WO2003033453A1 - Dicarboxylic acid derivatives, their preparation and therapeutical use - Google Patents
Dicarboxylic acid derivatives, their preparation and therapeutical use Download PDFInfo
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- WO2003033453A1 WO2003033453A1 PCT/DK2002/000692 DK0200692W WO03033453A1 WO 2003033453 A1 WO2003033453 A1 WO 2003033453A1 DK 0200692 W DK0200692 W DK 0200692W WO 03033453 A1 WO03033453 A1 WO 03033453A1
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- VVFCNIDCYNFNQD-WAYWQWQTSA-N CC(N/C(/N)=C(/COC)\O)=O Chemical compound CC(N/C(/N)=C(/COC)\O)=O VVFCNIDCYNFNQD-WAYWQWQTSA-N 0.000 description 1
- VLSTXUUYLIALPB-UHFFFAOYSA-N CCCNC(C)C Chemical compound CCCNC(C)C VLSTXUUYLIALPB-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
- C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
Definitions
- the present invention relates to novel dicarboxylic acid derivatives, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions compris- ing the compounds and to a method of treatment employing these compounds and compositions. More specifically, the compounds of the invention can be utilised in the treatment and/or prevention of conditions mediated by the Peroxisome Proliferator-Activated Receptors (PPAR).
- PPAR Peroxisome Proliferator-Activated Receptors
- 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 effi- cacious 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.
- 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 triglyceride-rich particles as well as reduced secretion of VLDL particles constitutes mechanisms that contribute to the hypolipidemic effect of fibrates.
- PPAR ⁇ activation was initially reported not to be involved in modulation of glucose or triglyceride levels. (Berger et al., / Biol. Chem. , 1999, Vol 274, pp. 6718-6725). Later it has been shown that PPAR ⁇ activation leads to increased levels of HDL cholesterol in dbldb mice (Leibowitz et al. FEBS letters 2000, 473, 333-336).
- a PPAR ⁇ agonist when dosed to insulin-resistant middle-aged obese rhesus monkeys caused a dramitic dose- dependent rise in serum HDL cholesterol while lowering the levels of small dense LDL, fasting triglycerides and fasting insulin (Oliver et al. PNAS 2001 , 98, 5306-5311).
- the same paper also showed that PPAR ⁇ activation increased the reverse cholesterol transporter ATP- binding cassette A1 and induced apolipoprotein A1 -specific cholesterol efflux.
- WO 99/63983 discloses multibinding compounds, which bind to PPAR ⁇ receptors.
- Glucose lowering as a single approach does not overcome the macrovascular cotn- plications 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 hy- pertriglyceridaemia associated with these syndromes as well as alleviation of hyperglycae- mia.
- C ⁇ n -alkyl wherein n' can be from 2 through 6, as used herein, represent a linear or branched, saturated hydrocarbon chain having the indicated number of carbon atoms.
- groups include, but are not limited to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tetf-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
- C 3 . n -cycloalkyl wherein n' can be from 4 through 6, as used herein, alone or in combination, represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms. Examples of such groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- C ⁇ n -alkylene wherein n' can be from 2 through 6, as used herein, represent a divalent linear or branched, saturated hydrocarbon chain having the indicated number of carbon atoms.
- groups include, but are not limited to methylene, ethylene, trimethylene, tetramethylene, propylene, ethylethylene, methylpropylene, ethylpropylene and the like.
- C . n -cycloalkylene wherein n' can be from 5 through 6, as used herein, represent a divalent saturated monocyclic hydrocarbon group having the indicated number of carbon atoms. Examples of such groups include, but are not limited to cyclopentylene, cyclohexylene and the like.
- C 2 . n .-alkenyl wherein n' can be from 3 through 6, as used herein, represent an olefinically unsaturated branched or straight hydrocarbon 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-propenyl, 1 ,3- butadienyl, 1-butenyl, hexenyl, pentenyl and the like.
- C 2 conducive n -alkenylene wherein n' can be from 3 through 6, as used herein, represent an divalent olefinically unsaturated branched or straight hydrocarbon group having from 2 to the specified number of carbon atoms and at least one double bond.
- C 4 exert n .-alkenynyl 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, especially preferred is 1-pentene-4-yne.
- C 4 _ n -cycloalkenylene wherein n' can be from 5 through 6, as used herein, represent an divalent unsaturated monocyclic hydrocarbon group having from 4 to the speci- fied number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to cyclohexenylene and the like.
- C 3 . n -alkynyl wherein n' can be from 4 through 6, as used herein, represent an unsaturated branched or straight hydrocarbon 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 2 . n - alkynylene wherein n' can be from 3 through 6, as used herein, represent an divalent unsaturated branched or straight hydrocarbon 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, propynylene (-CH 2 C ⁇ C-), the butynylene isomers (e.g., -
- C 4 . n -alkenynylene wherein n' can be from 5 through 9 as used herein, represent an divalent 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-ynylene, 3- penten-1-ynylene, 1 ,3-hexadiene-5-ynylene and the like.
- C 3 . n -divalent unsaturated carbon chain wherein n' can be from 4 through
- alkenylen or at least one triple bound (alkynylene) or a combination hereof (alkenynylene).
- C ⁇ _ n -alkoxy wherein n' can be from 2 through 6, as used herein, alone or in combination, refers to a straight or branched configuration linked through an ether oxygen having its free valence bond from the ether oxygen.
- linear alkoxy groups include, but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like.
- branched alkoxy examples include, but are not limited to isopropoxy, sec-butoxy, tert- butoxy, isopentyloxy, isohexyloxy and the like.
- C 3 _ n >-cycloalkoxy wherein n' can be from 4 through 6, as used herein, alone or in combination, represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms linked through an ether oxygen having its free valence bond from the ether oxygen.
- cycloalkoxy groups include, but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
- C-alkylthio wherein n' can be from 2 through 6, as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a C-i. 6 - alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 6 carbon atoms.
- Examples of such groups include, but are not limited to methylthio, ethylthio, propylthio, butylthio, pentylthio and the like.
- C 3 regularly n -cycloalkylthio wherein n' can be from 4 through 6, as used herein, alone or in combination, represent a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms linked through a divalent sulfur atom having its free valence bond from the sulfur atom.
- Examples of such cycloalkoxy groups include, but are not limited to cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
- aryl refers to an aromatic monocyclic or an aromatic fused bi- or tricyclic hydrocarbon group. Examples of such groups include, but are not limited to phenyl, naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like.
- arylene refers to divalent aromatic monocyclic or a divalent aromatic fused bi- or tricyclic hydrocarbon group (derived from aryl). Examples of such groups include, but are not limited to phenylene, naphthylene and the like.
- heteroaryl refers to a divalent substituent comprising a 5-7 membered monocyclic aromatic system or a 8-10 membered bicyclic fused aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur or a 10-16 membered tricyclic fused aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur e.g.
- heteroarylene refers to a divalent substituent (derived from heteroaryl) comprising a 5-7 membered monocyclic aromatic system or a 8-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur or a 10-16 membered tricyclic fused aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur e.g.
- a divalent polycyclic ringsystem refers to a divalent group formed from a polycyclic ringsystem containing indenpending of each other 2 trough 4 aryl or heteroaryl ring systems joined by single bonds.
- Example of such bi-, ter- and quaterarylylene having 2 through 4 identical aryl ring systems include, but are not limited to biphenylylene, binaphthylylene, terphenylylene, ternaphthylylene, quaterphenylylene, quaternaphthylylene and the like.
- Example of such bi-, ter- and quaterheteroarylylene having 2 through 4 identical heteroaryl ring systems include, but are not limited to bipyridylylene, biindolylylene, terpyridyl- ylene, terindolylylene, quaterpyridylylene, quaterindolylylene and the like.
- Example of such polycyclic ringsystems having non identical ring systems include, but are not limited to diphenyl- pyridine and the like.
- aralkoxy refers to a C ⁇ e-alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthyl- methoxy, 2-(1-naphtyl)ethoxy and the like.
- aralkyl 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-naphthylmethyl, 2-(1-naphthyl)ethyl and the like.
- halogen means fluorine, chlorine, bromine or iodine.
- treatment includes treatment, prevention and management of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR).
- PPAR Peroxisome Proliferator-Activated Receptors
- A is d. 3 -alkylene which is optionally substituted with one or more substituents se- lected from
- A is -O-A' or -S-A wherein -O- or -S- is linked to X in formula (I) and wherein A' is d- 3 - alkylene which is optionally substituted with one or more substituents selected from
- B is d-y-alkylene which is optionally substituted with one or more substituents selected from
- B is -O-B' or -S-B' wherein -O- or -S- is linked to Y in formula (I) and wherein B' is d- 3 - alkylene which is optionally substituted with one or more substituents selected from
- D is H, d_ 6 -alkyl or C 3 . 6 -cycloalkyl
- E is H, d_ 6 -alkyl or C . 6 -cycloalkyl
- L and M are independently -O- or -S-;
- T is C 3 . 9 divalent unsaturated carbon chain optionally substituted with one or more substituents selected from
- U is C 3 . 9 divalent unsaturated carbon chain optionally substituted with one or more substituents selected from
- X is arylene or heteroarylene each of which is optionally substituted with one or more substituents selected from
- Y is arylene or heteroarylene each of which is optionally substituted with one or more substituents selected from • halogen or hydroxy; or •
- Z is arylene, heteroarylene or a divalent polycyclic ringsystem each of which is optionally sub- stituted with one or more substituents selected from • halogen, oxo or hydroxy; or
- Ci-e-alkyl C 3 . 6 -cycloalkyl, d. 6 -alkoxy, C 3 . 6 -cycloalkoxy, d-e-alkylthio, C 3 . 6 - cycloalkylthio each of which is optionally substituted with one or more halogen; or
- the present invention is concerned with compounds of formula (I) wherein A is d. 3 -alkylene which is optionally substituted with one or more substituents selected from
- the present invention is concerned with compounds of formula (I) wherein A is methylene or ethylene each of which is optionally substituted with one or more substituents selected from
- the present invention is concerned with compounds of formula (I) wherein A is ethylene which is optionally substituted with ethoxy.
- the present invention is concerned with compounds of formula (I) wherein A is -O-A' or -S-A' wherein -O- or -S- is linked to X in formula (I) and wherein A is d. 3 -alkylene which is optionally substituted with .one or more substituents selected from
- the present invention is concerned with compounds of formula (I) wherein A is -O-A or -S-A' wherein -O- or -S- is linked to X in formula (I) and wherein A' is methylene or ethylene each of which is optionally substituted with one or more substitu- ents selected from methyl, methoxy or ethoxy.
- the present invention is concerned with compounds of formula (I) wherein B is d. -alkylene, which is optionally substituted with one or more substituents selected from • methyl, d. 3 -alkoxy, C 3 . 6 -cycloalkoxy or benzyloxy each of which is optionally substituted with halogen; or
- the present invention is concerned with compounds of formula (I) wherein B is methylene or ethylene each of which is optionally substituted with one or more substituents selected from
- the present invention is concerned with compounds of formula (I) wherein B is ethylene which is optionally substituted with ethoxy.
- the present invention is concerned with compounds of formula (I) wherein B is -O-B' or -S-B' wherein -O- or -S- is linked to Y in formula (I) and wherein B' is C ⁇ _ 3 -alkylene which is optionally substituted with one or more substituents selected from
- the present invention is concerned with compounds of formula (I) wherein B is -O-B' or -S-B' wherein -O- or -S- is linked to Y in formula (I) and wherein B' is methylene or ethylene each of which is optionally substituted with one or more substituents selected from methyl, methoxy or ethoxy.
- the present invention is concerned with compounds of formula (I) wherein D is H.
- the present invention is concerned with compounds of for- mula (I) wherein D is methyl or ethyl.
- the present invention is concerned with compounds of formula (I) wherein E is H.
- the present invention is concerned with compounds of formula (I) wherein E is methyl or ethyl.
- the present invention is concerned with compounds of formula (I) wherein L is -O-.
- the present invention is concerned with compounds of formula (I) wherein L is -S-.
- the present invention is concerned with compounds of for- mula (I) wherein M is -O-.
- the present invention is concerned with compounds of formula (I) wherein M is -S-.
- the present invention is concerned with compounds of formula (I) wherein T is C 3 . 9 divalent unsaturated carbon chain optionally substituted with one or more substituents selected from phenyl, benzyloxy or d. 3 -alkoxy which is optionally substituted with halogen.
- the present invention is concerned with compounds of formula (I) wherein T is an unsubstituted C 3 . 9 divalent unsaturated carbon chain.
- the present invention is concerned with compounds of for- mula (I) wherein T is C 3 . 9 alkenylene.
- the present invention is concerned with compounds of formula (I) wherein T is C 3 . 9 alkynylene.
- the present invention is concerned with compounds of formula (I) wherein T is C 5 . 9 alkenynylene.
- the present invention is concerned with compounds of formula (I) wherein U is C 3 . 9 divalent unsaturated carbon chain optionally substituted with one or more substituents selected from phenyl, benzyloxy or d. 3 -alkoxy which is optionally substituted with halogen.
- the present invention is concerned with compounds of formula (I) wherein U is an unsubstituted C 3 . 9 divalent unsaturated carbon chain.
- the present invention is concerned with compounds of formula (I) wherein U is C 3 . 9 alkenylene.
- the present invention is concerned with compounds of for- mula (I) wherein U is C 3 . 9 alkynylene.
- the present invention is concerned with compounds of formula (I) wherein U is C 5 . 9 alkenynylene.
- the present invention is concerned with compounds of formula (I) wherein X is arylene or heteroarylene each of which is optionally substituted with one or more substituents selected from
- the present invention is concerned with compounds of formula (I) wherein X is arylene optionally substituted with one or more substituents selected from
- the present invention is concerned with compounds of formula (I) wherein X is phenylene optionally substituted with one or more substituents selected from • halogen or
- Ci- 3 -alkyl optionally substituted with one or more halogen.
- the present invention is concerned with compounds of formula (I) wherein X is phenylene optionally substituted with one or more halogen.
- the present invention is concerned with compounds of formula (I) wherein Y is arylene or heteroarylene each of which is optionally substituted with one or more substituents selected from
- the present invention is concerned with compounds of formula (I) wherein Y is arylene optionally substituted with one or more substituents selected from • halogen or
- the present invention is concerned with compounds of formula (I) wherein Y is phenylene optionally substituted with one or more substituents selected from
- the present invention is concerned with compounds of for- mula (I) wherein Y is phenylene optionally substituted with one or more halogen.
- the present invention is concerned with compounds of formula (I) wherein Z is arylene, heteroarylene or a divalent polycyclic ringsystem each of which is optionally substituted with one or more substituents selected from • halogen, oxo or
- the present invention is concerned with compounds of for- mula (I) wherein Z is selected among the following groups:
- the present invention is concerned with compounds of for- mula (I) wherein Z is selected among the following groups:
- the present invention is concerned with compounds of formula (I) wherein Z is selected among the following groups:
- the present invention is concerned with compounds of gen- eral formula (I) as described by general formula (II)
- D, A, X, L, Z, U, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and G-, is H, d- 3 -alkyl, d_ 3 -alkoxy or d. 3 -aralkoxy each of which is optionally substituted with halogen; and
- G 2 is H, d_ 3 -alkyl, C 2 . 6 -alkenyl, C 2 . 6 -alkynyl, C 3 . 6 -alkenynyl, aryl, aralkyl, d. 3 -alkoxy or d. 3 - aralkoxy each of which is optionally substituted with halogen; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.
- the present invention is concerned with compounds of formula (II) wherein D, A, X, L, Z, U, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and Gi is H, d. 3 -alkyl or d. 3 -alkoxy each of which is optionally substituted with halogen; and G 2 is H, d_ 3 -alkyl or aryl each of which is optionally substituted with halogen.
- the present invention is concerned with compounds of formula (II) wherein D, A, X, L, Z, U, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and G 2 is H or methyl.
- the present invention is concerned with compounds of general formula (I) as described by general formula (III)
- D, A, X, L, Z, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and d and G 4 independently of each other are H, d. 3 -alkyl, d_ 3 -alkoxy or d. 3 -aralkoxy each of which is optionally substituted with halogen; and
- G 2 and G 3 independently of each other is H, d- 3 -alkyl, C 2 . 6 -alkenyl, C 2 . 6 -alkynyl, C 3 . 6 - alkenynyl, aryl, aralkyl, d. 3 -alkoxy or C 1 . 3 -aralkoxy each of which is optionally substituted with halogen; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.
- the present invention is concerned with compounds of formula (III) wherein D, A, X, L, Z, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and
- G-i and G 4 independently of each other are H, d. 3 -alkyl or d. 3 -alkoxy each of which is op- tionally substituted with halogen;
- G 2 and G 3 independently of each other are is H, C ⁇ - 3 -alkyl or aryl each of which is optionally substituted with halogen.
- the present invention is concerned with compounds of for- mula (III) wherein D, A, X, L, Z, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and G 2 and G 3 independently of each other are H or methyl.
- the present invention is concerned with compounds of general formula (I) as described by general formula (IV)
- D, A, X, L, Z, U, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and Gi is H, d. 3 -alkyl, d. 3 -alkoxy or d disturb 3 -aralkoxy each of which is optionally substituted with halogen; and
- G 2 is H, d-3-alkyl, C 2 . 6 -alkenyl, C 2 . 6 -alkynyl, C 3 . 6 -alkenynyl, aryl, aralkyl, d. 3 -alkoxy or d- 3 - aralkoxy each of which is optionally substituted with halogen; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.
- the present invention is concerned with compounds of formula (IV) wherein D, A, X, L, Z, U, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and
- Gi is H, d. 3 -alkyl or d. 3 -alkoxy each of which is optionally substituted with halogen; and G 2 is H, d- 3 -alkyl or aryl each of which is optionally substituted with halogen.
- the present invention is concerned with compounds of formula (IV) wherein D, A, X, L, Z, U, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and G 2 is H or methyl.
- the present invention is concerned with compounds of gen- eral formula (I) as described by general formula (V)
- D, A, X, L, Z, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and Gt and G independently of each other are H, d. 3 -alkyl, d_ 3 -alkoxy or d_ 3 -aralkoxy each of which is optionally substituted with halogen; and
- G 2 and G 3 independently of each other is H, C ⁇ -alkyl, C 2 . 6 -alkenyl, C 2 . 6 -alkynyl, C 3 . 6 - alkenynyl, aryl, aralkyl, d. 3 -alkoxy or d. 3 -aralkoxy each of which is optionally substituted with halogen; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.
- the present invention is concerned with compounds of formula (V) wherein D, A, X, L, Z, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and
- Gi and G 4 independently of each other are H, C-.-3-alkyl or d. 3 -alkoxy each of which is optionally substituted with halogen;
- G 2 and G 3 independently of each other are H, d. 3 -alkyl or aryl each of which is optionally substituted with halogen.
- the present invention is concerned with compounds of formula (V) wherein D, A, X, L, Z, M, Y, B and E are as defined for formula (I) or in any of the above preferred embodiments; and
- G 2 and G 3 independently of each other are H or methyl.
- the present invention is concerned with compounds of the present invention having a fra/is-configuration when possible. In another embodiment, the present invention is concerned with compounds of the present invention having a (SJ-configuration when possible.
- the present invention is concerned with compounds of the present invention having a c/s-configuration when possible.
- the present invention is concerned with compounds of the present invention which is a mixed PPAR ⁇ /PPAR ⁇ profile.
- the present invention is concerned with compounds of the present invention which is a mixed PPAR ⁇ /PPAR ⁇ profile.
- the present invention is concerned with compounds of the present invention which is a mixed PPAR ⁇ /PPAR ⁇ profile. In another embodiment, the present invention is concerned with compounds of the present invention which is a mixed PPAR ⁇ /PPAR ⁇ /PPAR ⁇ profile.
- the present invention is concerned with compounds of the present invention, which is a selective PPAR ⁇ profile.
- the present invention is concerned with compounds of the present invention, which is a selective PPAR ⁇ profile.
- the present invention is concerned with compounds of the present invention, which is a selective PPAR ⁇ profile.
- Examples of specific compounds of the invention are: 2-Ethoxy-3- ⁇ 4-[5-(4- ⁇ 5-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-pent-3-en-1-ynyl ⁇ - phenyl)-pent-2-en-4-ynyloxy]-phenyl ⁇ -propionic acid ethyl ester;
- the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
- Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically 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, hydroxynaph- thoates, 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, zinc, calcium salts and the like.
- amines and organic amines include ammonium, methylamine, di- methylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetrame- thylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N-methyl-D-glucamine, guanidine and the like.
- cationic amino acids include lysine, arginine, histidine and the like.
- the pharmaceutically acceptable salts are prepared by reacting the present compound 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 like 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 wherever applicable 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, hydroxynaphthoic acid, ascorbic
- 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 resolving the mixture of stereoisomers by conventional methods.
- Some of the preferred methods include use of microbial resolution, enzymatic 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, (R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like.
- the present compound may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, ami- noalcohols derived from aminoacids; 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 the compound of the present invnetion may be prepared by hydrolysing the pure diastereomeric amide.
- polymorphs of compound of the present invention forming part of this invention may be prepared by crystallization of compound of the invention under different condi- tions. 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 the present invention.
- 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 invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the the present invention 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 present invention or their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically ac- ceptable 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 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 present invention or pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical composition 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 pre- vention 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, hypergly- caemia, atherosclerosis, hyperiipidemia, coronary artery disease, myocardial ischemia and other cardiovascular disorders.
- the present compounds are effective in decreasing apoptosis in mammalian 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.
- the present compounds may also be administered in combination with one or more further pharmacologically active substances eg., selected from antiobesity agents, antidiabet- ics, antihypertensive 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 (melano- cortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin 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 sero- tonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth
- the antiobesity agent is dexamphetamine or amphetamine.
- the antiobesity agent is fenfluramine or dexfenfluramine.
- the antiobesity agent is sibutramine.
- the antiobesity agent is orlistat. In another embodiment 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, bigua- nides, 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 antihyperlipidemic 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 sulphonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
- present compounds are administered in combination with a biguanide eg. metformin.
- present compounds are administered in combination with a meglitinide eg. repaglinide or senaglinide.
- 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, glibenclamide, glipizide, glicazide or repaglinide.
- an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
- the present compounds may be administered in combination with nateglinide.
- the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofi- brate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
- an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofi- brate, 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 alprenolol, 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, nimodipine, 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., Mack Publishing
- 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 stereoisom- ers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates.
- the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
- the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
- the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
- compositions include a compound of the present invention 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.
- compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring sub ⁇ stances 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, trans ⁇ dermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, 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 the invention 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 pharmaceutical composition of the invention may comprise the compound of the present invention in combination with further pharmacologically active substances such as those described in the foregoing.
- 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.
- a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
- the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other fac- tors evident to those skilled in the art.
- a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
- the compounds used as starting materials are either known compounds or compounds which can readily be prepared by methods known per se.
- the structures of the compounds are confirmed by either elemental analysis (MA), nuclear magnetic resonance (NMR, 300 MHz), mass spectrometry (MS) or optical rotation.
- NMR shifts ( ⁇ ) are given in parts per million (ppm) and only selected peaks are given.
- Mp is melting point and is given in °C.
- Column chromatography was carried out using the technique described by W.C. Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel 60 (Art 9385).
- Z and T are defined as above and wherein Hlg is chlorine, bromine or iodine.
- A, X and D are defined as above except that D is not hydrogen, under Mitsunobu conditions, using a reagent such as triphenylphosphine/diethylazodicarboxylate and the like, to obtain a compound of formula (I), wherein A, B, D, E, L, M, T, U, X, Y and Z are defined as above, except that D and E is not hydrogen, and wherein A and B are identical and wherein X and Y are identical, and wherein L and M is oxygen.
- a reagent such as triphenylphosphine/diethylazodicarboxylate and the like
- A, D, T, X and Z are defined as above except that D is not hydrogen and wherein Hlg is chlorine, bromine and iodine, and wherein L is oxygen.
- A, D, T, U, X and Z are defined as above, and wherein L is oxygen.
- B, E and Y are defined as above except that E is not hydrogen, under Mitsunobu conditions, using a reagent such as triphenylphosphine/diethylazodicarboxylate and the like, to obtain a compound of formula (I), wherein A, B, D, E, L, M, T, U, X, Y and Z are defined as above, except that D and E is not hydrogen, and wherein L and M is oxygen.
- Step A Converting the -OH functionality in the compound of formula (c), wherein T, Z and U are defined as above, to an appropriate leaving group (Q) such as p-toluenesulfonate, methanesulfonate, halogen (for example by methods according to: Houben-Weyl, Methoden der organischen Chemie, Middle III, 6/1 b, Thieme-Verlag 1984, 4th Ed., pp. 927-939; Comprehensive Organic Transformations. A guide to functional group preparations, VCH Publishers 1989, 1 st Ed., pp. 353-363 and J. Org. Chem. ,Vol. 36 (20), 3044-3045, 1971), triflate and the like, to give a compound of formula (h)
- A, X, D and L are defined as above except that D is not hydrogen, to give a compound of formula (e) wherein A, D, L, T, X and Z are defined as above except that D is not hydrogen and wherein Hlg is chlorine, bromine and iodine.
- Step C Reacting a compound of formula (e), wherein A, D, L, T, X and Z is defined as above, and wherein Hlg is chlorine, bromine or iodine, with a appropriate compound of formula U- OH wherein U is defined as above, through a crosscoupling reaction employing a Pd catalyst such as Pd(PPh 3 ) 2 or PdCI 2 (PPh 3 ) 2 and a catalytic amount of in example copper(l)iodide and an organic amine base, such as and if needed a cosolvent to give a compound of formula (f) wherein A, D, L, T, U, X and Z are defined as above.
- a Pd catalyst such as Pd(PPh 3 ) 2 or PdCI 2 (PPh 3 ) 2
- a catalytic amount of in example copper(l)iodide and an organic amine base such as and if needed a cosolvent to give a compound of formula (f) wherein A, D
- Step B wherein R 6 is defined as above and wherein Z-. taken together with Z 2 form a divalent poly- cyclic ringsystem as defined for Z above, and wherein Hlg is chlorine, bromine or iodine and wherein G 3 and G 4 are defined as above.
- Z, G-,, G 2 , G 3 and G 4 is defined as above and wherein P is an appropriate protecting group such as tetf-butyldimethylsilyl and wherein R 6 is an d. 3 -alkyl group.
- Z, Gi, G 2 , G 3 and G 4 are defined as above and wherein P is an appropriate protecting group such as tetf-butyldimethylsilyl.
- A, D, X, Z, G 1 ( G 2 , G 3 and G 4 are defined as above and wherein P is an appropriate protecting group such as tetf-butyldimethylsilyl.
- A, D, X, Z, Gi, G 2 , G 3 and G 4 are defined as above.
- Step I Reacting a compound of formula (v) wherein A, D, X, Z, G 1 ( G 2 , G 3 and G 4 are defined as above, with a compound of formula (x)
- a reagent such as triphenylphosphine/diethylazodicarboxylate and the like
- R 5 OOC-T— Z-Hlg ( y ) wherein Z and T are defined as above and wherein Hlg is chlorine, bromine or iodine and wherein R 5 is d-e-alkyl.
- azodicarboxylic dipiperidide (404 mg, 2.0 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (404 mg, 2.0 mmol), (S)-2- ethoxy-3-(4-hydroxyphenyl)-propionic acid ethyl ester (Tetrahedron Letters, Vol. 35, No 19, 3139-3142, 1994)(357 mg, 1.5 mmol) and (E)(£) 5-[4-(5-hydroxy-pent-3-en-1-ynyl)-phenyl]- pent-2-en-4-yn-1-ol (120 mg, 0.5 mmol) in dry THF (25 mL).
- Step C Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (504 mg, 2.0 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (404 mg, 2.0 mmol), (3-chloro-4- hydroxyphenyl)propionic acid ethyl ester (322 mg, 1.5 mmol) and (£)(£) 5-[4-(5-hydroxy- pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-yn-1-ol (example 1 , Step A-B) (120 mg, 0.5 mmol) in dry THF (25 mL).
- azodicarboxylic dipiperidide (423 mg, 1.68 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (340 mg, 1.68 mmol), (S)-2- ethoxy-3-(4-hydroxyphenyl)-propionic acid ethyl este (Tetrahedron Letters, Vol. 35, No 19, 3139-3142, 1994)(400 mg, 1.68 mmol) and (£)(£) 5-[3-(5-hydroxy-pent-3-en-1-ynyl)-phenyl]- pent-2-en-4-yn-1-ol (200 mg, 0.84 mmol) in dry THF (20 mL).
- Step C Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (423 mg, 1.68 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (340 mg, 1.68 mmol), (3-chloro- 4-hydroxyphenyl)propionic acid ethyl ester (361 mg, 1.68 mmol) and (E)(E) 5-[3-(5-hydroxy- pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-yn-1-ol (example 5, Step A-B) (200 mg, 0.84 mmol) in dry THF (20 mL).
- azodicarboxylic dipiperidide (1.0 g, 4.0 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (808 mg, 4.0 mmol), (S)-2-(2- benzoyloxy-phenylamino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (820 mg, 2.18 mmol) and (£)(£) 5-[4-(5-hydroxy-pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-yn-1-ol (example 1 , Step A-B) (260 mg, 1.1 mmol) in dry THF (20 mL).
- Tetrakis(triphenylphoshine)palladium(0) (0.46 g, 0.4 mmol, 4 mol%) was added, un- der nitrogen, to a stirred solution of (£) 3-(4-iodophenyl)but-2-en-1-ol (2.74 g, 10.0 mmol) in DME (100 mL), and the solution stirred at room temperature for 10 min.
- Aqueous 2M sodium carbonate (30.0 ml, 60.0 mmol) was then added, the mixture stirred for 10 min, then 4-acetyl boronic acid (3.28 g, 20.0 mmol) was added, and the reaction mixture heated to 65°C for 18 h, under reflux, and at room temperature for anather 3 days.
- the reaction mixture was di- luted with 1N HCl (200 ml) and the products extracted into ethyl acetate (2 x 200 ml). The combined organic extracts were washed with brine, dried (MgSO 4 ), and evaporated to give the crude product, which was purified by column chromatography on silica gel using heptane/ ethyl acetate (3:2) eluent) graduated to heptane/ ethyl acetate (2:3) as eluent, to give 2.0 g (75%) of (£) 1-[4'-(3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-ethanone.
- azodicarboxylic dipiperidide (0.91 g, 3.62 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (0.89 mL, 3.62 mmol), (SJ-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.60 g, 2.53 mmol) and (£)(E) 3-(4'- ⁇ 3-[(tetf- butyldimethylsilanyl)-methoxy]-1-methylpropenyl ⁇ -biphenyl-4-yl)-but-2-en-1-ol (1.02 g, 2.41 mmol) in dry THF (15 ml).
- the mixture was warmed to room temperature, and stirred for 18 h.
- the resulting mixture was diluted with water and ethyl acetate, the aqueous layer collected and further extracted with ethyl acetate.
- the organic layers were combined, washed with brine, dried (MgSO 4 ) and evaporated.
- azodicarboxylic dipiperidide (0.50 g, 1.89 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (0.37 mL, 1.89 mmol), (SJ-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.32 g, 1.32 mmol) and (E)(E)(S) 2-ethoxy-3-(4- ⁇ 3- [4'- ⁇ 3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-but-2-enyloxy ⁇ -phenyl)-propionic acid ethyl ester (0.65 g, 1.26 mmol) in dry THF (15 ml).
- Step A To a solution of (E)(E)(S)(S) 2-ethoxy-3- ⁇ 4-[3-(4'- ⁇ 3-[4-(2-ethoxy-2-ethoxycarbonyl- ethyl)-phenoxy]-1 -methyl-propenyl ⁇ -biphenyl-4-yl)-but-2-enyloxy]-phenyl ⁇ -propionic acid ethyl ester (example 11) (367 mg 0.5 mmol) in ethanol (10 mL) was added 1 N sodium hydroxide (2 mL). The reaction mixture was stirred at room temperature for 18h, and at 60°C1 h.
- Step C To a solution of (E)(E) 2,7-bis-(5-hydroxy-3-methyl-pent-3-en-1-ynyl)-fluoren-9-one
- Step A To a solution of (£)(£)(S)(S) 2-ethoxy-3- ⁇ 4-[5-(7- ⁇ 5-[4-(2-ethoxy-2-ethoxycarbonyl- ethyl)-phenoxy]-3-methyl-pent-3-en-1-ynyl ⁇ -9-oxo-9 - -fluoren-2-yl)-3-methyl-pent-2-en-4- ynyloxy]-phenyl ⁇ -propionic acid ethyl ester (example 13) (185 mg, 0.23 mmol) in ethanol (10 mL) was added 1 N sodium hydroxide (2.3 mL).
- azodicarboxylic dipiperidide (406 mg, 1.61 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (325 mg, 1.61 mmol), methyl 4- hydroxyphenylacetate (268 mg, 1.61 mmol) and 3-[3-(3-hydroxy-prop-1-ynyl)-phenyl]-prop-2- yn-1-ol ( J Pharmacol Exp Ther 298: 1260-1268, 2001) (150 mg, 0.81 mmol) in dry THF (20 mL). The reaction mixture was stirred for 1 h at 0-5°C, and at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography using heptane/ ethyl acetate (1 :1) as eluent to give 218 mg (56%) of the title com- pound.
- azodicarboxylic dipiperidide (252 mg, 1.0 mmol) was added at room emperature to a stirred solution of tributylphosphine (202 mg, 1.0 mmol), (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (WO 01/00603 A1)(170 mg, 0.86 mmol) and (E)(E) 5-[4-(5-hydroxy-pent-3-en-1 -ynyl)-phenyl]-pent-2-en-4-yn-1 -ol (example 1 , Step A-B) (103 mg, 0.43 mmol) in dry THF (20 mL).
- Step C a) To a stirred solution of (S)-2-ethoxy-3-(4-hydroxyphenyl)-propionic acid ethyl ester (Tetrahedron Letters, Vol. 35, No 19, 3139-3142, 1994) (9.5 g, 40 mmol) in dry methylene chloride (100 ml) was over 1 h dropwise added a solution of bromine in methylene chloride (40 ml) at room temperature. The reaction was stirred for 60 min, washed with saturated so- dium sulfite and brine. The organic phase was dried (MgSO 4) and evaporated.
- Step C Under an atmosphere of nitrogen, azodicarboxylic dipiperidide (325 mg, 1.3 mmol) was added to a stirred solution of (3-hydroxyphenyl)-acetic acid ethyl ester (340 mg, 1.89 mmol), (E)(E) 5-[4-(5-hydroxy-pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-yn-1-ol (example 1 , step A-B)(150 mg, 0.63 mmol) and tributylphosphine (365 mg, 1.3 mmol) in dry THF (30 mL). After 1 h the reaction mixture was added water and the product extracted with ethyl acetate (3x).
- Step C A solution of aluminium chloride (19.6 g 0.147 mol) in diethyl ether (150 mL) was added to lithium aluminium hydride (16.6 g, 0.44 mol) in diethyl ether (150 mL) and the mixture was stirred for 30 min. Fluorine-2,7-diacrylic acid dimethyl ester (25.5 g, 76.3 mmol) in THF (1000 mL) was added portionwise to the mixture at 25-50 °C and the stirring was continued for 8 h. 20% NaOH (150 mL) was added dropwise, the suspension was decanted and the organic phase was poured into water (3000 mL).
- Step C a) o-Cresol (100 g, 0.925 mol) was dissolved in 2-butanone (1200 ml), potassium carbonate (191.7 g, 1.5 mol) and ethyl bromoacetate (162.2 g, 0.971 mol) were added and the mixture was refluxed under stirring for 24 h and then left to stand overnight. The solid was filtered off, the filtrate was evaporated and dissolved in benzene (400 ml). The solution was washed with water (200 ml), 5% solution of sodium carbonate (100 ml) and dried over MgSO 4 . The residue (cca 200 g) was distilled in vacuo.
- the PPAR transient transactivation assays are 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 is 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.
- DBD DNA binding domain
- LBD ligand binding domain
- the GAL4 DBD will direct the chimeric 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 nothing 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. Cells were seeded in 96-well plates the day before fransfection to give a confluency of 50-80 % at fransfection. A total of 0,8 ⁇ g DNA containing 0,64 ⁇ g pM1 ⁇ / ⁇ LBD, 0,1 ⁇ g pCMV ⁇ Gal, 0,08 ⁇ g pGL2(Gal4) 5 and 0,02 ⁇ g pADVANTAGE was transfected per well using FuGene fransfection reagent according to the manufacturers instructions (Roche). 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 synthesized by reverse transcription of mRNA from human liver, adipose tissue and plancenta re- spectively. Amplified cDNAs were cloned into pCR2.1 and sequenced.
- the ligand binding domain (LBD) of each PPAR isoform was generated by PCR (PPAR ⁇ : aa 167 - C-terminus; PPAR ⁇ : aa 165 - C-terminus; PPAR ⁇ : aa 128 - C-terminus) and fused to the DNA binding domain (DBD) of the yeast transcription factor GAL4 by subcloning fragments in frame into the vector pM1 (Sadowski et al. (1992), Gene 118, 137) generating the plasmids pMl ⁇ LBD, pMl ⁇ LBD and pM1 ⁇ . Ensuing fusions were verified by sequencing.
- the reporter was constructed by inserting an oligonucleotide encoding five repeats of the GAL4 recognition sequence (5 x CGGAGTACTGTCCTCCG(AG)) (Webster et al. (1988), Nucleic Acids Res. 16, 8192) into the vector pGL2 promotor (Promega) generating the plasmid pGL2(GAL4) 5 .
- pCMV ⁇ Gal was purchased from Clontech and pADVANTAGE was purchased from Promega.
- Luciferase assay Medium including test compound was aspirated and 100 ⁇ l PBS incl. 1 mM Mg++ and Ca++ was added to each well. The luciferase assay was performed using the LucLite kit according to the manufacturers instructions (Packard Instruments). Light emission was quantified by counting on a Packard LumiCounter. To measure ⁇ - galactosidase activity 25 ⁇ l supernatant from each fransfection lysate was transferred to a new microplate. ⁇ -galactosidase assays were performed in the microwell plates using a kit from Promega and read in a Labsystems Ascent Multiscan reader. The ⁇ -galactosidase data were used to normalize (fransfection efficiency, cell growth etc.) the luciferase data.
- the activity of a compound is calculated as fold induction compared to an untreated sample.
- the efficacy maximal activity
- the EC50 is the concentration giving 50% of maximal observed activity.
- EC50 values were calculated via non-linear regression using GraphPad PRISM 3.02 (GraphPad Software, San Diego, Ca). The results were expressed as means + SD.
Abstract
Description
Claims
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JP2003536195A JP2005505616A (en) | 2001-10-17 | 2002-10-15 | Dicarboxylic acid derivatives, their preparation, and therapeutic uses |
IL16117002A IL161170A0 (en) | 2001-10-17 | 2002-10-15 | Dicarboxylic acid derivatives, their preparation and therapeutical use |
BR0213253-2A BR0213253A (en) | 2001-10-17 | 2002-10-15 | Compound, use thereof, pharmaceutical composition, and methods for treating nuclear receptor-mediated conditions and type i diabetes, type ii diabetes, dyslipidemia, syndrome x (including metabolic syndrome, ie impaired glucose tolerance, insulin resistance , hypertriglyceridemia and / or obesity), cardiovascular disease (including atherosclerosis) or hypercholesteremia |
CA002462514A CA2462514A1 (en) | 2001-10-17 | 2002-10-15 | Dicarboxylic acid derivatives, their preparation and therapeutical use |
EP02772084A EP1438283A1 (en) | 2001-10-17 | 2002-10-15 | Dicarboxylic acid derivatives, their preparation and therapeutic use |
HU0401837A HUP0401837A2 (en) | 2001-10-17 | 2002-10-15 | Dicarboxylic acid derivatives, their preparation and therapeutical use and pharmaceutical compositions containing them |
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Also Published As
Publication number | Publication date |
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CN1571766A (en) | 2005-01-26 |
BR0213253A (en) | 2004-10-26 |
JP2005505616A (en) | 2005-02-24 |
RU2004114875A (en) | 2005-09-10 |
KR20050036876A (en) | 2005-04-20 |
CA2462514A1 (en) | 2003-04-24 |
IL161170A0 (en) | 2004-08-31 |
PL370244A1 (en) | 2005-05-16 |
HUP0401837A2 (en) | 2004-12-28 |
EP1438283A1 (en) | 2004-07-21 |
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