WO2004076428A1 - 4-(3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butansäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose - Google Patents

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

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Publication number
WO2004076428A1
WO2004076428A1 PCT/EP2004/001586 EP2004001586W WO2004076428A1 WO 2004076428 A1 WO2004076428 A1 WO 2004076428A1 EP 2004001586 W EP2004001586 W EP 2004001586W WO 2004076428 A1 WO2004076428 A1 WO 2004076428A1
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Prior art keywords
alkyl
methyl
oxazol
phenyl
ylmethoxy
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PCT/EP2004/001586
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German (de)
English (en)
French (fr)
Inventor
Christian Stapper
Stefanie Keil
Heiner Glombik
Eugen Falk
Jochen Goerlitzer
Dirk Gretzke
Hans-Ludwig Schaefer
Wolfgang Wendler
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Aventis Pharma Deutschland Gmbh
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Publication date
Priority to MXPA05008995A priority Critical patent/MXPA05008995A/es
Application filed by Aventis Pharma Deutschland Gmbh filed Critical Aventis Pharma Deutschland Gmbh
Priority to CA002517386A priority patent/CA2517386A1/en
Priority to EP04712503A priority patent/EP1599455B1/de
Priority to DK04712503T priority patent/DK1599455T3/da
Priority to AU2004215677A priority patent/AU2004215677B2/en
Priority to DE502004009690T priority patent/DE502004009690D1/de
Priority to AT04712503T priority patent/ATE435217T1/de
Priority to BRPI0407907-8A priority patent/BRPI0407907A/pt
Priority to JP2006501892A priority patent/JP2006519199A/ja
Publication of WO2004076428A1 publication Critical patent/WO2004076428A1/de
Priority to IL170314A priority patent/IL170314A/en
Priority to HR20050744A priority patent/HRP20050744A2/xx
Priority to NO20054398A priority patent/NO20054398L/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

  • Aryl-cycloalkyl-substituted alkanoic acid derivatives process for their preparation and their use as medicaments
  • the invention relates to aryl-cycloalkyl-substituted alkanoic acid derivatives and their physiologically tolerated 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) -acyloxy, OH, NO2; 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) -cycloalkyl, C6) heteroaryl, (G1-C3) -alkyl (C5-)
  • Carbon atoms may be replaced by oxygen atoms
  • CR12R13, SO, SO2; R 4 is H, F, (C 1 -C 6) -alkyl;
  • R5 is H, F, (C1-C6) -alkyl
  • R6 is H, (C1-C6) -alkyl; or F, if n is not 0;
  • R 7 is H, (C 1 -C 6) -alkyl, (C 2 -C 6) -alkenyl, (C 2 -C 6) -alkynyl, O- (C 1 -C 6) -alkyl,
  • Alkynyl, O- (C3-C8) -cycloalkyl, O-phenyl, O- (C5-C11) -heteroaryl, and wherein (C3-C8) -cycloalkyl, phenyl, (C5-C11) -heteroaryl may additionally be substituted by (C1-C6) -alkyl optionally wholly or partly substituted by F, O- (C1-C6) -alkyl optionally fully or partially substituted by F, Cl, Br, J, OH, NR10R11, CO- (C1-C6) - alkyl,
  • R8 is H, (C1-C6) -alkyl
  • R 9 is H, (C 1 -C 6) -alkyl, which is optionally substituted by phenyl;
  • R 10 is H, (C 1 -C 6) -alkyl, which is optionally substituted by phenyl;
  • R 11 is H, (C 1 -C 6) -alkyl, which is optionally substituted by phenyl;
  • R 12 is H, (C 1 -C 6) -alkyl;
  • R 13 is H, (C 1 -C 6) -alkyl
  • Oxygen atom may be replaced
  • 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
  • R 7 is H, (C 1 -C 6) -alkyl, (C 2 -C 6) -alkenyl, (C 2 -C 6) -alkynyl, O- (C 1 -C 6) -alkyl,
  • R6 and R7 together with the C atom bearing them (C3-C6) -cycloalkyl, especially cyclopentyl; or
  • R 10 and R 11 are H, (C 1 -C 6) -alkyl; or
  • R12 and R13 are hydrogen.
  • R 7 is H, (C 1 -C 6) -alkyl, (C 2 -C 6) -alkenyl, (C 2 -C 6) -alkynyl, O- (C 1 -C 6) -alkyl,
  • 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
  • R 7 is H, (C 1 -C 6) -alkyl, O- (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl-O- (G 1 -C 6) -alkyl, O- (C 2 -C 6) -alkenyl, O - (C2-C6) alkynyl, CH2NR10R11, where alkyl, O-alkyl and alkenyl may be substituted by phenyl or (G5-G6) heteroaryl, which may in turn be substituted by (G1-C6) -alkyl, O- ( C1-C6) -alkyl, CF3;
  • R6 and R7 together with the C atom (C3-C6) -cycloalkyl carrying them;
  • R 10 is (C 1 -C 6) -alkyl
  • R 11 is (C 1 -C 6) -alkyl which is substituted by phenyl;
  • alkyl, alkenyl, alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 can be both straight-chain and branched.
  • aryl is meant 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.
  • the compounds of formula I may be in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and diastereomer mixtures.
  • the present invention encompasses all these isomeric forms of the compounds of the formula I. These isomeric forms, although sometimes not expressis verbis described, can be obtained by known methods.
  • Suitable pharmaceutically acceptable salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must be a pharmaceutically acceptable anion or . Have cation.
  • 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 as well as organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, 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, such as trifluoroacetate, 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 of the invention, for example, an ester capable of (directly or indirectly), when administered to a mammal, such as a human Formula I or to form 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 of the invention may also be in various polymorphic forms, e.g. 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.
  • Peroxisome Proliferator Activated Receptors PPARs
  • PPARs Peroxisome Proliferator Activated Receptors
  • PPARgamma There are two variants of PPARgamma, PPARgamma and gamma 2 , which are the result of alternative use of promoters and differential mRNA splicing (Vidal-Puig et al J. Clin Invest, 97: 2553-2561, 19g6).
  • 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
  • Carbohydrate metabolism are crucially involved. To play z.
  • PPARalpha receptors play an important role in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARgamma, for example, plays a crucial role in the regulation of fatty cell differentiation.
  • 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. Corresponding reviews on functions, physiological effects and
  • 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.
  • the compounds of the formula I are suitable for the treatment, control and prophylaxis of the indications described below, as well as a number of other related pharmaceutical applications (see, for example, Joel Berger et al., Annu. Rev.
  • Diabetes mellitus especially type 2 diabetes, including the prevention of associated sequelae.
  • 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:
  • Various other conditions that may be associated with the metabolic syndrome include: - obesity, including abdominal obesity
  • High blood pressure heart failure e.g. (but not limited to) in the condition of myocardial infarction, hypertensive heart disease or cardiomyopathy
  • Atherosclerosis e.g. (but not limited to) coronary sclerosis including angina pectoris or heart attack
  • stroke e.g., stroke
  • - fatty cell carcinoma e.g. Liposarcomas - solid tumors and neoplasias, 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.
  • Parkinson's disease - erythemato-squamous dermatoses, e.g. 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, e.g. venereal papillomata, viral warts, e.g. Molluscum contagiosum, leukoplakia
  • - 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 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 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.
  • injectable ampoules, and orally administrable unit dose formulations such as tablets or capsules, 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 likewise be present, including further compounds of the formula I.
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the ingredients with pharmacologically acceptable carriers and / or excipients ,
  • 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 depends on the nature and severity of the condition to be treated and on the nature of the particular compound of formula I used.
  • coated formulations and coated slow release formulations are within the scope of the invention. Preferred are.
  • Acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • 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, although the administration may also be subcutaneous, intramuscular or intradermal as an 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%.
  • Transdermal administration is also possible.
  • Suitable pharmaceutical compositions for transdermal applications may be present as single patches for long-term close contact with the epidermis of the patient are suitable.
  • 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 have a positive effect on the fat and sugar metabolism, they reduce in particular the triglyceride level and are suitable for the prevention and treatment of type II diabetes and atherosclerosis as well as their diverse secondary diseases.
  • 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
  • hypoglycemic drugs drugs for the treatment of dyslipidemias
  • Antiatherosclerotic drugs antiadipositas
  • Anti-inflammatory drugs Drugs for the treatment of malignant tumors
  • Antithrombotic drugs High blood pressure drugs
  • Drugs for the treatment of heart failure and agents for the treatment and / or prevention of diabetes-related complications They can be combined with the compounds of the formula I according to the invention in particular for the synergistic effect improvement.
  • the administration of the active ingredient combination can be carried out either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation.
  • Examples include:
  • Antidiabetics are disclosed, for example, in the Red List 2001, Chapter 12 or 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 A / S.
  • the orally active hypoglycemic agents preferably include sulphonylureas, 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 compounds Reduce food intake or intake, PPAR and PXR modulators, and drugs that act on the ATP-dependent potassium channel of beta cells.
  • sulphonylureas biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, gluco
  • the compounds of the formula I are administered in combination with insulin.
  • the compounds of the formula I are used in combination with substances which have an influence on hepatic glucose production, such as glycogen phosphorylase inhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03 / No. 084922, WO 03/104188)
  • the compounds of the formula I are administered in combination with a sulphonylurea such as tolbutamide, glibenclamide, glipizide or glimepiride.
  • the compounds "of formula I are administered in combination with an agent acting on the ATP-dependent potassium channel of the beta cells, such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the beta cells such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • the compounds of formula I are used in combination with a biguanide, e.g. Metformin, administered.
  • a biguanide e.g. Metformin
  • the compounds of formula 1 are used in combination with a meglitinide, e.g. Repaglinide, administered.
  • a meglitinide e.g. Repaglinide
  • the compounds of 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. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
  • a thiazolidinedione such as, for example, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thia
  • the compounds of formula I are used in combination with a DPPIV inhibitor, e.g. in WO98 / 19998, WO99 / 61431, WO99 / 67278, WO99 / 67279, WO01 / 72290, WO 02/38541, WO03 / 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) amino] acetyl] -pyrrolidine-2-carbonitrile monobenzene sulfonate)
  • a DPPIV inhibitor e.g. in WO98 / 19998, WO99 / 6
  • the compounds of the formula I are administered in combination with a PPARgamma agonist, such as rosiglitazone, pioglitazone.
  • a PPARgamma agonist such as rosiglitazone, pioglitazone.
  • the compounds of the formula I are disclosed, directly or indirectly, in combination with compounds having an inhibitory effect on SGLT-1 and / or 2, for example in PCT / EP03 / 06841, PCT / EP03 / 13454 and PCT / EP03 / 13455, administered.
  • the compounds of formula I are administered in combination with an ⁇ r-glucosidase inhibitor, e.g. Miglitol or acarbose, administered.
  • the compounds of formula I are used in combination with more than one of the aforementioned compounds, e.g. 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.
  • 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 adsorbent, e.g. Cholestyramine, colesevelam.
  • a polymeric bile acid adsorbent e.g. Cholestyramine, colesevelam.
  • 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 inducible (see, for example, US Pat. No. 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.
  • 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] phenylmethyl] 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. In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example CP-529, 414 (torcetrapib).
  • a CETP inhibitor for example 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 the formula I are administered in combination with an antioxidant.
  • 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, such as orlistat.
  • a lipase inhibitor such as orlistat.
  • the other active ingredient is fenfluramine or dexfenfluramine.
  • the other active ingredient is sibutramine.
  • the compounds of the formula I are used in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript-influenced energy 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] pyridin-5-yl) -1- (4-ch
  • 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), drugs acting on the angiotensin-renin system, calcium antagonists, beta-blockers, etc.
  • medicaments having effects on the cardiovascular and blood vessel systems such as, e.g. ACE inhibitors (e.g., ramipril), drugs acting 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, which is integrated in the genome of the cell line.
  • a PPARalpha ligand Without the addition of a PPARalpha ligand, the expression of the luciferase reporter gene is only slight if fatty acid-depleted fetal calf serum (cs-FKS) is used in the test.
  • cs-FKS fatty acid-depleted fetal calf serum
  • PPARalpha ligands bind and activate the PPARalpha fusion protein and cause expression of the luciferase 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') were cloned 5 ' upstream of a 68 bp MMTV minimal promoter (Genbank accession # V01175). 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.
  • the cDNA coding for the N-terminal 76 amino acids of the glucocorticoid receptor was first linked to the cDNA segment coding for amino acids 1-147 of the yeast transcription factor GAL4 (Genbank Accession # P04386).
  • PPARalpha receptor 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 cytornegalovirus 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 PPARalpha reporter cell line is cultured to 80% confluency 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 5 (# R250-01, Invitrogen), 0.5 mg / ml G418 (# 10131-027, Invitrogen); 1% penicillin-streptomycin solution (# 15140-122, Invitrogen) and 2mM L-glutamine (# 25030-024, Invitrogen).
  • Cultivation is carried out in standard cell culture bottles (# 353112, Becton Dickinson) in a cell culture incubator at 37 ° C. in the presence of 5% CO 2 .
  • the 80% confluent cells are washed once with 15 ml PBS (# 14190-094,
  • PPARalpha agonists to be tested are in a concentration of 10 mM in
  • Test substances are tested in 11 different concentrations ranging from 10 ⁇ M to 100 pM. More potent compounds are available in concentration ranges of
  • 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.
  • 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
  • test plates 30 100 ⁇ 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.
  • Each plate was overlayed with a standard PPARalpha agonist, which was also diluted in 11 different concentrations to demonstrate the operability of the assay in each plate.
  • the test plates are incubated for 24 h in an incubator at 37 ° C and 5% CO 2 .
  • the treated with the test substances PPARalpha reporter cells are removed from the incubator and the medium 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 are measured in the luminescence meter (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 91 are in the range of O. ⁇ nM to> 10 ⁇ M in this assay.
  • 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 pGLSbasic from Promega.
  • the reporter plasmid five binding sites of the yeast transcription factor GAL4 (each binding site with the sequence 5'-CTCGGAGGACAGTACTCCG-3 '), 5 ' - above were cloned into pGLSbasic together with a 160 bp thymidine kinase prornotor segment (Genbank accession # AF027128) , S '-unterraum of Thymidinkinasepromotörs is the complete luciferase gene from Photinus pyralis (Genbank Accession # M 15077) which is already part of the plasmid used pGLSbasic.
  • the cloning and sequencing of the reporter plasmid pGL3basic-5xGAL4-TK was carried out analogously as in Sambrook J. et. al. (
  • the cDNA coding for amino acids 1-147 of the yeast transcription factor GAL4 (Genbank Accession # P04386) was first cloned into the plasmid pcDNA3 (from Invitrogen) 3'- below the cytomegalovirus promoter. 3 '-unterhaIb the GAL4 DNA binding domain was then the cDNA of the ligand binding domain (LBD) of the human PPARgamma receptor was cloned (amino acids I152-Y475; Accession # gl480099).
  • HEK cells Prior to transfection, HEK cells are cultured in DMEM medium (# 41965-039, Invitrogen) supplemented with 10% FCS (# 16000-044, Invitrogen), 1% penicillin-streptomycin solution (# 15140 -122, Invitrogen) and 2mM L-glutamine (# 25030-024, Invitrogen).
  • solution A is prepared, a transfection mixture which, in addition to DMEM medium, contains all four plasmids already described.
  • solution A is prepared, a transfection mixture which, in addition to DMEM medium, contains all four plasmids already described.
  • 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 pGLSbasic 5xGAL4-TK (10 ng / ⁇ l), 100 ⁇ l PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD (100 ng / ⁇ l) and 78 ⁇ l plasmid pBluescript-SK (+) (500 ng / ⁇ l)
  • solution A 3 ml of solution A are mixed with 2 ml of solution B to 5 ml of solution C, mixed thoroughly by repeated pipetting and incubated for 10 min at room temperature.
  • 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.
  • the cells are then resuspended in 15 ml of DMEM medium (# 41965-039, Invitrogen) supplemented with 10% FCS 5 (# 16000-044, Invitrogen), 1% penicillin-streptomycin solution (# 15140-122, Invitrogen). and 2mM L-glutamine (# 25030-024, Invitrogen).
  • FCS 5 # 16000-044, Invitrogen
  • penicillin-streptomycin solution # 15140-122, Invitrogen
  • 2mM L-glutamine # 25030-024, Invitrogen.
  • the suspension is diluted to 250,000 cells / ml.
  • 200 ⁇ l of the suspension are seeded per well of a 96 well microtiter plate with clear plastic bottom (# 3610, 10 Coming Costar).
  • the plates are incubated for 24 h in a cell culture incubator at 37 ° C and 5% CO
  • PPAR agonists to be tested are at a concentration of 10 mM in DMSO
  • 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
  • test plates 25 100 ⁇ 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
  • the firefly luciferase Photinus pyralis
  • 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 are calculated with the program XL.Fit according to the manufacturer's instructions (IDBS company).
  • IDBS company manufacturer's instructions
  • RingA cis -cyclohexane-1,3-diyl
  • W CH
  • the dashed line indicates the point of attachment.
  • Process A This process is used for the synthesis of the building block A-A, in which R1, R2, W and R3 have the abovementioned meanings.
  • ester A-1 wherein R3 has the abovementioned meaning, is reacted with sodium nitrite and hydrochloric acid to oxime A-2, which is reduced by hydrogenation with hydrogen on palladium / carbon to the amine A-3.
  • the compound A-3 is reacted with acid chlorides of the general formula A-4 wherein R1, W and R2 have the meanings given above, and base (for example triethylamine) to the compound A-5.
  • Compound A-5 is converted to compound A-6 by heating in phosphoryl chloride.
  • Ester A-6 is reduced with lithium aluminum hydride in diethyl ether to alcohol A-7. This is converted into the iodide A-8 with iodine, imidazole (ImH) and triphenylphosphine.
  • Method B This process is used for the synthesis of the building block A-8, in which R1, R2, W and R3 have the abovementioned meanings.
  • the compound B-3 is boiled in phosphoryl chloride, the
  • the compound C-1 is boiled with dibutyltin oxide in toluene under reflux on a water separator. After addition of dimethylformamide, cesium fluoride and compound A-8 (see method A) the suspension is at room temperature touched. In this case, the compound C-2 is obtained. This is done with Chirazym L-2 in
  • Compound C-5 is added with osmium tetroxide and sodium periodate in diethyl ether
  • Compound C-9 is hydrogenated with hydrogen on palladium / carbon to compound C-10.
  • Examples 1 to 4 can be synthesized.
  • Compound D-1 is now used either with trimethylsulfonium iodide and sodium hydride in dimethyl sulfoxide to give compound D-2, or with a secondary amine NR10R11 wherein R10 and R11 have the meanings described above, to compound D-3 or with an aryl halide and a palladium ( 0) catalyst reacted in a Heck reaction to compound D-4.
  • Compound D-4 is then hydrogenated with palladium on carbon to compound D-5.
  • the compounds D-2, D-3 and D-5 are reacted with sodium hydroxide to give compounds of general formula D-6, wherein R6 and R7 have the meanings described above. According to this method, Examples 5 to 9 can be synthesized.
  • Compound C-5 is dihydroxylated with osmium tetroxide, 1, 5-diazabicyclo [2.2.2] pctane (DABCO) and N-methylmorpholine N-oxide to give compound E-1. Subsequently, the primary hydroxyl group is protected as trialkylsilyl ether E-2 by stirring compound E-1 with a trialkylchlorosilane (e.g., tert-butyldimethylsilyl chloride) and imidazole as a base in dimethylformamide at room temperature.
  • a trialkylchlorosilane e.g., tert-butyldimethylsilyl chloride
  • the Compound E-2 is reacted with a strong base (e.g., sodium hydride or potassium tert-butylate) and an alkyl halide to give compound E-3 wherein R7 is as described above.
  • a strong base e.g., sodium hydride or potassium tert-butylate
  • the silyl protecting group is cleaved with tetrabutylammonium fluoride in tetrahydrofuran to give compound E-4.
  • Compound E-4 is stirred with Dess-Martin periodinane (DMP) in dichloromethane at room temperature for several hours, worked up and then reacted with sodium chlorite and hydrogen peroxide in acetonitrile to give compound E-5.
  • DMP Dess-Martin periodinane
  • E-5 can be synthesized from E-4 by direct oxidation of E-4 with a chromium (VI) compound (eg CrO3 in sulfuric acid). According to this method, Examples 10 to 27 can be
  • the racemic or enantiomerically pure compound F-1 wherein PG has the meaning given in the diagram, is dihydroxylated with osmium tetroxide, 1, 5-diazabicyclo [2.2.2] octane (DABCO) and N-methylmorpholine N-oxide to give compound F-2 , Subsequently, the primary hydroxyl group is protected as trialkylsilyl ether F-3 by stirring compound F-2 with a trialkylchlorosilane (eg tert-butyldimethylsilyl chloride) and imidazole as a base in dimethylformamide at room temperature.
  • a trialkylchlorosilane eg tert-butyldimethylsilyl chloride
  • the compound F-3 is reacted with a strong base (e.g., sodium hydride or potassium tert-butylate) and an alkyl halide to give the compound F-4 wherein R7 is as described above.
  • a strong base e.g., sodium hydride or potassium tert-butylate
  • the benzyl protecting group is hydrogenolytically cleaved with hydrogen on Pd (10% on carbon), the benzoyl protecting group is cleaved with potassium carbonate in methanol and the trityl group with formic acid in methanol to give the compound F-5.
  • the compound F-5 is reacted with the alkyl iodide A-8 in the presence of a strong base (e.g., sodium hydride or potassium tert-butylate) in an inert solvent (e.g., MTBE, chlorobenzene) to give compound E-3 wherein R1, R2 , R3, R7 and W have the abovementioned meaning implemented.
  • a strong base e.g., sodium hydride or potassium tert-butylate
  • an inert solvent e.g., MTBE, chlorobenzene
  • Compound G-6 is hydrogenated with hydrogen on palladium to give compound G-7 wherein R1, R2, W and R3 are as defined above.
  • Compound G-7 is coupled with carboxylic acid derivatives G-8, wherein R4, R5, R6 and R7 are as defined above.
  • Examples 28 to 90 can be synthesized.
  • 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole was obtained from diacetylmonoxime and p-tolualdehyde.
  • 4-iodomethyl-5-methyl-2-p-biphenyl-oxazol 4-iodomethyl-5-methyl-2-p-biphenyloxazole was obtained from diacetylmonoxime and p-biphenylcarbaldehyde.
  • 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole 4-iodomethyl-5-methyl-2-naphthyloxazole was obtained from diacetylmonoxime and 2-naphthalenecarbaldehyde.
  • 4-iodomethyl-5-phenyl-2-p-tolyl-oxazol 4-iodomethyl-5-methyl-2- (2,6-dimethylphenyl) -oxazole was obtained from diacetylmonoxime and 2,6-dimethylbenzaldehyde.
  • 4-iodomethyl-2- (4-methoxyphenyl) -5-methyl-oxazole was obtained from diacetylmonoxime and 4-methoxybenzaldehyde.
  • Example 2 Adapted to the Reaction Conditions of Example 1, 2 - ((1R, 3S) - [3- (2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy) -cyclohexyloxy] acetaldehyde and ethyl 2- (diethoxy-phosphoryl) -pentanoate 2-propyl-4- [3- (2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy) -cyclohexyl-oxy] -butanoic acid.
  • Example 1 Adapted to the reaction conditions of Example 1 is obtained from 2 - ((1 R, 3S) - [3- (2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy) cyclohexyloxy] acetaldehyde and 2- (Diethoxyphosphoryl) -acetic acid ethyl ester 4- ⁇ 3- [2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy] -cyclohexyloxy ⁇ -butanoic acid
  • Example 4 Adapted to the Reaction Conditions of Example 1, 2 - ((1R, 3S) - [3- (2- (4-fluoro-phenyl) -5-methyl-oxazol-4-ylmethoxy) -cyclohexyloxy] -acetaldehyde 'and 2- (diethoxyphosphoryl) -propionic acid ethyl ester 4- ⁇ 3- [2- (4-FIuoro-phenyl) -5-methyl-oxazol-4-ylmethoxy] cyclohexyloxy ⁇ -2-methyl-butanoic acid
  • Example 13 Adapted to the reaction conditions of Example 10, 1- (tert-butyl-dimethyl-silanyloxy) -3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy ) - cyclohexyloxy] propan-2-ol and methyl iodide 3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyloxy] -2-methoxypropionic acid.
  • Example 13 Example 13:
  • Example 15 Adapted to the reaction conditions of Example 10, 1- (tert-butyl-dimethyl-silanyloxy) -3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) - cyclohexyloxy] -propan-2-ol and 3-trifluoromethylbenzylbromide 3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyloxy] -2- ( 3-trifluoromethylbenzyloxy) propanoic acid.
  • Example 15 Example 15:
  • Example 17 3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyloxy] -2- (4-methylbenzyloxy) -propanoic acid
  • Example 10 Adapted to the reaction conditions of Example 10, 1- (tert-butyl-dimethyl-silanyloxy) -3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy ) - cyclohexyloxy] -propan-2-ol and 2-trifluoromethylbenzylbromide 3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-o-azol-4-ylmethoxy) -cyclohexyloxy] -2- (2-trifluoromethylbenzyloxy) propanoic acid.
  • Example 20 3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyloxy] -2- (2-chlorothien-5-ylmethoxy) -propionic acid
  • Example 10 Adapted to the reaction conditions of Example 10, 1- (tert-butyl-dimethyl-silanyloxy) -3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy ) - cyclohexyloxy] -propan-2-ol and 2-chlorothien-5-ylmethyl chloride 3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyl-oxy] -2- (2-chlorothien-5-ylmethoxy) propionic acid.
  • Example 21 3 - [(1R, 3S) -3- (5-methyl-2-m-tolyl-oxazol-4-ylmethoxy) -cyclohexyloxy] -2- (2-butynoxy) -propionic acid
  • Osmium tetroxide ((2R / 2S) -3 - [(1R, 3S) -3-trityloxymethylcyclohexyloxypropane-1,2-diol.
  • Example 38 2-Methoxy-3 - ⁇ (1R, 3S) -3- [5-ethyl-2- (3-methoxyphenyl) -oxazol-4-ytmethoxy ⁇ -cyclohexyloxy ⁇ -propionic acid
  • Example 40 2-Methoxy-3 - ⁇ (1R, 3S) -3- [5-ethyl-2- (2-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ⁇ -cyclohexyloxy ⁇ -propionic acid
  • Example 44 3 - ⁇ (1R, 3S) -3- [5-methyl-2- (3-trifluoromethoxy-phenyl) -oxazol-4-ylmethoxy-cyclohexyloxy ⁇ -2-propoxy-propionic acid
  • Example 46 3 - ⁇ (1R, 3S) -3- [5-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy-cyclohexyloxy ⁇ -2-propoxy-propionic acid
  • Example 48 3 - ⁇ (1R, 3S) -3- [5-Methyl-2- (4-trifluoromethoxyphenyl) -oxazol-4-ylmethoxy-cyclohexyloxy ⁇ -2-propoxy-propionic acid
  • Example 54 3 - ⁇ (1R, 3S) -3- [5-ethyl-2- (4-methylphenyl) -oxazol-4-ylmethoxy-cyclohexyloxy ⁇ -2-propoxy-propionic acid
  • Example 58 Adapted to the reaction conditions of Example 28, from (2R / 2S) -3- [(1S, 3R) -3-benzyloxycyclohexyloxy] -2-ethoxypropyl-tert-butyldiphenylsilyl ether and 5-methyl-2- (3-trifluoromethyl) phenyl) -oxazol-4-ylmethyl-iodide 2-ethoxy-3 - ⁇ (1R, 3S) -3- [5-methyl-2- (3-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -cyclohexyloxy ⁇ -propionic acid ,
  • Example 58 Example 58:
  • Example 72 2-Ethoxy-3 - ⁇ (1R, 3S) -3- [5-methyl-2- (3-methoxyphenyl) -oxazol-4-ylmethoxy ⁇ cyclohexyl-oxy ⁇ -propionic acid
  • the residue is chromatographed on silica gel (flash master, heptane / ethyl acetate 1: 0 -> 1: 1 -> 0: 1).
  • the product-containing fractions are concentrated, the residue (420 mg) is dissolved in 10 ml of THF and admixed with 174 mg of TBAF.
  • water and MTBE are added, the organic phase is separated, washed with NaCl solution, dried over MgSO4 and concentrated.
  • the residue is dissolved in 2 ml of acetone, treated with 0.5 ml of 1.9M Jones reagent and stirred at RT overnight. After addition of water and MTBE, the organic phase is separated, dried over MgSO4 and concentrated.
PCT/EP2004/001586 2003-02-27 2004-02-19 4-(3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butansäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose WO2004076428A1 (de)

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DE502004009690T DE502004009690D1 (de) 2003-02-27 2004-02-19 4-(3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butansäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose
CA002517386A 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
EP04712503A EP1599455B1 (de) 2003-02-27 2004-02-19 4-(3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butansäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose
DK04712503T DK1599455T3 (da) 2003-02-27 2004-02-19 4-(3-(2-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butansyrederivater og beslægtede forbindelser som PPAR modulatorer til behandling af type 2 diabetes og aterosclerose
AU2004215677A AU2004215677B2 (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
MXPA05008995A MXPA05008995A (es) 2003-02-27 2004-02-19 Derivados de acido 4 - (3-(2-feniloxazol - 4 - ilmetoxi) ciclohexiloxi) - butanoico y compuestos relacionados como moduladores de ppar para tratar la diabetes tipo 2 y la aterosclerosis.
AT04712503T ATE435217T1 (de) 2003-02-27 2004-02-19 4-(3- (2-phenyl-oxazol-4-ylmethoxy)- cyclohexyloxy)-butansäure derivate und verwandte verbindungen als ppar modulatoren zur behandlung von typ 2 diabetes und atherosklerose
BRPI0407907-8A BRPI0407907A (pt) 2003-02-27 2004-02-19 derivados de ácido alcánico substituìdos com aril-cicloaquila, processos para preparação dos mesmos e uso dos mesmos como medicamentos
JP2006501892A JP2006519199A (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４−（３−（２−フェニル−オキサゾール−４−イルメトキシ）−シクロヘキシルオキシ）−ブタン酸誘導体および関連化合物
IL170314A IL170314A (en) 2003-02-27 2005-08-16 4 - (3 -(2 - phenyl - oxazol - 4 - ylmethoxy) - cyclohexyloxy) - butane acid derivatives and related compounds, pharmaceutical compositions comprising them and use thereof
HR20050744A HRP20050744A2 (en) 2003-02-27 2005-08-26 4-(3-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butane acid derivates and related compounds as ppar modulators for treating diabetes of type 2 and atherosclerosis
NO20054398A NO20054398L (no) 2003-02-27 2005-09-22 4-(3-(2-fenyl-oksazol-4-ylmetoksy)-cykloheksyloksy)-butansyrederivater og lignende forbindelser som PPAR-modulatorer til behandling av type 2 diabetes og aterosklerose

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