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WO2000063190A1 - Nouveaux composes, leur preparation et utilisation - Google Patents

Nouveaux composes, leur preparation et utilisation Download PDF

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Publication number
WO2000063190A1
WO2000063190A1 PCT/DK2000/000189 DK0000189W WO0063190A1 WO 2000063190 A1 WO2000063190 A1 WO 2000063190A1 DK 0000189 W DK0000189 W DK 0000189W WO 0063190 A1 WO0063190 A1 WO 0063190A1
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alkyl
compound according
halogen
hydroxy
compound
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Inventor
Lone Jeppesen
Per Sauerberg
Anthony Murray
Paul Stanley Bury
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Novo Nordisk AS
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Novo Nordisk AS
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Priority to AU39579/00A priority Critical patent/AU3957900A/en
Priority to EP00918724A priority patent/EP1171431A1/fr
Priority to JP2000612282A priority patent/JP2002542237A/ja
Publication of WO2000063190A1 publication Critical patent/WO2000063190A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to novel compounds, pharmaceutical compositions containing them, methods for preparing the compounds and their use as medicaments. More specifically, compounds of the invention can be utilised in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Re- ceptors (PPAR).
  • PPAR Peroxisome Proliferator-Activated Re- ceptors
  • Coronary artery disease is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e. patients that fall within the 'deadly quartet' category of impaired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity).
  • hypolipidaemic fibrates and antidiabetic thiazolidinediones separately display moderately effective triglyceride-lowering activities although they are neither potent nor efficacious enough to be a single therapy of choice for the dyslipidaemia often observed in Type 2 diabetic or metabolic syndrome patients.
  • the thiazolidinediones also potently lower circulating glucose levels of Type 2 diabetic animal models and humans.
  • the fibrate class of compounds are without beneficial effects on glycaemia.
  • thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased and decreased expression of specific enzymes and apolipoproteins respectively, both key-players in regulation of plasma triglyceride content.
  • Fibrates on the one hand, are PPAR ⁇ activators, acting primarily in the liver.
  • Thiazolidinediones on the other hand, are high affinity ligands for PPAR ⁇ acting primarily on adipose tissue.
  • Adipose tissue plays a central role in lipid homeostasis and the maintenance of energy balance in vertebrates.
  • Adipocytes store energy in the form of triglycerides during periods of nutritional affluence and release it in the form of free fatty acids at times of nutritional deprivation.
  • white adipose tissue is the result of a continuous differentiation process throughout life.
  • Much evidence points to the central role of PPAR ⁇ activation in initiating and regulating this cell differentiation.
  • Several highly specialised proteins are induced during adipocyte differentiation, most of them being involved in lipid storage and metabolism. The exact link from activation of PPAR ⁇ to changes in glucose metabolism, most notably a decrease in insulin resistance in muscle, has not yet been clarified.
  • a possible link is via free fatty acids such that activation of PPAR ⁇ induces Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoA Synthetase (ACS) in adipose tissue but not in muscle tissue.
  • LPL Lipoprotein Lipase
  • FATP Fatty Acid Transport Protein
  • ACS Acyl-CoA Synthetase
  • PPAR ⁇ is involved in stimulating ⁇ -oxidation of fatty acids.
  • a PPAR ⁇ -mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis in rodents.
  • the phenomenon of peroxisome proliferation is not seen in man.
  • PPAR ⁇ is also involved in the control of HDL cholesterol levels in rodents and humans. This effect is, at least partially, based on a PPAR ⁇ -mediated transcriptional regulation of the major HDL apolipoproteins, apo A-l and apo A-ll.
  • the hypotriglyceridemic action of fibrates and fatty acids also involves PPAR ⁇ and can be summarised as follows: (I) an increased lipolysis and clearance of remnant particles, due to changes in lipoprotein lipase and apo C-lll levels, (II) a stimulation of cellular fatty acid uptake and their subsequent conversion to acyl-CoA derivatives by the induction of fatty acid binding protein and acyl-CoA synthase, (III) an induction of fatty acid -oxidation pathways, (IV) a reduction in fatty acid and triglyceride synthesis, and finally (V) a decrease in VLDL production.
  • both enhanced catabolism of triglycehde-rich particles as well as reduced secretion of VLDL particles constitutes mechanisms that contribute to the hypolipidemic effect of fibrates.
  • Glucose lowering as a single approach does not overcome the macrovascular complications associated with Type 2 diabetes and metabolic syndrome.
  • Novel treatments of Type 2 diabetes and metabolic syndrome must therefore aim at lowering both the overt hypertriglyceri- daemia associated with these syndromes as well as alleviation of hyperglycaemia.
  • ring A and ring B, fused to the ring containing X and T, independently of each other represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro, cyano, formyl, or d- ⁇ -alkyl, C 4 . 12 - alkenynyl, C 2 . 12 -alkenyl, C 2 . ⁇ 2 -alkynyl, C ⁇ .
  • R 6 and R 7 independently of each other are selected from hydroxy, halogen, perhalomethyl, d_ 6 -alkoxy or amino optionally substituted with one or more d. 6 -alkyl or perhalomethyl; or aryl , wherein the aryl optionally can be substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or heteroaryl, wherein the heteroaryl optionally can be substituted with halogen, amino hydroxy, d_ 6 -alkyl or d. 6 -alkoxy; or heterocyclyl, wherein the heterocyclyl optionally can be substituted with halogen, amino, hydroxy, C ⁇ . 6 -alkyl or d_ 6 -alkoxy;
  • X is -O-, -S- or -(NR 8 )- wherein R 8 is hydrogen, halogen, hydroxy, nitro, cyano, formyl, d_ 12 -alkyl, d. 12 -alkoxy, aryl, aryloxy, arylalkyl, arylalkoxy, heterocyclyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, d. 12 -alkyl-amino, arylamino, arylalkylamino, aminod.
  • T is N or CR 14 , wherein R 14 is hydrogen, d.i 2 -alkoxy, d. 12 -alkyl, C . 12 -alkenynyl, C 2 . 12 -alkenyl, C 2 . 12 -alkynyl, aryl or arylalkyl;
  • Y is C, O, S, CO, SO, SO 2 or NR 11 , wherein R 11 is hydrogen, d- ⁇ -alkyl;
  • k is 1 or 2;
  • Ar represents arylene, heteroarylene, or a divalent heterocyclic group each of which can optionally be substituted with one or more halogen, d-e-alkyl, amino, hydroxy, d_ 6 -alkoxy or aryl;
  • R represents hydrogen, hydroxy, halogen, C ⁇ . 12 -alkoxy, d- 12 -alkyl, C 4 . 12 -alkenynyl, C 2 . 12 - alkenyl, C 2 . ⁇ 2 -alkynyl or arylalkyl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;
  • R 2 represents hydrogen, hydroxy, halogen, d. 12 -alkoxy, d. 12 -alkyl, C 4 . 12 -alkenynyl, C 2 . 12 - alkenyl, C 2 . 12 -alkynyl or arylalkyl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or R 2 forms a bond together with R 3 ;
  • R 3 represents hydrogen, hydroxy, halogen, d_ ⁇ 2 -alkoxy, d. 12 -alkyl, C _ ⁇ 2 -alkenynyl, C 2 . ⁇ 2 - alkenyl, C 2 . 12 -alkynyl, acyl or arylalkyl; optionally substituted with one or more halogen, per- halomethyl, hydroxy, nitro or cyano; or R 3 forms a bond together with R 2 ;
  • R 4 represents hydrogen, d. 12 -alkyl, C 4 . 12 -alkenynyl, C 2 . 12 -alkenyl, C 2 . 12 -alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;
  • R 5 represents hydrogen, d. 12 -alkyl, C 4 . 12 -alkenynyl, C 2 . ⁇ 2 -alkenyl, C 2 . ⁇ 2 -alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;
  • Z represents oxygen or NR 12 , wherein R 12 represents hydrogen d. 12 -alkyl, aryl, hydroxyd. 12 -alkyl or arylalkyl groups or when Z is NR 12 , R 4 and R 2 may form a 5 or 6 membered nitrogen containing ring, optionally substituted with one or more C ⁇ _ 6 -alkyl;
  • Q represents oxygen or NR 13 , wherein R 13 represents hydrogen d. 12 -alkyl, aryl, hydroxyd. 12 -alkyl or arylalkyl groups or when Q is NR 13 , R 5 and R 13 may form a 5 or 6 membered nitrogen containing ring, optionally substituted with one or more d. 6 -alkyl;
  • the present invention is concerned with compounds of formula l wherein ring A and ring B, fused to the ring containing X and T independently of each other represents a 5-6 membered cyclic ring, optionally substituted with halogen, d. 6 -alkyl or aryl, wherein the aryl can be substituted with one or more halogen or C ⁇ _ 6 -alkyl; or heterocyclyl, wherein the heterocyclyl can be substituted with d. 6 -alkyl.
  • the present invention is concerned with compounds of formula I wherein ring A and ring B, fused to the ring containing X and T independently of each other represents a 5-6 membered cyclic ring.
  • the present invention is concerned with compounds of formula I wherein ring A and ring B, fused to the ring containing X and T independently of each other represents aryl.
  • the present invention is concerned with compounds of formula I wherein X is O.
  • the present invention is concerned with compounds of formula I wherein T is N.
  • the present invention is concerned with compounds of formula I wherein k is 2.
  • the present invention is concerned with compounds of formula I wherein Ar represents arylene.
  • the present invention is concerned with compounds of formula I wherein R 1 , R 2 and R 3 represents hydrogen. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein R 4 and R 5 represents hydrogen or methyl.
  • the present invention is concerned with compounds of formula I wherein Z and Q represents O.
  • the present invention is concerned with compounds of formula I wherein n is 1.
  • the present invention is concerned with compounds of formula I wherein m is 1.
  • the present invention is concerned with compounds of formula I wherein p is 0.
  • Preferred compounds of the invention are:
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric forms.
  • d- 12 -alkyl as used herein, alone or in combination is intended to include those alkyl groups of the designated length in either a linear or branched or cyclic configuration, represents e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like. Typical d.
  • 6 -alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like.
  • C 2 . n -alkenyl wherein n' can be from 3 through 15, as used herein, represents an olefinically unsaturated branched or straight group having from 2 to the specified number of carbon atoms and at least one double bond.
  • groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-proppenyl, 1 ,3-butadienyl, 1-butenyl, hex- enyl, pentenyl and the like.
  • C 2 . n -alkynyl wherein n' can be from 3 through 15, as used herein, represent an unsaturated branched or straight group having from 2 to the specified number of carbon atoms and at least one triple bond.
  • examples of such groups include, but are not limited to, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.
  • C 4 . n -alkenynyl wherein n' can be from 5 through 15, as used herein, represent an unsaturated branched or straight hydrocarbon group having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Examples of such groups include, but are not limited to, 1 -penten-4-yne, 3-penten-1-yne, 1 ,3- hexadiene-5-yne and the like.
  • d. ⁇ 2 -alkoxy as used herein, alone or in combination is intended to include those d. 2 -alkyl groups of the designated length in either a linear or branched or cyclic configuration linked thorugh an ether oxygen having its free valence bond from the ether oxygen.
  • linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like.
  • branched alkoxy are isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy and the like.
  • cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • d. 12 -alkylthio refers to a straight or branched or cyclic monovalent substituent comprising a d. 12 -alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 12 carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio and the like.
  • cyclic alkylthio are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
  • d. 12 -alkylamino refers to a straight or branched or cyclic monovalent substituent comprising a d. 12 -alkyl group linked through amino having a free valence bond from the nitrogen atom e.g. methylamino, ethylamino, propylamino, butylamino, pentylamino and the like.
  • cyclic alkylamino are cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like.
  • hydroxyd is hydroxyd.
  • 12 -alkyl refers to a d-12-alkyl as defined herein whereto is attached a hydroxy group, e.g. hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and the like.
  • arylamino refers to an aryl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. phenylamino, naphthylamino and the like.
  • arylalkylamino refers to an arylalkyl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. benzylamino, phenethylamino, 3-phenylpropylamino, 1-naphtylmethylamino, 2-(1- naphtyl)ethylamino and the like.
  • aminod- 12 -alkyl refers to a d.i ⁇ -alkyi as defined herein whereto is attached an amino group, e.g. aminoethyl, 1-aminopropyl, 2- aminopropyl and the like.
  • aryloxycarbonyl refers to an aryloxy as defined herein linked through a carbonyl having a free valence bond from the carbon atom, e.g. phenoxy carbonyl, 1-naphthyloxycarbonyl or 2-naphthyloxycarbonyl and the like.
  • arylalkoxycarbonyl refers to an arylalkoxy as defined herein linked through a carbonyl having a free valence bond from the carbon atom, e.g. benzyloxycarbonyl, phenethoxycarbonyl, 3-phenylpropoxycarbonyl, 1- naphthylmethoxycarbonyl, 2-(1-naphtyl)ethoxycarbonyl and the like.
  • d- 12 - alkyl as defined herein whereto is attached a d. 12 -alkoxy as defined herein, e.g. methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like.
  • aryloxyd. 12 -alkyl refers to a d. ⁇ 2 -alkyl as defined herein whereto is attached an aryloxy as defined herein, e.g. phenoxymethyl, phenoxydodecyl, 1-naphthyloxyethyl, 2-naphthyloxypropyl and the like.
  • arylalkoxyd. ⁇ -alkyl refers to a d-12-alkyl as defined herein whereto is attached an arylalkoxy as defined herein, e.g. benzyloxymethyl, phenethoxydodecyl, 3-phenylpropoxyethyl, 1-naphthylmethoxypropyl, 2-(1- naphtyl)ethoxymethyl and the like.
  • thiod- 12 -alkyl refers to a C ⁇ . ⁇ 2 -alkyl as defined herein whereto is attached a group of formula -SR'" wherein R"' is hydrogen, d-e- alkyl or aryl, e.g. thiomethyl, methylthiomethyl, phenylthioethyl and the like.
  • C ⁇ .i 2 -alkoxycarbonylamino refers to a d- 12 -alkoxycarbonyl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. methoxycarbonylamino, carbethoxyamino, propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, tert-butoxycarbonylamino and the like.
  • aryloxycarbonylamino refers to an aryloxycarbonyl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. phenoxycarbonylamino, 1-naphthyloxycarbonylamino or 2- naphthyloxycarbonylamino and the like.
  • arylalkoxycarbonylamino refers to an arylalkoxycarbonyl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. benzyloxycarbonylamino, phenethoxycarbonylamino, 3- phenylpropoxycarbonylamino, 1 -naphthylmethoxycarbonylamino, 2-(1 - naphtyl)ethoxycarbonylamino and the like.
  • aryl is intended to include aromatic rings, such as carboxylic aromatic rings selected from the group consisting of phenyl, naphthyl, (1-naphtyl or 2-naphtyl) and the like optionally substituted with halogen, amino, hydroxy, d-e-alkyl or d-e-alkoxy and the like.
  • arylene is intended to include divalent aromatic rings, such as carboxylic aromatic rings selected from the group consisting of phenylene, naphthylene and the like optionally substituted with halogen, amino, hydroxy, d-e-alkyl or d- ⁇ -alkoxy and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • perhalomethyl means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
  • dimethylamino N- ethyl-N-methylamino, diethylamino, dipropylamino, N-(n-butyl)-N-methylamino, di(n- pentyl)amino and the like.
  • acyl refers to a monovalent substituent comprising a d-e-alkyl group linked through a carbonyl group; such as e.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and the like.
  • acyloxy refers to acyl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy and the like.
  • d. ⁇ -alkoxycarbonyl refers to a monovalent substituent comprising a d. 12 -alkoxy group linked through a carbonyl group; such as e.g. methoxycarbonyl, carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec- butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.
  • bicycloalkyl refers to a monovalent substituent comprising a bicyclic structure made of 6-12 carbon atoms such as e.g. 2-norbornyl, 7-norbomyl, 2- bicyclo[2.2.2]octyl and 9-bicyclo[3.3.1]nonanyl and the like.
  • heteroaryl refers to a monovalent substituent comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.
  • heteroarylene refers to a divalent group comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.
  • heteroaryloxy refers to a heteroaryl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom e.g. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine linked to oxygen, and the like.
  • oxygen atom e.g. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline
  • arylalkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.
  • aryloxy refers to phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
  • arylalkoxy refers to a d- 6 -alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1- naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like.
  • heteroarylalkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl group; such as (2- furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl- 1-(2-pyrimidyl)ethyl and the like.
  • heteroarylalkoxy refers to a heteroarylalkyl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom, e.g. (2- furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl- 1-(2-pyrimidyl)ethyl linked to oxygen, and the like.
  • d. 6 -alkylsulfonyl refers to a monovalent substituent comprising a d_ 6 -alkyl group linked through a sulfonyl group such as e.g.
  • d- ⁇ -monoalkylaminosulfonyl refers to a monovalent substituent comprising a d. 6 -monoalkylamino group linked through a sulfonyl group such as e.g.
  • methylaminosulfonyl methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n- butylaminosulfonyl, sec-butylaminosulfonyl, isobutylaminosulfonyl, tert-butylaminosulfonyl, n- pentylaminosulfonyl, 2-methylbutylaminosulfonyl, 3-methylbutylaminosulfonyl, n- hexylaminosulfonyl, 4-methylpentylaminosulfonyl, neopentylaminosulfonyl, n- hexylaminosulfonyl, 2,2-dimethylpropylaminosulfonyl and the like.
  • C ⁇ . 6 -dialkylaminosulfonyl refers to a monovalent substituent comprising a d-e-dialkylamino group linked through a sulfonyl group such as dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, N-(n-butyl)-N-methylaminosulfonyl, di(n-pentyl)aminosulfonyl and the like.
  • acylamino refers to an amino group wherein one of the hydrogen atoms is substituted with an acyl group, such as e.g. acetamido, propionamido, isopropylcar- bonylamino and the like.
  • (C 3 . 6 -cycloalkyl)C 1 . 6 -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms and being monosubstituted with a C 3 . 6 -cycloalkyl group, the cycloalkyl group optionally being mono- or polysubstituted with d-e-alkyl, halogen, hydroxy or d. 6 -alkoxy; such as e.g. cyclopropylmethyl, (l-methylcyclopropyl)methyl, 1-(cyclopropyl)ethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
  • arylthio refers to an aryl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom, the aryl group optionally being mono- or polysubstituted with d-e-alkyl, halogen, hydroxy or C ⁇ _ 6 -alkoxy; e.g. phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl)thio and the like.
  • arylsulfonyl refers to an aryl group linked through a sulfonyl group, the aryl group optionally being mono- or polysubstituted with d. 6 -alkyl, halogen, hydroxy or d. 6 -alkoxy; such as e.g. phenylsulfonyl, tosyl and the like.
  • d-e-monoalkylaminocarbonyl refers to a monovalent substituent comprising a Ci-e-monoalkylamino group linked through a carbonyl group such as e.g. methyl- aminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n- butylaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, 2-methylbutylaminocarbonyl, 3-methylbutylaminocarbonyl, n- hexylaminocarbonyl, 4-methylpentylaminocarbonyl, neopentylaminocarbonyl, n- hexylaminocarbonyl, 2-2-dimethylpropylaminocarbonyl and the
  • d. 6 -dialkylaminocarbonyl refers to a monovalent substituent comprising a d. 6 -dialkylamino group linked through a carbonyl group such as dimethylaminocar- bonyl, N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N-(n- butyl)-N-methylaminocarbonyl, di(n-pentyl)aminocarbonyl and the like.
  • heterocyclyl means a monovalent saturated or unsaturated non aromatic group being monocyclic and containing one or more, such as from one to four carbon atom(s), and from one to four N, O or S atom(s) or a combination thereof.
  • heterocyclyl includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. pyrrolidine, pyrroline and the like); 5-membered heterocycles having two heteroatoms in 1 ,2 or 1 ,3 positions (e.g.
  • pyrazoline pyrazolidine, 1 ,2-oxathiolane, imidazolidine, imi- dazoline, 4-oxazolone and the like
  • 5-membered heterocycles having three heteroatoms e.g. tetrahydrofurazan and the like
  • 5-membered heterocycles having four heteroatoms 6- membered heterocycles with one heteroatom (e.g. piperidine and the like); 6-membered het- erocycles with two heteroatoms (e.g. piperazine, morpholine and the like); 6-membered heterocycles with three heteroatoms; and 6-membered heterocycles with four heteroatoms, and the like.
  • a divalent heterocyclic group means a divalent saturated or un- saturated system being monocyclic and containing one or more, such as from one to four carbon atom(s), and one to four N, O or S atom(s) or a combination thereof.
  • the phrase a divalent heterocyclic group includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. pyrrolidine, pyrroline and the like); 5-membered heterocycles having two heteroatoms in 1 ,2 or 1 ,3 positions (e.g.
  • pyrazoline pyrazolidine, 1 ,2-oxathiolane, imida- zolidine, imidazoline, 4-oxazolone and the like
  • 5-membered heterocycles having three heteroatoms e.g. tetrahydrofurazan and the like
  • 5-membered heterocycles having four heteroatoms 6-membered heterocycles with one heteroatom (e.g. piperidine and the like); 6- membered heterocycles with two heteroatoms (e.g. piperazine, morpholine and the like); 6- membered heterocycles with three heteroatoms; and 6-membered heterocycles with four heteroatoms, and the like.
  • a 5-6 membered cyclic ring means an unsaturated or saturated or aromatic system containing one or more carbon atoms and optionally from one to four N, O or S atom(s) or a combination thereof.
  • the phrase “a 5-6 membered cyclic ring” includes, but is not limited to, e.g.
  • cyclopentyl cyclohexyl, phenyl, cyclohexenyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiomorpholinyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1 ,3-dioxolanyl, 1 ,4-dioxolanyl and the like, 5-membered heterocycles having one hetero atom (e.g.
  • 5-membered heterocycles having two heteroatoms in 1 ,2 or 1 ,3 positions e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines and the like
  • 5-membered heterocycles having three heteroatoms e.g. triazoles, thiadiazoles and the like
  • 5-membered heterocycles having four heteroatoms 6-membered heterocycles with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthridine, cyclohepta[b]pyridine and the like); 6-membered heterocycles with two heteroatoms (e.g.
  • pyridazines cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines, morpholines and the like
  • 6-membered heterocycles with three heteroatoms e.g. 1 ,3,5-triazine and the like
  • 6-membered heterocycles with four heteroatoms and the like e.g. 1 ,3,5-triazine and the like.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceu- tically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphtho- ates, glycero
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, di- methylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethyl- ammonium, butylammonium, tetramethylammonium salts and the like.
  • organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula I with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents lilke ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used.
  • acid addition salts whereever ap- plicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphth
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by re- solving the mixture of stereoisomers by conventional methods.
  • Some of the preferred meth- ods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • the compound of formula I may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, amino acids, amino alcohols derived from amino acids; conventional reaction conditions may be employed to convert acid into an amide; the dia-stereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula I may be prepared by hydrolysing the pure diastereomeric amide.
  • polymorphs of compound of general formula I forming part of this invention may be prepared by crystallization of compound of formula I under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula (I).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the present compounds of formula I can be utilised in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).
  • nuclear receptors in particular the Peroxisome Proliferator-Activated Receptors (PPAR).
  • PPAR Peroxisome Proliferator-Activated Receptors
  • the present invention relates to a method of treating and/or preventing Type I or Type II diabetes.
  • the present invention relates to the use of one or more compounds of the general formula I or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment and/or prevention of Type I or Type II diabetes.
  • the present compounds are useful for the treatment and/or prevention of IGT.
  • the present compounds are useful for the treatment and/or prevention of Type 2 diabetes.
  • the present compounds are useful for the delaying or prevention of the progression from IGT to Type 2 diabetes.
  • the present compounds are useful for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
  • the present compounds reduce blood glucose and triglyceride levels and are accordingly useful for the treatment and/or prevention of ailments and disorders such as diabetes and/or obesity.
  • the present compounds are useful for the treatment and/or prophylaxis of insulin resistance (Type 2 diabetes), impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, insulin resistance, hyperglycaemia, atherosclerosis, hyperlipidemia, coronary artery disease, myocardial ischemia and other cardiovascular disorders.
  • Type 2 diabetes Type 2 diabetes
  • disorders related to Syndrome X such as hypertension, obesity, insulin resistance, hyperglycaemia, atherosclerosis, hyperlipidemia, coronary artery disease, myocardial ischemia and other cardiovascular disorders.
  • the present compounds are effective in decreasing apoptosis in mam- malian cells such as beta cells of Islets of Langerhans.
  • the present compounds are useful for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.
  • the present compounds may also be useful for improving cognitive functions in dementia, treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS) and prevention and treatment of bone loss, e.g. osteoporosis.
  • PCOS polycystic ovarian syndrome
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
  • the invention relates to the use of compounds of the general formula I or their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR) such as the conditions mentioned above.
  • PPAR Peroxisome Proliferator-Activated Receptors
  • the present invention also relates to a process for the preparation of the above said novel compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates.
  • a compound of formula I can be prepared as described below:
  • A, B, X, Y and p are defined as previously, may be alkylated with a suitable electro- philic reagent such as ethylene oxide, ethyl bromoacetate followed by reduction of the ester to an alcohol, 2-bromoethanol or 2-bromoethanol to give a compound of formula X
  • A, B, X, Y, p and n are defined as previously.
  • the PPAR gene transcription activation assays were based on transient transfection into human HEK293 cells of two plasmids encoding a chimeric test protein and a reporter protein respectively.
  • the chimeric test protein was a fusion of the DNA binding domain (DBD) from the yeast GAL4 transcription factor to the ligand binding domain (LBD) of the human PPAR proteins.
  • the GAL4 DBD will force the fusion protein to bind only to Gal4 enhancers (of which none existed in HEK293 cells).
  • the reporter plasmid contained a Gal4 enhancer driving the expression of the firefly luciferase protein.
  • HEK293 cells expressed the GAL4-DBD-PPAR-LBD fusion protein.
  • the fusion protein will in turn bind to the Gal4 enhancer controlling the luciferase expression, and do noth- ing in the absence of ligand.
  • luciferase protein Upon addition to the cells of a PPAR ligand, luciferase protein will be produced in amounts corresponding to the activation of the PPAR protein. The amount of luciferase protein is measured by light emission after addition of the appropriate substrate.
  • HEK293 cells were grown in DMEM + 10% FCS, 1% PS. Cells were seeded in 96-well plates the day before transfection to give a confluency of 80 % at transfection. 0,8 ⁇ g DNA per well was transfected using FuGene transfection reagent ac- cording to the manufacturers instructions (Boehringer-Mannheim). Cells were allowed to express protein for 48 h followed by addition of compound.
  • Plasmids Human PPAR ⁇ and ⁇ was obtained by PCR amplification using cDNA templates from liver, intestine and adipose tissue respectively. Amplified cDNAs were cloned into pCR2.1 and sequenced. The LBD from each isoform PPAR was generated by PCR (PPAR ⁇ : aa 167 - C-term; PPAR ⁇ : aa 165 - C-term) and fused to GAL4-DBD by subcloning fragments in frame into the vector pM1 generating the plasmids pMl ⁇ LBD and pMl ⁇ LBD. Ensuing fusions were verified by sequencing. The reporter was constructed by inserting an oligonucleotide encoding five repeats of the Gal4 recognition sequence into the pGL2 vector (Promega).
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • the present compounds may also be administered in combination with one or more further pharmacologically active substances eg. selected from antiobesity agents, antidiabetics, an- tihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • further pharmacologically active substances eg. selected from antiobesity agents, antidiabetics, an- tihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, uro- cortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing
  • the antiobesity agent is dexamphetamine or amphetamine.
  • the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine.
  • the antiobesity agent is orlistat.
  • the antiobesity agent is mazindol or phentermine.
  • Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihypieripidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), compounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potassium channel of the ⁇ -cells.
  • the present compounds are administered in combination with insulin.
  • the present compounds are administered in combination with a sul- phonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
  • a sul- phonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
  • the present compounds are administered in combination with a bi- guanide eg. metformin.
  • the present compounds are administered in combination with a meglitinide eg. repaglinide.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg. miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor eg. miglitol or acarbose.
  • the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg. tolbutamide, gliben- clamide, glipizide, glicazide or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg. tolbutamide, gliben- clamide, glipizide, glicazide or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an antihyperiipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihypieripidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the present compounds are administered in combination with more than one of the above-mentioned compounds eg. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alpre- nolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, ni- modipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed.,
  • compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 th Ed., 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intra urethra I, intramuscular, in- tranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of diseases related to the regulation of blood sugar.
  • Such mammals include also animals, both domestic animals, e.g. household pets, and non- domestic animals such as wildlife.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used.
  • a most preferable dosage is about 0.1 mg to about 70 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the present invention are dispensed in unit dosage form comprising from about 0.1 to about 100 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonary or transdermal administration comprise from about 0.001 mg to about 100 mg, preferably from about 0.01 mg to about 50 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.

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Abstract

L'invention concerne des composés de formule générale (I). Ces composés permettent de traiter et/ou de prévenir des états induits par des récepteurs nucléaires, en particulier les récepteurs activés par le proliférateur des péroxysomes (PPAR).
PCT/DK2000/000189 1999-04-20 2000-04-17 Nouveaux composes, leur preparation et utilisation Ceased WO2000063190A1 (fr)

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JP2000612282A JP2002542237A (ja) 1999-04-20 2000-04-17 新規な化合物、それらの製造及び使用

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Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6534517B2 (en) 1999-04-20 2003-03-18 Novo Nordisk A/S Compounds, their preparation and use
WO2003031432A1 (fr) 2001-10-12 2003-04-17 Novo Nordisk A/S Nouvelles piperidines substituees
WO2003055482A1 (fr) 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
WO2004002481A1 (fr) 2002-06-27 2004-01-08 Novo Nordisk A/S Activateurs de la glycokinase
WO2004048333A1 (fr) * 2002-11-26 2004-06-10 Shenzhen Chipscreen Biosciences Ltd. Derives d'acides arylalcanoiques substitues servant d'agonistes de ppar pan ayant une forte activite antihyperglycemique et antihyperlipidemique
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EP1634605A2 (fr) 2000-03-08 2006-03-15 Novo Nordisk A/S Traitement de la dyslipidémie chez un patient souffrant de diabète de type 2
US6982251B2 (en) 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
EP1911462A2 (fr) 2001-01-26 2008-04-16 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
US7417039B2 (en) 2001-01-26 2008-08-26 Schering Corporation Use of substituted azetidinone compounds for the treatment of sitosterolemia
US7612058B2 (en) 2001-01-26 2009-11-03 Schering Corporation Methods for inhibiting sterol absorption
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US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
US7132415B2 (en) 2001-09-21 2006-11-07 Schering Corporation Methods and therapeutic combinations for the treatment of xanthoma using sterol absorption inhibitors
US7053080B2 (en) 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
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US7268157B2 (en) 2002-11-26 2007-09-11 Shenzhen Chipscreen Biosciences, Ltd. Substituted arylalcanoic acid derivatives as PPAR pan agonists with potent antihyperglycemic and antihyperlipidemic activity
WO2004048333A1 (fr) * 2002-11-26 2004-06-10 Shenzhen Chipscreen Biosciences Ltd. Derives d'acides arylalcanoiques substitues servant d'agonistes de ppar pan ayant une forte activite antihyperglycemique et antihyperlipidemique
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