. A compound of the formula I as claimed in one or more of claims 1 to 2, in which Ring A is cis-cyclohexane-1,3-diyl R1, R2 independently of one another are H, F, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl, or R1 and R2 together with the phenyl ring = naphthyl;

R3 is (C1-C6)-alkyl, (C3-C8)-cycloalkyl, phenyl;
W is CH if o = 1;
W is O or S if o = 0;
X is CH2O or CH2-O-CH2;
Y1 is CH2;
Y2 is CH2, O, S, SO, SO2 or NR9;
n is 0;
R4 is H;
R5 is H;
R6 is H, (C1-C6)-alkyl, benzyl;
R7 is H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl, benzyl, R6 and R7 together with the carbon atom that carries them are (C3-C6)-cycloalkyl;
R8 is H;
R9 is H; (C1-C6)-alkyl which may be unsubstituted or substituted by (C3-C6)-cycloalkyl, phenyl, (C5-C6)-heteroaryl; CO-(C1-C6)-alkyl, CO-(C1-C6)-alkyl-phenyl, CO-phenyl, C(O)-O-(C1-C6)-alkyl, CO-NH-phenyl, SO2-(C1-C4)-alkyl, SO2-(C1-C4)-alkyl-SO2-(C1-C4)-alkyl, SO2-tolyl, where phenyl for its part may be substituted by O-(C1-C3)-alkyl;
and its physiologically acceptable salts.
4. A pharmaceutical, comprising one or more compounds of formula I
as claimed in one or more of claims 1 to 3.
5. A pharmaceutical, comprising one or more compounds of the formula I as claimed in one or more of claims 1 to 3 and one or more active compounds having favorable effects on metabolic disorders or diseases associated therewith.
6. A pharmaceutical, comprising one or more compounds of the formula I as claimed in one or more of claims 1 to 3 and one or more antidiabetics.
7. A pharmaceutical, comprising one or more compounds of the formula I as claimed in one or more of claims 1 to 3 and one or more lipid modulators.
8. The use of the compounds of the formula I as claimed in one or more of claims 1 to 3 for the treatment and/or prevention of disorders of the fatty acid metabolism and glucose utilization disorders.
9. The use of the compounds of the formula I as claimed in one or more of claims 1 to 3 for the treatment and/or prevention of disorders where insulin resistance is involved.
10. The use of the compounds of the formula I as claimed in one or more of claims 1 to 3 for the treatment and/or prevention of diabetes mellitus and its sequelae.
11. The use of the compounds of the formula I as claimed in one or more of claims 1 to 3 for the treatment and/or prevention of dyslipidemias and their sequelae.
12. The use of the compounds of the formula I as claimed in one or more of claims 1 to 3 for the treatment and/or prevention of states associated with metabolic syndrome.
13. The use of the compounds as claimed in one or more of claims 1 to 3 in combination with at least one further active compound for the treatment and/or prevention of disorders of the fatty acid metabolism and glucose utilization disorders.
14. The use of the compounds as claimed in one or more of claims 1 to 3 in combination with at least one further active compound for the treatment and/or prevention of disorders in which insulin resistance is involved.
15. A process for preparing a pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3, which comprises mixing the active compound with a pharmaceutically acceptable carrier and bringing this mixture into a form suitable for administration.
CA 2517381 2003-02-27 2004-02-19 3-(2-phenyl-oxazol-4-yl methoxy) cyclohexylmethoxy acetic acid derivatives and related compounds used as ppar modulators for treating type 2 diabetes and arteriosclerosis Abandoned CA2517381A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
DE2003108355 DE10308355A1 (en) 2003-02-27 2003-02-27 Aryl-cycloalkyl substituted alkane acid derivatives, processes for their preparation and their use as medicaments
DE10308355.3 2003-02-27
PCT/EP2004/001579 WO2004076427A1 (en) 2003-02-27 2004-02-19 3-(2-phenyl-oxazol-4-yl methoxy) cyclohexylmethoxy acetic acid derivatives and related compounds used as ppar modulators for treating type 2 diabetes and arteriosclerosis

Publications (1)

Publication Number Publication Date
CA2517381A1 true true CA2517381A1 (en) 2004-09-10

Family

ID=32920629

Family Applications (3)

Application Number Title Priority Date Filing Date
CA 2516620 Abandoned CA2516620A1 (en) 2003-02-27 2004-02-19 3-methyl-2- (3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexanecarbonyl-amino butyric acid derivatives and related compounds as ppar modulators for the treatment of type 2 diabetes and atherosclerosis
CA 2517381 Abandoned CA2517381A1 (en) 2003-02-27 2004-02-19 3-(2-phenyl-oxazol-4-yl methoxy) cyclohexylmethoxy acetic acid derivatives and related compounds used as ppar modulators for treating type 2 diabetes and arteriosclerosis
CA 2517386 Abandoned CA2517386A1 (en) 2003-02-27 2004-02-19 4-(3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butane acid derivatives and related compounds as ppar modulators for treating diabetes of type 2 and atherosclerosis

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA 2516620 Abandoned CA2516620A1 (en) 2003-02-27 2004-02-19 3-methyl-2- (3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexanecarbonyl-amino butyric acid derivatives and related compounds as ppar modulators for the treatment of type 2 diabetes and atherosclerosis

Family Applications After (1)

Application Number Title Priority Date Filing Date
CA 2517386 Abandoned CA2517386A1 (en) 2003-02-27 2004-02-19 4-(3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butane acid derivatives and related compounds as ppar modulators for treating diabetes of type 2 and atherosclerosis

Country Status (11)

Country Link
US (5) US7259177B2 (en)
EP (3) EP1599453B1 (en)
JP (3) JP2006519194A (en)
KR (3) KR20050106461A (en)
CN (3) CN100398526C (en)
CA (3) CA2516620A1 (en)
DE (4) DE10308355A1 (en)
DK (3) DK1599453T3 (en)
ES (3) ES2329366T3 (en)
RU (3) RU2005129992A (en)
WO (3) WO2004076428A1 (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7576131B2 (en) 1999-06-04 2009-08-18 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia
US6262118B1 (en) * 1999-06-04 2001-07-17 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes and hyperlipidemia
US7399777B2 (en) * 2001-08-31 2008-07-15 Sanofi-Aventis Deutschland Gmbh Diarylcycloalkyl derivatives, processes for their preparation and their use as pharmceuticals
DE10308353A1 (en) * 2003-02-27 2004-12-02 Aventis Pharma Deutschland Gmbh Diarylcycloalkylderivate, processes for their preparation and their use as medicaments
DE102004038403B4 (en) * 2004-08-07 2006-08-31 Sanofi-Aventis Deutschland Gmbh A process for preparing the enantiomeric forms of cis-configured 3-hydroxycyclohexanecarboxylic acid derivatives
DE102004039532B4 (en) * 2004-08-14 2006-09-21 Sanofi-Aventis Deutschland Gmbh Cyclohexyl-methyloxy-substituted acetic acid derivatives, processes for their preparation and their use as medicaments
DE102004039533B4 (en) * 2004-08-14 2006-09-28 Sanofi-Aventis Deutschland Gmbh Acetic acid derivatives having cyclohexylmethoxy substituents, processes for their preparation and their use as medicaments
DE102004039509B4 (en) * 2004-08-14 2006-09-21 Sanofi-Aventis Deutschland Gmbh Aryl-cycloalkyl substituted alkane acid derivatives, processes for their preparation and their use as medicaments
DE102004060227B3 (en) * 2004-12-15 2006-07-20 Sanofi-Aventis Deutschland Gmbh A process for the production of oxazoles by condensation of aromatic aldehydes with α-ketoximes to N-oxides and subsequent reaction with activated acid derivatives
JP2008543767A (en) * 2005-06-10 2008-12-04 ノバルティス アクチエンゲゼルシャフト Direct compression formulations and methods of dpp-iv inhibitors and glitazones
RU2008112198A (en) 2005-09-29 2009-10-10 Санофи-Авентис (Fr) Derivatives phenyl-1,2,4-oxadiazolones, processes for their preparation and their use as pharmaceuticals
KR101398715B1 (en) 2006-08-10 2014-05-27 가부시키가이샤 미모잭스 Hypoglycemic composition containing component originating in the bark of tree belonging to the genus acacia
JP5340287B2 (en) 2007-08-16 2013-11-13 ソルヴェイ(ソシエテ アノニム) 4-fluoro-substituted 3-oxo - process for the preparation of esters of alkanoic acids
RU2495877C2 (en) 2008-02-29 2013-10-20 Ниссан Кемикал Индастриз, Лтд. Method of producing thiophene derivative and intermediate product thereof
US7615661B2 (en) * 2008-03-12 2009-11-10 International Flavors & Fragrances Inc. Thioester compounds and their use in fragrance or flavor applications

Family Cites Families (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2663336B1 (en) 1990-06-18 1992-09-04 Adir New peptide derivatives, their process for the preparation and pharmaceutical compositions containing them.
FR2663464B1 (en) 1990-06-19 1992-09-11 Commissariat Energie Atomique Circuit integrated in silicon on insulator technology with a field-effect transistor and method for making.
US5723458A (en) 1993-02-15 1998-03-03 Glaxo Wellcome Inc. Hypolipidaemic compounds
WO1994018183A1 (en) 1993-02-15 1994-08-18 The Wellcome Foundation Limited Hypolipidaemic condensed 1,4-thiazepines
JP3144624B2 (en) 1995-06-02 2001-03-12 杏林製薬株式会社 N- benzyl-dioxo-thiazolyl Gilles benzamide derivatives and their preparation
WO1997026265A1 (en) 1996-01-17 1997-07-24 Novo Nordisk A/S Fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives, their preparation and use
CN1190434C (en) 1996-12-31 2005-02-23 雷迪实验室有限公司 Novel heterocyclic compounds and process for its preparation, and pharmaceutical compositions containing them and their use in treatment of diabetes and related diseases
ES2283025T3 (en) 1996-08-30 2007-10-16 Novo Nordisk A/S GLP-1.1.
DE69729947D1 (en) 1996-11-07 2004-08-26 Novartis Ag N-substituted 2-cyanopyrrolidines
DE19726167B4 (en) 1997-06-20 2008-01-24 Sanofi-Aventis Deutschland Gmbh Insulin, process for its preparation and pharmaceutical preparation containing
RU2215004C2 (en) 1997-07-16 2003-10-27 Ново Нордиск А/С Condensed derivative of 1,2,4-thiadiazine, pharmaceutical composition and method for preparing medicine
US6380230B1 (en) 1997-09-19 2002-04-30 Sanofi-Synthelabo Carboxamidothiazole derivatives, preparation, pharmaceutical compositions containing them
WO1999046232A1 (en) * 1998-03-10 1999-09-16 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivatives and drugs containing the same as the active ingredient
DE19823831A1 (en) 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim New pharmaceutical use of isoleucyl thiazolidide and its salts
DK1084102T3 (en) 1998-06-04 2004-02-02 Astrazeneca Ab New 3-arylpropionic acid derivatives and analogs
CN1310881C (en) 1998-06-04 2007-04-18 阿斯特拉曾尼卡有限公司 New 3-aryl-2-hydroxypropionic acid derivative I
US6221897B1 (en) 1998-06-10 2001-04-24 Aventis Pharma Deutschland Gmbh Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use
DE19828114A1 (en) 1998-06-24 2000-01-27 Probiodrug Ges Fuer Arzneim Prodrugs of unstable inhibitors of dipeptidyl peptidase IV
DE19828113A1 (en) 1998-06-24 2000-01-05 Probiodrug Ges Fuer Arzneim Prodrugs of inhibitors of dipeptidyl peptidase IV
EP1108713A4 (en) * 1998-08-27 2006-04-05 Ono Pharmaceutical Co Carboxylic acid derivatives and drugs containing the same as the active ingredient
DE19845405C2 (en) 1998-10-02 2000-07-13 Aventis Pharma Gmbh Aryl-substituted propanolamine and their use
GB9900416D0 (en) 1999-01-08 1999-02-24 Alizyme Therapeutics Ltd Inhibitors
DE19916108C1 (en) 1999-04-09 2001-01-11 Aventis Pharma Gmbh With sugar residues substituted 1,4-benzothiazepine-1,1-dioxide derivatives, processes for their preparation and their use
WO2000063208B1 (en) 1999-04-16 2000-12-14 Novo Nordisk As Substituted imidazoles, their preparation and use
US6908926B1 (en) 1999-04-16 2005-06-21 Novo Nordisk A/S Substituted imidazoles, their preparation and use
KR100709498B1 (en) 1999-04-28 2007-04-20 사노피-아벤티스 도이칠란트 게엠베하 Di-aryl acid derivatives as PPAR receptor ligands
WO2000064876A1 (en) * 1999-04-28 2000-11-02 Aventis Pharma Deutschland Gmbh Tri-aryl acid derivatives as ppar receptor ligands
EP1175421A1 (en) 1999-04-30 2002-01-30 Neurogen Corporation 9H-PYRIMIDO[4,5-b]INDOLE DERIVATIVES: CRF1 SPECIFIC LIGANDS
GB9911863D0 (en) 1999-05-21 1999-07-21 Knoll Ag Therapeutic agents
DE60029446D1 (en) 1999-06-18 2006-08-31 Merck & Co Inc Arylthiazolidinedione and aryloxa zolidinedion derivatives
US6413737B1 (en) 1999-07-09 2002-07-02 Cohesion Technologies, Inc. Ecarin prothrombin protease and methods
DE60004066T2 (en) 1999-07-29 2004-04-15 Eli Lilly And Co., Indianapolis Benzofurylpiperazine: 5-HT2C agonist serotonin receptor
EP1218341B1 (en) 1999-09-01 2005-08-24 Aventis Pharma Deutschland GmbH Sulfonyl carboxamide derivatives, method for their production and their use as medicaments
JP4332315B2 (en) 1999-09-22 2009-09-16 ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company Useful substituents acid derivatives and methods as antidiabetic agents and antiobesity agents
JP2003515580A (en) 1999-12-03 2003-05-07 アストラゼネカ アクチボラグ (S)-2-ethoxy-3- [4- (2- [4-methanesulfonyloxy-phenyl] ethoxy) phenyl] finely divided form propanoic acid
ES2215769T3 (en) 1999-12-03 2004-10-16 Astrazeneca Ab -2-ethoxy-3- (4- (2- (4-methanesulfonyloxyphenyl) ethoxy) phenyl) propanoic acid crystalline form (s).
DK1283735T4 (en) 2000-03-31 2013-02-04 Royalty Pharma Collection Trust A method of improving the signaling of islet cells in diabetes mellitus and for the prevention thereof
WO2001081327A1 (en) 2000-04-25 2001-11-01 Kyorin Pharmaceutical Co., Ltd. Novel stable crystal of thiazolidinedione derivative and process for producing the same
WO2001083451A1 (en) 2000-04-28 2001-11-08 Asahi Kasei Kabushiki Kaisha Novel bicyclic compounds
EP1280777B1 (en) 2000-05-11 2005-11-23 Bristol-Myers Squibb Company Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
EP1289526A4 (en) 2000-05-30 2005-03-16 Merck & Co Inc Melanocortin receptor agonists
ES2215902T3 (en) 2000-06-09 2004-10-16 Aventis Pharma Deutschland Gmbh Acyl derivatives-phenyl-ureas, process for their preparation and their use as medicaments.
DE10038709A1 (en) 2000-08-09 2002-02-28 Aventis Pharma Gmbh Substituted and unsubstituted Benzooxathiazole as well as compounds derived therefrom
EP1182251A1 (en) * 2000-08-11 2002-02-27 Yissum Research Development Company of the Hebrew University of Jerusalem Methods for identifying compounds that inhibit ubiquitin-mediated proteolysis of IkB
ES2288982T3 (en) 2000-08-23 2008-02-01 Eli Lilly And Company Oxazolyl-derivatives ariloxiacetico acid and their use as PPAR agonists.
JP2004506721A (en) * 2000-08-23 2004-03-04 イーライ・リリー・アンド・カンパニーEli Lilly And Company Oxazolyl - use as arylpropionic acid derivatives and their ppar agonist
JP3987890B2 (en) 2000-11-10 2007-10-10 大正製薬株式会社 Cyanopyrrolidine derivative
JPWO2002046146A1 (en) 2000-12-05 2004-04-08 杏林製薬株式会社 Substituted carboxylic acid derivatives
GB0031103D0 (en) * 2000-12-20 2001-01-31 Glaxo Group Ltd Chemical compounds
DE50111751D1 (en) 2000-12-21 2007-02-08 Sanofi Aventis Deutschland New diphenzylazetidinone, process for their preparation, these compounds containing drug and its use for treatment of lipid metabolic disorders
CA2432211C (en) * 2000-12-25 2010-07-13 Ono Pharmaceutical Co., Ltd. Dihydronaphthalene derivative compounds and agent comprising the derivative as active ingredient
JP2004529097A (en) 2001-02-15 2004-09-24 ファイザー・プロダクツ・インク Ppar agonist
KR20040003007A (en) 2001-05-25 2004-01-07 아벤티스 파마 도이칠란트 게엠베하 Carboxamide-substituted phenylurea derivatives and method for production thereof as medicaments
DE60216094D1 (en) * 2001-06-07 2006-12-28 Lilly Co Eli Modulators of peroxisome proliferator-activated receptors (PPAR)
WO2003005025A1 (en) 2001-07-03 2003-01-16 Biovitrum Ab Methods for identifying compounds modulating the activity of ppar-gamma
FR2827859B1 (en) 2001-07-30 2005-09-23 Lipha Derivatives 4- (arylthio) - or 4- (heteroarylthio) -butyric acid in the preparation of medicaments for treating diabetes
RU2330846C2 (en) 2001-08-31 2008-08-10 Санофи-Авентис Дойчланд Гмбх Diarylcycloalkyl derivatives, method of their obtaining, and application as ppar-activators
DE10154689A1 (en) 2001-11-09 2003-05-22 Probiodrug Ag substituted aminoketone
EP1474385B1 (en) 2002-02-05 2009-06-10 Eli Lilly And Company Urea linker derivatives for use as ppar modulators
DE10215907A1 (en) 2002-04-11 2003-11-06 Aventis Pharma Gmbh Acyl-4-carboxyphenyl urea derivatives, processes for their preparation and their use
DE10215908B4 (en) 2002-04-11 2005-08-18 Aventis Pharma Deutschland Gmbh Acyl-3-carboxyphenyl urea derivatives and their use as medicaments
DE10225635C1 (en) 2002-06-07 2003-12-24 Aventis Pharma Gmbh N-Benzoylureido acid derivatives, processes for their preparation and their use
JP4579681B2 (en) 2002-07-09 2010-11-10 ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company Useful substituents heterocyclo derivatives and methods as antidiabetic agents and antiobesity agents
US7148246B2 (en) * 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals

Also Published As

Publication number Publication date Type
US7872034B2 (en) 2011-01-18 grant
RU2005129992A (en) 2006-02-10 application
WO2004076426A1 (en) 2004-09-10 application
CN100439345C (en) 2008-12-03 grant
CN1753881A (en) 2006-03-29 application
DE10308355A1 (en) 2004-12-23 application
US7365084B2 (en) 2008-04-29 grant
CN1753879A (en) 2006-03-29 application
US20080167354A1 (en) 2008-07-10 application
DK1599453T3 (en) 2009-08-24 grant
EP1599452B1 (en) 2007-06-20 grant
EP1599455A1 (en) 2005-11-30 application
EP1599453A1 (en) 2005-11-30 application
RU2005130002A (en) 2006-01-27 application
CA2516620A1 (en) 2004-09-10 application
US7335671B2 (en) 2008-02-26 grant
EP1599455B1 (en) 2009-07-01 grant
JP2006519193A (en) 2006-08-24 application
DE502004004139D1 (en) 2007-08-02 grant
ES2326418T3 (en) 2009-10-09 grant
US20040209920A1 (en) 2004-10-21 application
DE502004009453D1 (en) 2009-06-18 grant
WO2004076428A1 (en) 2004-09-10 application
CN100398526C (en) 2008-07-02 grant
DE502004009690D1 (en) 2009-08-13 grant
US20080015238A1 (en) 2008-01-17 application
WO2004076427A1 (en) 2004-09-10 application
DK1599452T3 (en) 2007-10-01 grant
CN1756748A (en) 2006-04-05 application
CN100439347C (en) 2008-12-03 grant
EP1599453B1 (en) 2009-05-06 grant
US20050101637A1 (en) 2005-05-12 application
RU2005129995A (en) 2006-01-27 application
JP2006519199A (en) 2006-08-24 application
DK1599455T3 (en) 2009-11-09 grant
US7259177B2 (en) 2007-08-21 grant
CA2517386A1 (en) 2004-09-10 application
ES2329366T3 (en) 2009-11-25 grant
KR20050105492A (en) 2005-11-04 application
EP1599452A1 (en) 2005-11-30 application
US20050215596A1 (en) 2005-09-29 application
ES2287700T3 (en) 2007-12-16 grant
KR20050106462A (en) 2005-11-09 application
KR20050106461A (en) 2005-11-09 application
JP2006519194A (en) 2006-08-24 application

Similar Documents

Publication Publication Date Title
US20040082626A1 (en) Cyclic compounds exhibiting thrombopoietin receptor agonism
US6437146B1 (en) Oxazole compounds as prostaglandin e2 agonists or antagonists
US20070082907A1 (en) Peroxisome proliferator activated receptor modulators
US20070197522A1 (en) Dpp-iv inhibitors
US6294580B1 (en) Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma
WO2004035550A1 (en) Novel bicyclic inhibitors of hormone sensitive lipase
EP0359418A1 (en) 5'-Indolinyl-5beta-amidomethyloxazolidin-2-ones, 3-(fused-ring substituted)phenyl-5beta-amidomethyloxazolidin-2-ones and 3-(nitrogen substituted)phenyl-5beta-amidomethyloxazolidin-2-ones
US6417212B1 (en) Modulators of peroxisome proliferator activated receptors
US5599826A (en) Thiazolidinediones and drugs containing them
WO2004063166A1 (en) Heterocyclic ppar modulators
WO2001017994A1 (en) Oxazole ppar antagonists
WO2002018355A1 (en) Oxazolyl-aryloxyacetic acid derivatives and their use as ppar agonists
WO2000016760A2 (en) New use of prostaglandin e2 antagonists
US5972965A (en) 4,5-diaryl oxazole derivatives
WO1998000137A1 (en) Hypoglycemic and hypolipidemic compounds
WO2003072102A1 (en) Peroxisome proliferator activated receptor modulators
WO2002100403A1 (en) Modulators of peroxisome proliferator activated receptors (ppar)
WO2007039178A2 (en) Phenyl-[1,2,4]-oxadiazol-5-one derivatives with phenyl group, processes for their preparation and their use as pharmaceuticals
WO2007017669A1 (en) Azole and thiazole derivatives and their use
US6624185B2 (en) Diarylcycloalkyl derivatives, processes for their preparation and their use as pharmaceuticals
WO2006111321A1 (en) Azole derivatives in the form of lipase and phospholipase inhibitors
US6884812B2 (en) Diarylcycloalkyl derivatives, processes for their preparation and their use as pharmaceuticals
WO2002016331A1 (en) Oxazolyl-arylpropionic acid derivatives and their use as ppar agonists
WO2008149110A1 (en) Bicyclor [2.2.1] hept-7-ylamine derivatives and their use in the treatment of diseases and conditions in which m3 muscarinic receptor activity and beta-adrenergic activity are implicated
WO2003048130A2 (en) Peroxisome proliferator activated receptor agonists

Legal Events

Date Code Title Description
EEER Examination request
FZDE Dead