WO2004076427A1 - 3-(2-phenyl-oxazol-4- ylmethoxy)-cyclohexylmethoxy -essigsäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose - Google Patents

3-(2-phenyl-oxazol-4- ylmethoxy)-cyclohexylmethoxy -essigsäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose Download PDF

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Publication number
WO2004076427A1
WO2004076427A1 PCT/EP2004/001579 EP2004001579W WO2004076427A1 WO 2004076427 A1 WO2004076427 A1 WO 2004076427A1 EP 2004001579 W EP2004001579 W EP 2004001579W WO 2004076427 A1 WO2004076427 A1 WO 2004076427A1
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Prior art keywords
cis
methyl
alkyl
phenyl
tert
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PCT/EP2004/001579
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German (de)
English (en)
French (fr)
Inventor
Christian Stapper
Dirk Gretzke
Heiner Glombik
Eugen Falk
Jochen Goerlitzer
Stefanie Keil
Hans-Ludwig Schaefer
Wolfgang Wendler
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Aventis Pharma Deutschland Gmbh
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Priority to BRPI0407758-0A priority Critical patent/BRPI0407758A/pt
Application filed by Aventis Pharma Deutschland Gmbh filed Critical Aventis Pharma Deutschland Gmbh
Priority to DK04712490T priority patent/DK1599452T3/da
Priority to JP2006501886A priority patent/JP2006519194A/ja
Priority to CA002517381A priority patent/CA2517381A1/en
Priority to DE502004004139T priority patent/DE502004004139D1/de
Priority to MXPA05008988A priority patent/MXPA05008988A/es
Priority to AU2004215673A priority patent/AU2004215673B2/en
Priority to EP04712490A priority patent/EP1599452B1/de
Publication of WO2004076427A1 publication Critical patent/WO2004076427A1/de
Priority to IL170316A priority patent/IL170316A/en
Priority to TNP2005000204A priority patent/TNSN05204A1/en
Priority to HR20050743A priority patent/HRP20050743A2/xx
Priority to NO20054408A priority patent/NO20054408L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic 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
    • C07D263/32—Heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic 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
    • C07D413/12—Heterocyclic 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 linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to cycloalkyl-methoxy-substituted acetic acid derivatives, processes for their preparation and their use as medicaments and their physiologically acceptable salts and physiologically functional derivatives.
  • the invention was based on the object to provide compounds that allow a therapeutically useful modulation of lipid and / or carbohydrate metabolism and thus are suitable for the prevention and / or treatment of diseases such as type 2 diabetes and atherosclerosis and their multiple sequelae.
  • the compounds are useful for activating PPARalpha and PPARgamma, although the extent of relative activation may vary depending on the compounds.
  • the invention therefore relates to compounds of the formula
  • Ring A (C 3 -C 8) -cycloalkanediyl, (C 3 -C 8) -cycloalkendiyl, where in the cycloalkanediyl or cycloalkendiyl rings one or more carbon atoms may be replaced by oxygen atoms;
  • R 1 , R 2 independently of one another are H, F, Cl, Br, CF 3 , OCF 3 , (C 1 -C 6) -alkyl, O- (C 1 -C 6) -alkyl, SCF 3 , SF 5 , OCF 2 -CHF 2 , ( C6-C10) -aryl, (C6-C10) -aryloxy, OH, NO 2; or R1 and R2 taken together with the phenyl, pyridine, 1-H-pyrrole, thiophene or furan ring condensed, partially or unsaturated bicyclic (C6-C10) -aryl, (C5-C11) -heteroaryl;
  • R 3 is H, (C 1 -C 6) -alkyl, (C 3 -C 8) -cycloalkyl, (C 1 -C 3) -alkyl- (C 3 -C 8) -cycloalkyl, phenyl, (C 1 -C 3) -alkyl-phenyl, (C 5 -C 6) -alkyl, C6) -heteroaryl, (C1-C3) -alkyl- (C5-)
  • Carbon atoms may be replaced by oxygen atoms
  • Y 2 is CH 2, O, -S, SO, SO 2, NR 9; - R 4 is H, (C 1 -C 6) -alkyl; or F, if Y2 is other than O, NR9;
  • R5 is H, (C1-C6) -alkyl; or F, if Y2 is other than O, NR9;
  • R6 is H, (C1-C6) ⁇ alkyl; or F, if n is not 0;
  • R 7 is H, F (if n is not 0), (C 1 -C 6) -alkyl, (C 1 -C 6) -alkoxy, (C 2 -C 6) -alkenyl,
  • R8 is H, (C1-C6) -alkyl
  • R 9 is H, (C 1 -C 6) -alkyl, (C 2 -C 6) -alkenyl, (C 2 -C 6) -alkynyl, aryl- (C 1 -C 4) -alkyl, CO-
  • Heteroaryl may optionally be substituted by (C 1 -C 6) -alkyl, O- (C 1 -C 6) -alkyl, F, Cl, CO- (C 1 -C 6) -alkyl;
  • R 10 is H, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl-phenyl; ,
  • R 11 is H, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl-phenyl
  • R 12 is H, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl-phenyl
  • R 13 is H, (C 1 -C 6) -alkyl
  • R 14 is H, (C 1 -C 6) -alkyl
  • Cycloalkandiyl- or Cycloalkendiylringen a carbon atom may be replaced by oxygen atom;
  • Carbon atom (to ring A) is replaced by oxygen atom.
  • R2 is hydrogen; or R 3 is H, (C 1 -C 6) -alkyl, (C 3 -C 8) -cycloalkyl, (C 1 -C 3) -alkyl (C 5 -C 6) -cycloalkyl,
  • Phenyl (C 1 -C 3) -alkyl-phenyl
  • X is CH 2 -O or CH 2 -O-CH 2 ;
  • R6 is H, (C1-C6) -alkyl
  • R6 and R7 together with the C atom bearing them (C3-C6) -cycloalkyl, especially cyclopentyl; or
  • R 7 is (C 1 -C 6) -alkyl, where alkyl may optionally be substituted by one or more radicals from the series hydroxy, phenyl, (C 5 -C 11) -heteroaryl, (C 1 -C 6) -alkoxy and NR 11 R 12, with R 11 and R 12 H, (C 1 -C 6) -alkyl; or
  • R13 and R14 are hydrogen.
  • R 7 is (C 1 -C 4) -alkyl, (C 1 -C 4) -alkyl-O- (C 1 -C 4) -alkyl or benzyl;
  • R 7 is (C 1 -C 4) -alkyl or benzyl. Very particular preference is furthermore given to the compounds of the formula I
  • R 1, R 2 independently of one another are H, F, CF 3, (C 1 -C 6) -alkyl, O- (C 1 -C 6) -alkyl, phenyl, or (
  • R 3 is (C 1 -C 6) -alkyl, (C 3 -C 8) -cycloalkyl, phenyl;
  • X is CH 2 -O, CH 2 -O-CH 2;
  • Y2 is CH2, O, S, SO, SO2, NR9;
  • R6 is H, (C1-C6) -alkyl, benzyl;
  • R 7 is H, (C 1 -C 6) -alkyl, (C 3 -C 6) -cycloalkyl, phenyl, benzyl,
  • R6 and R7 together with the C atom (C3-C6) -cycloalkyl carrying them;
  • Phenyl may in turn be substituted by O- (C 1 -C 3) -alkyl
  • alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 can be both straight-chain and branched.
  • aryl an aromatic carbocyclic mono- or bicyclic ring system containing from 6 to 10 atoms in the ring or in the rings.
  • Heteroaryl is a mono- or bicyclic aromatic ring system having 4 to 11 ring members, wherein at least one atom in the ring system is a heteroatom from the series N, O and S.
  • the compounds of formula I contain at least two centers of asymmetry and moreover can contain more. Therefore, the compounds of formula I in the form of their racemates, racemic mixtures, pure enantiomers,
  • Diastereomers and diastereomer mixtures are present.
  • the present invention includes all of these isomeric forms of the compounds of formula I. These isomers
  • Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric acid.
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.
  • Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.
  • physiologically functional derivative refers to any physiologically acceptable derivative of a compound of formula I, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.
  • the physiologically functional derivatives also include prodrugs of the compounds according to 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 or may not be effective.
  • the compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
  • This invention further relates to the use of compounds of formulas I and their pharmaceutical compositions as PPAR receptor ligands.
  • the PPAR receptor ligands according to the invention are suitable as modulators of the activity of the PPAR receptors.
  • PPARs Peroxisome Proliferator Activated Receptors
  • PPARdelta 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).
  • PPARgamma peroxisome proliferator-activated receptor
  • PPARgammai peroxisome proliferator-activated receptor
  • gamma There are two variants of PPARgamma, PPARgammai and gamma, which are the result of alternative use of promoters and differential mRNA splicing (Vidal-Puig et al J. Clin Invest, 97: 2553-2561, 1996).
  • the different PPAR receptors have a different tissue distribution and modulate different physiological functions.
  • the PPAR receptors play a key role in different aspects of the regulation of a variety of genes whose gene products are directly or indirectly linked to the lipid and
  • PPARalpha receptors in the regulation of fatty acid catabolism or the Lipoprotein metabolism in the liver plays an important role, while PPARgamma, for example, in the regulation of fat cell differentiation is critically involved.
  • PPAR receptors are also involved in the regulation of many other physiological processes, including those that are not directly related to carbohydrate or lipid metabolism.
  • the activity of different PPAR receptors can be modulated to varying degrees by various fatty acids, fatty acid derivatives and synthetic compounds.
  • physiological effects and pathophysiology see: Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; Timothy Wilson et al. J. Med. Chem., 2000, Vol. 4, 527-550; Steven Kliewer et al., Recent Prague Horm Res. 2001; 56: 239-63.
  • the present invention relates to compounds of the formula I which are suitable for modulating the activity of PPAR receptors, in particular the activity of PPARalpha and PPARgamma. Depending on the profile of the modulation are the.
  • Compounds of formula I are useful for the treatment, control and prophylaxis of the indications described below, as well as a number of other related pharmaceutical applications (see eg Joel Berger et al., Annu Rev. Med 2002, 53, 409-435, Timothy Wilson et J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al., Recent Prog Horm Res.
  • dyslipidemias and their consequences e.g. Atherosclerosis, coronary heart disease, cerebrovascular diseases etc, especially those (but not limited to) characterized by one or more of the following factors:
  • Heart failure e.g. (but not limited to) at state after
  • - atherosclerosis such as (but not limited to) coronary sclerosis, including angina pectoris or myocardial infarction, stroke
  • fatty cell carcinomas e.g. liposarcoma
  • solid tumors and neoplasms e.g. (but not limited to) carcinomas of the gastrointestinal tract, liver, biliary tract and pancreas, endocrine tumors, carcinomas of the lung, kidney and urinary tract organs, genital tract, prostate carcinomas, etc. - acute and chronic myeloprolifeative disorders and lymphomas
  • Psoriasis psoriasis
  • Dermatitides e.g. seborrheic dermatitis or light dermatitis
  • Keratitis and keratoses e.g. seborrheic keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or follicular keratosis
  • HPV Human papilloma viral infections, such as venereal papillomata, viral warts, such as molluscum contagiosum, leukoplakia - Papular dermatoses, such as Liehen planus
  • - skin cancer e.g. Basal cell carcinomas, melanomas or cutaneous T-cell lymphomas
  • PCOS Polycystic Ovarian Syndrome
  • Lupus erythematosus or inflammatory rheumatic diseases, e.g. Rheumatoid arthritis
  • ARDS - Acute Respiratory Distress Syndrome
  • the amount of a compound of Formula I required to achieve the desired biological effect is dependent upon a number of factors, e.g. the chosen specific compound, the intended
  • the daily dose is in the range of 0.001 mg to 100 mg (typically 0.01 mg and 50 mg) per day per kilogram of body weight, for example 0.1 to 10 mg / kg / day.
  • an intravenous dose may range from 0.001 mg to 1.0 mg / kg, which may conveniently be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
  • Suitable infusion solutions for these purposes may be, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter, contain.
  • Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
  • injectable ampoules, and orally administrable unit dose formulations may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg.
  • the compounds according to formula I can themselves be used as compound, but they are preferably present with a compatible carrier in the form of a pharmaceutical composition.
  • the carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Other pharmaceutically active substances may also be present, including other compounds according to formula I.
  • the pharmaceutical compositions according to the invention may be prepared by one of the known pharmaceutical methods, which consist essentially in mixing the ingredients with pharmacologically acceptable carriers and / or adjuvants ,
  • compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is of the type and severity of the treatment to be treated State and on the nature of the particular compound used in accordance with formula I is dependent.
  • coated formulations and coated slow release formulations are within the scope of the invention.
  • Suitable pharmaceutical preparations for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
  • the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded if necessary.
  • a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients.
  • Pressed tablets may be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant in a suitable machine.
  • Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, albeit the administration can also be subcutaneous, intramuscular or intradermal injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
  • Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil.
  • Vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these substances can be used as the carrier.
  • the active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
  • Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%.
  • the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
  • the compounds of the formula I are distinguished by favorable effects on metabolic disorders. They influence the fat 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 their multiple sequelae.
  • the compounds according to the invention can be administered alone or in combination with one or more further pharmacologically active substances which, for example, have beneficial effects on metabolic disorders or diseases frequently associated therewith.
  • Such medications are for example
  • drugs for the treatment of heart failure and 10. drugs for the treatment and / or prevention of complications caused by diabetes or associated with diabetes.
  • the administration of the drug combination can either by separate administration of the active ingredients to the. Patients or in the form of combination preparations, wherein several active ingredients are present in a pharmaceutical preparation carried out.
  • Examples include:
  • Antidiabetics Suitable antidiabetics are disclosed, for example, in the Red List 2001, Chapter 12 or the USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville 2003.
  • Antidiabetics include all insulins and insulin derivatives such as, for example, Lantus ® (see www.lantus.com) or Apidra ®, and other fast-acting insulins (see US 6,221, 633), GLP-1 receptor modulators as described in WO 01/04146 described , or even such as those disclosed in WO 98/08871 by Novo Nordisk AS.
  • the orally active hypoglycemic agents preferably include sulphonylfhams, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, oral GLP-1 agonists, DPP-IV inhibitors, potassium channel openers such as those described in WO 97/26265 and US Pat WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, lipid metabolism altering compounds that alter the lipid composition of the blood, compounds containing the Reduce food intake or intake, PPAR and PXR modulators, and drugs that act on the ATP-dependent potassium channel of beta cells.
  • the compounds of the formula I are administered in combination with insulin.
  • the compounds of formula I in combination with substances having egg flow on the hepatic glucose production, such. Glycogen phosphorylase inhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188)
  • the compounds of the formula I are used in combination with a sulphonylurea, such as e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
  • the compounds of formula I are administered in combination with an agent which acts on the ATP-dependent potassium channel of beta cells, e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • an agent which acts on the ATP-dependent potassium channel of beta cells e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • the compounds of formula I are administered in combination with a biguanide such as metformin.
  • the compounds of formula I are administered in combination with a meglitinide, such as repaglinide.
  • the compounds of the formula I are used in combination with a thiazolidinedione such as, for example, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med.
  • the compounds of formula I are administered in combination with a PPARgamma agonist, e.g. Rosiglitazone, pioglitazone.
  • a PPARgamma agonist e.g. Rosiglitazone, pioglitazone.
  • the compounds of formula I are administered in combination with a ⁇ -glucosidase inhibitor such as miglitol or acarbose.
  • a ⁇ -glucosidase inhibitor such as miglitol or acarbose.
  • the compounds of the formula I are used in combination with more than one of the abovementioned compounds, for example in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone , Insulin and lovastatin, etc. administered.
  • lipid modulators such as miglitol or acarbose.
  • the compounds of formula I are administered in combination with an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.
  • an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.
  • the compounds of formula I are administered in combination with a bile acid resorption inhibitor (see, e.g., U.S. 6,245,744, U.S. 6,221,897, U.S. 6,277,831, EP 0 683 773, EP 0 683 774).
  • a bile acid resorption inhibitor see, e.g., U.S. 6,245,744, U.S. 6,221,897, U.S. 6,277,831, EP 0 683 773, EP 0 683 774).
  • the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
  • a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam.
  • the compounds of formula I are administered in combination with a cholesterol resorption inhibitor, e.g. in WO 0250027, or Ezetimibe, Tiqueside, Pamaqueside.
  • a cholesterol resorption inhibitor e.g. in WO 0250027, or Ezetimibe, Tiqueside, Pamaqueside.
  • the compounds of formula I are administered in combination with an LDL receptor inducible (see, e.g., U.S. 6,342,512).
  • the compounds of formula I in combination with bulking agents preferably insoluble bulking agents (see, for example, carob / Caromax ® (Zunft HJ; et al, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct). 18 (5), 230-6)); Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main) administered. Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®. Caromax ® can also be administered in the form of food, such as in baked goods or muesli bars. In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARalpha agonist.
  • the compounds of formula I in combination with a mixed PPAR alpha / gamma agonist e.g. AZ 242 (Tesaglitazar, (S) -3- (4- [2- (4-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 in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, WO96 / 38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.
  • AZ 242 Tesaglitazar, (S) -3
  • the compounds of formula I are used in combination with a fibrate, e.g. Fenofibrate, gemfibrozil, clofibrate, bezafibrate.
  • a fibrate e.g. Fenofibrate, gemfibrozil, clofibrate, bezafibrate.
  • the compounds of the formula I are administered in combination with nicotinic acid or niacin.
  • the compounds of formula I in combination with a CETP inhibitor e.g. CP-529, 414 (torcetrapib).
  • the compounds of the formula I are administered in combination with an ACAT inhibitor
  • the compounds of formula I are administered in combination with an MTP inhibitor, e.g. Implitapide, administered.
  • an MTP inhibitor e.g. Implitapide
  • the compounds of 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.
  • the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor.
  • the compounds of the formula I are administered in combination with a squalene synthetase inhibitor.
  • the compounds of the formula I are administered in combination with a lipoprotein (a) antagonist.
  • the compounds of formula I are administered in combination with a lipase inhibitor, e.g. Orlistat, administered.
  • a lipase inhibitor e.g. Orlistat
  • the other active ingredient is fenfluramine or dexfenfluramine. In yet another embodiment, the other active ingredient is sibutramine.
  • the compounds of the formula I are used in combination with CART modulators (see “Cpcaine-amphetamine-regulated transcriptinfluor fl icient in fl ammant metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.: Hormones and Metabolism Research (2001), 33 (9), 554-558), NPY antagonists eg naphthalene-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl-cyclohexylmethyl ⁇ -amide; hydrochloride (CGP 71683A)), MC4 agonists (eg, 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3 , 3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyri
  • 5HT agonist e.g. 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (eg, human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2 -diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see, eg, EP 0462
  • decoupling protein 2- or 3-modulators decoupling protein 2- or 3-modulators, leptin agonists (see eg Lee, Daniel W., Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia, Leptin agonists as a potential approach to the treatment of obesity of the Future (2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors (eg WO
  • PPAR modulators e.g., WO 00/78312
  • RXR modulators e.g., TR # agonists
  • the further active ingredient is leptin.
  • the other active ingredient is dexamphatamine, amphetamine, mazindol or phentermine.
  • the compounds of formula I are administered in combination with medicaments having effects on the cardiovascular and blood vessel systems, such as, e.g. ACE inhibitors (e.g., ramipril), medicines based on the
  • angiotensin-renin system calcium antagonists, beta-blockers etc.
  • the compounds of formula I are administered in combination with anti-inflammatory drugs.
  • the compounds of the formula are administered in combination with drugs used for cancer therapy and cancer prevention.
  • HEK human embryo kidney
  • PPARalpha reporter cell line contains two genetic elements, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD), which mediates expression of the luciferase reporter element as a function of a PPARalpha ligand.
  • the stable and constitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD binds in the nucleus of the PPARalpha reporter cell line via the GAL4 protein portion to the GAL4 DNA binding motifs 5 ' - above the luciferase reporter element present in the genome the cell line is integrated. Without the addition of a PPARalpha ligand, the expression of the luciferase reporter gene is only slight, if the assay uses fatty acid-depleted fetal calf serum (cs-FKS). PPARalpha ligands bind and activate the PPARalpha fusion protein, thereby causing expression of the leuiferase reporter gene. The luciferase formed can be detected via a corresponding substrate by means of chemiluminescence.
  • the PPARalpha reporter cell line was prepared in 2 steps: First, 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 ' ) 5 ' - above a 68 bp minimum MMTV promoter (Genbank accession # V01175) were cloned. The minimal MMTV promoter portion contains a CCAAT box and a TATA element to allow efficient transcription by RNA polymerase II. The cloning and sequencing of the GAL4MMTV construct was carried out analogously as in Sambrook J. et. al.
  • PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) was introduced into the described stable cell clone.
  • glucocorticoid receptor Genbank accession # P04150
  • cDNA coding cDNA with the for the Linked to 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 was cloned in (amino acids S167-Y468; Genbank accession # S74349).
  • the fusion construct (GR-GAL4-humanPPARalpha-LBD) thus prepared was recloned into the plasmid pcDNA3 (Invitrogen company) to allow constitutive expression by the cytomegalovirus promoter therein.
  • This plasmid was linearized with a restriction endonuclease and stably transfected into the cell clone already described containing the luciferase reporter element.
  • the final PPARalpha reporter cell line containing a luciferase reporter cell was isolated and constitutively the PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD ) expressed.
  • the activity of PPARalpha agonists is determined in a 3-day test, which is described below:
  • the PPARalpha reporter cell line is cultured to 80% confluence in DMEM medium (# 41965-039, Invitrogen) supplemented with the following: 10% cs-FKS (fetal calf serum, # SH-30068.03, Hyclone) , 0.5 mg / ml Zeocin (# R250-01, Invitrogen), 0.5 mg / ml G418 (# 10131-027, Invitrogen), 1% Penjcillin streptomycin solution (# 15140-122, Invitrogen) and 2 mM L-glutamine (# 25030-024, Invitrogen).
  • 10% cs-FKS fetal calf serum, # SH-30068.03, Hyclone
  • Cultivation is carried out in standard cell culture bottles (# 353112, Becton Dickinson) in a cell culture incubator at 37 ° C. in the presence of 5% CO 2 .
  • the 80% confluent cells are washed once with 15 ml PBS (# 14190-094, Invitrogen), treated with 3 ml trypsin solution (# 25300-054, Invitrogen) for 2 min at 37 ° C, in 5 ml of the described DMEM. Medium recorded and counted in a cell counter. After dilution to 500,000 cells / ml, each 35,000 cells per well of a 96 well microtiter plate with clear plastic bottom (# 3610, Coming Costar) seeded. The plates are incubated for 24 h in a cell culture incubator at 37 ° C and 5% CO 2 .
  • PPARalpha agonists to be tested are dissolved in DMSO at a concentration of 10 mM.
  • This stock solution is diluted in DMEM medium (# 41965-039, Invitrogen) supplemented with 5% cs-FKS (# SH-30068.03, Hyclone), 2mM L-glutamine (# 25030-024, Invitrogen) and those already described Antibiotics (Zeozin, G418, penicillin and streptomycin) is added.
  • test substances are tested in 11 different concentrations ranging from 10 ⁇ M to 100 pM. More potent compounds are tested in concentration ranges from 1 ⁇ M to 10 pM or between 100 nM and 1 pM.
  • the medium of the PPARalpha reporter cell line seeded on day 1 is completely aspirated off and the test substances diluted in medium are immediately added to the cells
  • test substances diluted in medium is 100 ⁇ l per well of a 96-well microtiter plate.
  • the DMSO concentration in the test is below 0.1% v / v to avoid cytotoxic effects of the solvent.
  • a standard PPARalpha agonist also available in
  • test plates 20 11 different concentrations is diluted to demonstrate the functionality of the test in each single plate.
  • the test plates are incubated for 24 h in an incubator at 37 ° C and 5% CO 2 .
  • the PPAR ⁇ reporter cells treated with the test substances are removed from the incubator and the medium is aspirated.
  • 50 ⁇ l Bright Glo reagent (Promega) per well of a 96-well microtiter plate are pipetted. After a 10 minute incubation in the dark at room temperature, the microtiter plates in the luminescence (Trilux from Wallac)
  • the measuring time per well of a microtiter plate is 1 sec.
  • the PPARalpha EC50 values for the compounds of Examples 1 to 85 in this assay range from 0.07nM to> 10 ⁇ M.
  • HEK cells human embryonic kidney cells
  • the expression of the luciferase reporter gene is induced by the activated fusion protein GAL4-humanPPARgammaLBD, which can be detected after addition of a luciferase subtrate in the form of a chemiluminescence signal.
  • the two components luciferase reporter plasmid and PPARgamma expression plasmid
  • the two components are transiently transfected into HEK cells because the stable and permanent expression of the PPARgamma fusion protein is cytotoxic.
  • the luciferase reporter plasmid pGL3basic-5xGAL4-TK is based on the vector pGL3basic from Promega.
  • the reporter plasmid five binding sites of the yeast transcription factor GAL4 (each binding site with the Sequence 5'-CTCGGAGGACAGTACTCCG-3 ' ), 5 ' - cloned into pGL3basic above together with a 160 bp thymidine kinase promoter section (Genbank accession # AF027128).
  • the thymidine kinase promoter is the entire luciferase gene of Photinus pyralis (Genbank Accession # M 15077), which is already part of the plasmid pGL3basic used.
  • the cloning and sequencing of the reporter plasmid pGL3basic-5xGAL4-TK was carried out analogously as in Sambrook J. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989).
  • the cDNA coding for amino acids 1-147 of the yeast transcription factor GAL4 was first cloned into the plasmid pcDNA3 (Invitrogen) 3 ' - below the cytomegalovirus promoter. 3 '-unter devis the GAL4 DNA binding domain, the cDNA was then the ligand binding domain (LBD) of the human PPARgamma receptor was cloned (amino acids I152-Y475; Accession # g1480099).
  • HEK cells Prior to transfection, HEK cells are cultured in DMEM medium (# 41965-039, Invitrogen), which is supplemented with the following additions: 10% FCS (# 16000-044, Invitrogen), 1% penicillin-streptomycin solution (# 15140-122, Invitrogen) and 2mM L-glutamine (# 25030-024, Invitrogen).
  • Solution A is first prepared, a transfection mixture which contains all four plasmids already described in addition to DMEM medium.
  • the following amounts are used per 96-well microtiter plate for the preparation of 3 ml of solution A: 2622 ⁇ l antibiotic and serum-free DMEM medium (# 41965-039, Invitrogen), 100 ⁇ l reference plasmid pRL-CMV (1 ng / ⁇ l) , 100 ⁇ l luciferase reporter plasmid pGL3basic
  • HEK cells 80% confluent HEK cells from a 175 cm 2 cell culture flask are washed once with 15 ml PBS (# 14190-094, Invitrogen) and treated with 3 ml trypsin solution (# 25300-054, Invitrogen) for 2 min at 37 ° C. After that, the cells are in
  • PPAR agonists to be tested are dissolved in DMSO at a concentration of 10 mM.
  • This stock solution is diluted in DMEM medium (# 41965-039, Invitrogen) containing 2% Ultroser (# 12039-012, Biosepra), 1% penicillin-streptomycin solution (# 15140-122, Invitrogen) and 2mM L-glutamine (# 25030-024, Invitrogen).
  • Test substances are tested in a total of 11 different concentrations ranging from 10 ⁇ M to 100 pM. More potent compounds are tested in concentration ranges from 1 ⁇ M to 10 pM.
  • the medium of the HEK cells transfected and seeded on day 1 is completely aspirated off and the test substances diluted in medium are added immediately to the cells.
  • the dilution and addition of the substances is carried out with a robot (Beckman FX).
  • the final volume of the test substances diluted in medium is 100 ⁇ l per well of a 96-well microtiter plate.
  • Each plate is loaded with a standard PPARgamma agonist, which is also diluted in 11 different concentrations to demonstrate the functionality of the test in each plate.
  • the test plates are incubated for 48 h in an incubator at 37 ° C and 5% CO 2 .
  • Dual-Glo TM reagent Dual-Glo TM Luciferase Assay System, Promega Company
  • 50 ⁇ l of Dual-Glo TM reagent Dual-Glo TM Luciferase Assay System, Promega Company
  • the firefly luciferase-mediated chemiluminescence is measured in the measuring instrument (1 sec. Measuring time / well; Trilux from Wallac).
  • Dual-Glo TM Stop & Glo reagent Dual-Glo TM luciferase assay system, Promega company
  • 50 ⁇ l of the Dual-Glo TM Stop & Glo reagent is added per well to stop the activity of the firefly luciferase and to excite the substrate for the reference plasmid pRL-CMV To provide Renilla luciferase.
  • the chemiluminescence mediated by the Renilla luciferase is again measured in the measuring device for 1 sec / well.
  • the raw data of the Lumineszenzmeß marers be transferred to a Microsoft Excel file.
  • the quotient Firefly / Renilla luciferase activity is determined.
  • the dose-response curves and EC50 values of PPAR agonists with the program XL. Fit calculated according to the manufacturer's specifications (IDBS company).
  • IDBS company manufacturer's specifications
  • the compound A-1 is reacted in an alcohol R-8OH.
  • the product thus obtained is protected on the secondary hydroxyl group (e.g., by stirring at RT with TBDPSCl and imidazole in DMF) to give compound A-2 wherein R8 is as described above.
  • A-2 is in an ethereal solvent reduced with lithium aluminum hydride to compound A-3.
  • the compound A-3 is reacted in a two-phase system of toluene and 50% sodium hydroxide solution at 10 ° C with bromoacetic acid tert-butyl ester and tetrabutylammonium hydrogen sulfate to compound A-4.
  • the compound A-4 is reacted in tetrahydrofuran with lithium diisopropylamide and an alkyl iodide of the general formula R6-I, wherein R6 has the meaning described above.
  • the compound thus obtained is reacted in tetrahydrofuran with lithium diisopropylamide and another alkyl iodide of the general formula R7-I wherein R7 has the meaning described above.
  • the protecting group is cleaved to give the compound of the general formula A-5.
  • the compound A-5 is reacted in methyl tert-butyl ether or dimethylformamide with sodium hydride and the compound A-6 (see method A) wherein R1, R2, R3 and W have the meanings described above, to the compound A-7.
  • the product A-7 is stirred for several hours in trifluoroacetic acid or HCI / dioxane. Thereby, the compound of the general formula A-8 is obtained.
  • Examples 31 to 51 can be synthesized.
  • the ester is cleaved by adding compound B-6 for several hours
  • compound B-7 is reacted with one equivalent of hydrogen peroxide in trifluoroacetic acid at room temperature to give the compound of general formula B-8 wherein R1, R2, R3, R6, W and R7 are those described above
  • compound B-7 becomes three equivalents
  • Examples 52 to 71 can be synthesized.
  • R6 and R7 have the meanings described above, converted to the compound C-3.
  • the compound C-3 is by stirring for several hours in trifluoroacetic acid to
  • Examples 72 to 78 can be synthesized.
  • Compound D-1 is protected at the hydroxyl group with a suitable protecting group, for example the methoxymethyl protecting group. Subsequently, the
  • the compound D-3 is deprotected (for example with concentrated hydrochloric acid in
  • the compound D-4 is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0 ° C and reacted with an alkyl iodide of the general formula R6-I, wherein R6 has the meaning described above. Subsequently, the resulting compound is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0 ° C and with an alkyl iodide of the general formula R7-I, wherein R7 is the same as described above
  • Compound D-5 is mixed with bismuth tribromide, triethylsilane and compound B-1
  • the compound E-2 is reacted with tert-butyldiphenylsilyl chloride and imidazole as the base in dimethylformamide, worked up and then reacted with osmium tetroxide and sodium periodate in diethyl ether.
  • the compound thus obtained is reacted with Triphenylphosphoranylidenessigklandre tert-butyl ester and n-butyllithium in a Wittig reaction and then hydrogenated with hydrogen on palladium / carbon to compound F-1.
  • the compound F-1 is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0 ° C and with an alkyl iodide of the general formula R6-I, wherein R6 is the above has described meaning implemented. Subsequently, the resulting compound is deprotonated with lithium diisopropylamide in tetrahydrofuran at 0 ° C and reacted with an alkyl iodide of the general formula R7-I, wherein R7 has the meaning described above, to the compound F-2. The compound F-2 is reacted for deprotection with tetrabutylammonium fluoride in tetrahydrofuran. Subsequently, the alcohol thus obtained is reacted with sodium hydride and the compound A-6 in dimethylformamide to give the compound F-3.
  • the tert-butyl ester is cleaved by stirring compound F-3 in trifluoroacetic acid for several hours to give compound F-4.
  • Examples 85 to 92 were synthesized.
  • the compound E-4 is reacted with an amino acid ester of the general formula G-1, wherein R6, R7 and R8 are as defined above, in the presence of a borohydride reagent (eg sodium triaeetoxyborohydride) to give the compound G-2.
  • a borohydride reagent eg sodium triaeetoxyborohydride
  • the compound G-2 is reacted with a chloride R12-Cl, wherein R12 has the abovementioned meaning, to the compound G-3 (R12 can also be isocyanate or isothiocyanate).
  • R12 can also be isocyanate or isothiocyanate
  • R3 have the meanings given above.
  • ester H-1 wherein R3 has the abovementioned meaning, is reacted with sodium nitrite and hydrochloric acid to oxime H-2, which is reduced by hydrogenation with hydrogen on palladium / carbon to the amine H-3.
  • the compound H-3 is reacted with acid chlorides of the general formula H-4 wherein R1, W and R2 have the meanings given above, and base (for example triethylamine) to the compound H-5.
  • Compound H-5 is converted to compound H-6 by heating in phosphoryl chloride.
  • the ester H-6 is reduced to the alcohol H-7 with lithium aluminum hydride in diethyl ether. This is converted into the iodide A-6 with iodine, imidazole (ImH) and triphenylphosphine.
  • compound H-7 is oxidized with oxalyle chloride, dimethylsulfoxide and triethylamine in dichloromethane at -78 ° C to give aldehyde B-1.
  • 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole was obtained from diacetylmonoxime and p-tolualdehyde.
  • 4-iodomethyl-2- (4-methoxyphenyl) -5-methyl-oxazole was obtained from diacetylmonoxime and 4-methoxybenzaldehyde.
  • 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole was obtained from diacetylmonoxime and m-tolualdehyde.
  • 4-iodomethyl-5-phenyl-2-p-tolyI-oxazole 4-iodomethyl-5-methyl-2-p-biphenyl-oxazole was obtained from diacetylmonoxime and p-phenylbenzaldehyde.
  • 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole 4-iodomethyl-5-methyl-2-thiophen-2-yioxazole was obtained from diacetylmonoxime and thiophene-2-carbaldehyde.
  • 4-iodomethyl-2- (4-isopropyl-phenyl) -5-methyl-oxazole was obtained from diacetylmonoxime and 4-isopropylbenzaldehyde.
  • Tetrabutylammoniumhydrogensulfat added.
  • the suspension is cooled to 10 ° C.
  • 10 ml of 50% NaOH are added to the suspension.
  • the mixture is allowed to come to room temperature and after 3 h, the aqueous phase is separated and extracted with methyl tert-butyl ether.
  • the combined organic phases are dried over MgSO4 and concentrated.
  • After flash column chromatography on silica gel heptane / ethyl acetate 10/1 ⁇ 2/1
  • 1.10 g of (cis-3-methoxymethypxycyclohexylmethoxy) -acetic acid tert-butyl ester as a colorless oil are obtained.
  • tert-butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate are dissolved in 5 ml of dimethylformamide and 20 mg of NaH (95%) are added.
  • 460 mg of 5-methyl-2-p-tolyl-oxazol-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 NH4Cl solution are added.
  • tert-butyl 2- (cis-3-hydroxycyclohexylmethoxy) -2-methylpropionate 50 mg are dissolved in 0.5 ml of dimethylformamide and 22 mg of NaH (60%) are added. After stirring for 30 minutes, 112 mg of 5-methyl-2-p-tolyl-oxazol-4-ylmethyl iodide are added at room temperature. The mixture is placed in the ultrasonic bath for 10 minutes and then stirred for 3 hours at room temperature. Subsequently, 10 ml of methyl tert-butyl ether and 10 ml of water are added.
  • tert-butyl (cis-3-hydroxycyclohexylmethoxy) cyclopentanecarboxylate are dissolved in 3 ml of dimethylformamide and 10 mg of NaH are added.
  • the suspension is stirred for 30 min at room temperature, then cooled to 0 ° C and treated dropwise with 150 mg of methyl-2-p-tolyl-oxazol-4-ylmethyliodid in 1 ml of dimethylformamide.
  • the suspension is stirred for 2 h at room temperature and diluted with methyl tert-butyl ether and saturated NaCl solution.
  • the aqueous phase is separated and extracted with methyl tert-butyl ether.
  • reaction Control 5 results in the formation of a new product (monomethyl compound).
  • the reaction mixture is mixed with 200 ml of saturated ammonium chloride solution and extracted with water / methyl tert-butyl ether.
  • the crude product is obtained as a dark red oil, which is reacted without purification in the same reaction sequence to the geminal dimethyl compound.
  • the crude product is purified on silica gel 10 (heptane / ethyl acetate 50: 1-10: 1).
  • Example 10 Analogously to Example 10 is obtained from 2- (cis-3-hydroxycyclohexylmethoxy) -2-methyl-propionic acid tert-butyl ester and 5-methyl-2- (5-methyl-furan-2-yl) -oxazol-4-ylmethyliodid 2-Methyl-2 - ⁇ (1R, 3S) -cis-3- [5-methyl-2- (5-methyl-furan-2-yl) -oxazol-4-ylmethoxy] -cyclohexylmethoxy ⁇ -propionic acid.
  • Example 10 Analogously to Example 10 is obtained from 2- (cis-3-hydroxycyclohexylmethoxy) -2-methyl-propionic acid tert-butyl ester and methyl 2- (3-trifluoromethoxyphenyl) -oxazol-4-ylmethyliodid 2-methyl-2 - [(1R, 3S) -cis-3- [5-methyl-2- (3-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy] -cyclohexylmethoxy] -propionic acid
  • Example 22 cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -acetic acid:
  • Example 30 Analogously to Example 22, 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and 2-mercaptovaleric acid ethyl ester 2- [cis-3- (5-methyl-2-tolyloxazole -4-ylmethoxy) -cyclohexylmethylsulfanyl] valeric acid as a mixture of diastereomers. C24H33NO4S (431, 60), MS (ESI): 432.39 (MH + ).
  • Example 31 Analogously to Example 22, 4- (cis-3-iodomethylcyclohexyloxymethyl) -5-methyl-2-p-tolyl-oxazole and 1-mercaptocyclobutanecarboxylic acid ethyl ester 1- [cis-3- (5- Methyl-2-p-tolyloxazole-4-ylmethoxy) -cyclohexylmethylsulfanyl] -cyclobutancarbonklare.
  • Methyl 2-mercapto-2-methylpropionate is obtained from 2-bromo-2-methylpropionic acid ethyl ester analogously to the building block synthesis of methyl 2-mercaptobutyrate.
  • Racemate Analogous to building block synthesis of 2-mercaptobutyric acid methyl ester is obtained from 2-bromo-2-cyclohexylessigkladremethylester 2-mercapto-2-cyclohexylessigkladremethylester.
  • Racemate Analogous to building block synthesis of 2-mercaptobutyric acid methyl ester is obtained from 1-Bromcyclobutancarbonklathylester 1 -Mercaptocyclobutancarbon mecanicreethylester.
  • Example 32 cis-3- (5-Methyl-2-p-tolyloxazole-4-ylmethoxy) -cyclohexylmethylsulfinyl] acetic acid:
  • Example 35 Analogously to Example 32, 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfanyl] -3-methylbutyric acid gives 2- [cis-3- (5-methyl -2-p-tolyloxazole-4 ylmethoxy) -cyclohexylmethylsulfinyl] -3-methylbutyric acid as a mixture of diastereomers. C24H33NO5S (447.60), MS (ESI): 448.43 (MH + ).
  • Example 37 cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethylsulfonyl] -acetic acid:
  • Example 40 Analogously to Example 37, 2- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) cyclohexylmethylsulfanyl] -3-methylbutyric acid gives 2- [cis-3- (5-methyl -2-p-tolyloxazole-4 ylmethoxy) cyclohexylmethylsulfonyl] -3-methylbutyric acid as a mixture of diastereomers. C24H33NO6S (463.60), LCMS (ESI): 464.1 (MH + ).
  • Example 45 Analogously to Example 43, (S) -3-methyl-2 - ⁇ [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino ⁇ - butyric acid tert-butyl ester and methylsulfonyl chloride (S) -2- ⁇ methylsulfonyl- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] amino ⁇ -3-methylbutyric acid. C25H36N2O6S (492.23); LCMS (ESI): 493.26 (MH + ).
  • Example 48 Analogously to Example 43, (S) -3-methyl-2 - ⁇ [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino ⁇ - butyric acid tert-butyl ester and methyl chloroformate (S) -2- ⁇ methoxycarbonyl- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] amino ⁇ -3-methylbutyric acid. C26H36N2O6 (472.26), LCMS (ESI): 473.37 (MH + ).
  • Example 42 Analogously to Example 42 is obtained from cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) - cyclohexanecarbaldehyde and glycine isopropyl ester hydrochloride 2 - ⁇ [cis-3- (5-methyl-2-p - tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino ⁇ -acetic acid trifluoroacetic acid salt.
  • C21 H28N2O4 (486.49), MS (ESI): 487 (MH + ).
  • Example 51 Analogous to Example 50, (S) -3-methyl-2 - ⁇ [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexylmethyl] -amino ⁇ - butyric acid tert-butyl ester and benzyl bromide (S) -2- ⁇ benzylyl- [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 +).
  • Example 52 2- ⁇ Benzyl- [cis-3- (5-methyl-2-p-tolyloxazol-4-ylmethoxy) -cyclohexylmethyl] -amino ⁇ -acetic acid cis / racemate cis / racemate
  • Tetrabutylammoniumhydrogensulfat added.
  • the suspension is cooled to 10 ° C.
  • 20 ml of 50% NaOH are added to the suspension.
  • the mixture is stirred for 6 h at 10 ° C, then the aqueous phase is separated and extracted with methyl tert-butyl ether.
  • the combined organic phases are dried over MgSO4 and concentrated.
  • 2.23 g of [cis-3- (methoxymethoxymethyl) -cyclohexylmethoxy] -acetic acid tert-butyl ester are obtained as a colorless oil.
  • Lithium diisopropylamide solution in tetrahydrofuran / hexane fraction was added dropwise.
  • the solution is first stirred at -78 ° C for 20 min, then warmed to 0 ° C (ice bath) and treated with 950 mg of methyl iodide.
  • the solution is stirred for 1 h at 0 ° C. 1 ml sat. NH4Cl 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 MgSO4 and concentrated.
  • the crude product is abs in 10 ml.
  • Example 55 Analogously to Example 55 is obtained from [cis-3- (methoxymethoxymethyl) - cyclohexylmethoxy) -acetic acid tert-butyl ester, methyl iodide, ethyl iodide and 5-methyl-2-p-tolyl-oxazole-4-carbaldehyde 2- [cis-3 - (5-methyl-2-p-tolyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylbutyric acid. C25H35NO5 (429.25); MS (ES): 428.22 (M-H + ).
  • Example 59 Analogously to Example 57, tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-methyl-2-naphthyl-oxazol-4-ylmethoxymethyl chloride 2- [cis-3- (5- Methyl 2-naphthyl-oxazol-4-ylmethoxymethyl) cyclohexylmethoxy] -2-methylpropionic acid. C27H33NO5 (451, 57); MS (ESI): 458 (MH + ).
  • Example 63 Analogously to Example 57, tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-ethyl-2-p-isopropyl-oxazol-4-ylmethoxymethyl chloride 2- [cis-3- ( 5-ethyl-2-p-isopropyl-oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C27H39NO5 (457.62); MS (ESI): 458 (MH + ).
  • Example 66 Analogously to Example 57 there are obtained tert-butyl 2- [cis-3-hydroxymethylcyclohexylmethoxy] -2-methylpropionate and 5-ethyl-2- (3-trifluoromethyl) oxazol-4-ylmethoxymethyl chloride 2- [cis-3 - (5-ethyl-2- (3-trifluoromethyl) -oxazol-4-ylmethoxymethyl) -cyclohexylmethoxy] -2-methylpropionic acid. C26H34F3NO5 (497.56); MS (ESI): 498 (MH + ).
  • Triethylphosphonobutyrat are dissolved in 5 ml of tetrahydrofuran and treated at -20 ° C with 0.5 ml of a 2.5 M n-butyllithium solution in n-hexane. The mixture is stirred for 1 hour at -20 ° C, then 386 mg ⁇ cis-3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl ⁇ -acetaldehyde, dissolved in 4 ml of tetrahydrofuran, added.
  • Example 67 Analogously to Example 67 was from 2-ethyl-4- ⁇ cis-3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl ⁇ -but-2-enoic acid ethyl ester 2 Ethyl 4- ⁇ cis-3- [2- (3-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyl ⁇ -butyric acid.
  • reaction mixture is diluted by addition of 150 ml of methyl tert-butyl ether and washed with saturated NaCl solution.
  • the organic phase is dried over MgSO4 and then the solvent is removed in vacuo.
  • This product is dissolved in 20 ml of tetrahydrofuran and treated at -78 ° C with 6 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran.
  • the mixture is stirred for 2 hours at -78 ° C, then the reaction mixture is warmed to 0 ° C and after 10 minutes at 0 ° C with 2.5 ml
  • Trifluoroacetic acid is added. The mixture is stirred for 1 hour at room temperature. It will be appreciated that
  • Residue is purified by RP-HPLC. This gives 180 mg of 2,2-dimethyl-4- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -butyric acid as an oil.
  • C24H33NO4 399.53
  • Example 72 Analogously to Example 71, tert-butyl 4- (cis-3-hydroxycyclohexyl) -2,2-dimethylbutyrate and 4-iodomethyl-5-methyl-2- (3-trifluoromethylphenyl) -oxazole 2,2-dimethyl-4- ⁇ 3- [5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -hydroxy ⁇ -butyric acid.
  • Racemate 5.5 ml of tert-butyl diethylphosphonoacetate are dissolved in 20 ml of dimethylformamide and treated at 0 ° C in portions with 820 mg of sodium hydride (60% in paraffin oil). The Suspension is stirred for 15 minutes at 0 ° C and then treated with 2.4 ml of isopropyl iodide. It is stirred for 12 hours at room temperature. Then, 250 ml of ethyl acetate are added and the reaction mixture is washed three times with 150 ml of water each time. The organic phase is dried over MgSO4 and concentrated in vacuo.
  • Example 76 was from 2-allyl-2- ⁇ 2- [cis-3- (tert-butyl-diphenyl-silanyloxy) cyclohexyl] ethyl ⁇ -pent-4-enoic acid tert-butyl ester and 4 -lodmethyl-5-methyl-2- (3-trifluoromethyl-phenyl) -oxazole 2- (2- ⁇ cis-3- [5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] - cyclohexyl ⁇ -ethyl) -2-propyl-pentanoic acid.
  • Example 78 1- ⁇ 2- [cis-3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyl] -ethyl ⁇ -cyclopentanecarboxylic acid
PCT/EP2004/001579 2003-02-27 2004-02-19 3-(2-phenyl-oxazol-4- ylmethoxy)-cyclohexylmethoxy -essigsäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose WO2004076427A1 (de)

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MXPA05008988A MXPA05008988A (es) 2003-02-27 2004-02-19 Derivados de acido 3-(2-fenil-oxazol-4-ilmetoxi) ciclohexilmetoxiacetico y compuestos relacionados utilizados como moduladores de ppar para tratar diabetes de tipo 2 y arterioesclerosis.
DK04712490T DK1599452T3 (da) 2003-02-27 2004-02-19 3- (2-phenyloxazol- 4-ylmethoxy) - cyclohexylmethoxyeddikesyrederivater og beslægtede forbindelser som PPAR modulatorer til behandling af type 2 diabetes og atherosklerosw
JP2006501886A JP2006519194A (ja) 2003-02-27 2004-02-19 ２型糖尿病およびアテローム性動脈硬化症の治療のためのｐｐａｒモジュレーターとしての３−（２−フェニル−オキサゾール−４−イルメトキシ）シクロヘキシルメトキシ酢酸誘導体および関連化合物
CA002517381A 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
DE502004004139T DE502004004139D1 (de) 2003-02-27 2004-02-19 3-(2-phenyl-oxazol-4- ylmethoxy)-cyclohexylmethoxy -essigsäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose
BRPI0407758-0A BRPI0407758A (pt) 2003-02-27 2004-02-19 derivados de 3-(2-fenil-oxazol-4-ilmetóxi)-ciclohexilmetóxi-acético e compostos afins como modula-dores de ppar para o tratamento de diabetes do tipo 2 e aterosclerose.
AU2004215673A AU2004215673B2 (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
EP04712490A EP1599452B1 (de) 2003-02-27 2004-02-19 3-(2-phenyl-oxazol-4- ylmethoxy)-cyclohexylmethoxy -essigsäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose
IL170316A IL170316A (en) 2003-02-27 2005-08-16 Cycloalkyl-methoxy substituted acetic acid derivatives and pharmaceutical compositions comprising them
TNP2005000204A TNSN05204A1 (en) 2003-02-27 2005-08-26 3-2-phenyl-oxazol-4-ylmethoxy)cyclohexylmethoxy acetic acid derivatives and related compounds used as ppar modulators for treating type 2 diabetes and arteriosclerosis
HR20050743A HRP20050743A2 (en) 2003-02-27 2005-08-26 3-(2-phenyl-oxazol-4-yl methoxy) cyclohexylmethoxy acetic acid derivates and related compounds used as ppar modulators for treating type 2 diabetes and arteriosclerosis
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DE102004039532B4 (de) * 2004-08-14 2006-09-21 Sanofi-Aventis Deutschland Gmbh Cyclohexyl-methyloxy substituierte Essigsäurederivate, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
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WO2006018118A1 (de) * 2004-08-14 2006-02-23 Sanofi-Aventis Deutschland Gmbh 2-{-3-`2-(phenyl)-oxazol-4-ylmethoxymethyl!-cyclohexylmethoxy}-propionsäure derivate als ppar-liganden (peroxisomen-proliferatoren-aktivierte rezeptoren) zur behandlung von hyperlipidämie und diabetes
DE102004039532A1 (de) * 2004-08-14 2006-03-02 Sanofi-Aventis Deutschland Gmbh Cyclohexyl-methyloxy substituierte Essigsäurederivate, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
DE102004039533A1 (de) * 2004-08-14 2006-03-02 Sanofi-Aventis Deutschland Gmbh Essigsäurederivate mit Cyclohexylmethoxy-Substituenten, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
DE102004039509A1 (de) * 2004-08-14 2006-03-23 Sanofi-Aventis Deutschland Gmbh Aryl-cycloalkyl substituierte Alkansäurederivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
WO2006018116A1 (de) * 2004-08-14 2006-02-23 Sanofi-Aventis Deutschland Gmbh N-(phenyl-oxazol-4-ylmethoxymethyl)-cyclohexyl-bernsteinsäureamid derivate und werwandte verbindungen als ppar-liganden (peroxisomen-proliferatoren-aktivierte rezeptoren) zur behandlung von hyperlipidämie und diabetes
DE102004039509B4 (de) * 2004-08-14 2006-09-21 Sanofi-Aventis Deutschland Gmbh Aryl-cycloalkyl substituierte Alkansäurederivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US7538131B2 (en) 2004-08-14 2009-05-26 Sanofi-Aventis Deutschland Gmbh 2-{-3-′2-(phenyl)-oxazol-4-ylmethoxymethyl-cyclohexylmethoxy}-propionic acid derivatives useful as peroxisome proliferator-activated receptor (PPAR) ligands for the treatment of hyperlipidemia and diabetes
US7956077B2 (en) 2004-08-14 2011-06-07 Sanofi-Aventis Deutschland Gmbh 2-{-3,′2-(phenyl)-oxazol-4-ylmethoxyl-cyclohexyl methoxy}-propionic acid derivatives used as peroxisome proliferator-activated receptor (PPAR) ligands for the treatment of hyperlipidemia and diabetes
DE102004039533B4 (de) * 2004-08-14 2006-09-28 Sanofi-Aventis Deutschland Gmbh Essigsäurederivate mit Cyclohexylmethoxy-Substituenten, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
US7598281B2 (en) 2004-08-14 2009-10-06 Sanofi-Aventis Deutschland Gmbh Arylcycloakyl-substituted alkanoic acid derivatives useful as peroxisome proliferator-activated receptor (PPAR) ligands for the treatment of hyperlipidemia and diabetes
WO2007039177A2 (en) 2005-09-29 2007-04-12 Sanofi-Aventis Phenyl- and pyridinyl- 1, 2 , 4 - oxadiazolone derivatives, processes for their preparation and their use as pharmaceuticals
US8481778B2 (en) 2007-08-16 2013-07-09 Solvay (Societe Anonyme) Process for the preparation of esters of 4-fluorosubstituted 3-oxo-alcanoic acids

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