WO2001055085A1 - Derives de l'acide propionique et leur utilisation dans le traitement du diabete et de l'obesite - Google Patents

Derives de l'acide propionique et leur utilisation dans le traitement du diabete et de l'obesite Download PDF

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WO2001055085A1
WO2001055085A1 PCT/DK2001/000058 DK0100058W WO0155085A1 WO 2001055085 A1 WO2001055085 A1 WO 2001055085A1 DK 0100058 W DK0100058 W DK 0100058W WO 0155085 A1 WO0155085 A1 WO 0155085A1
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Prior art keywords
phenyl
ethoxy
propionic acid
enyloxy
biphenyl
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PCT/DK2001/000058
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English (en)
Inventor
John Patrick Mogensen
Per Sauerberg
Paul Stanley Bury
Lone Jeppesen
Ingrid Pettersson
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Novo Nordisk A/S
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Priority to IL15026001A priority Critical patent/IL150260A0/xx
Priority to KR1020027009463A priority patent/KR20020070508A/ko
Priority to BR0107901-8A priority patent/BR0107901A/pt
Priority to PL01357010A priority patent/PL357010A1/xx
Priority to JP2001555028A priority patent/JP2003520838A/ja
Priority to AU28319/01A priority patent/AU2831901A/en
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to CA002395298A priority patent/CA2395298A1/fr
Priority to EP01946844A priority patent/EP1254101A1/fr
Priority to MXPA02007286A priority patent/MXPA02007286A/es
Priority to HU0204574A priority patent/HUP0204574A3/hu
Publication of WO2001055085A1 publication Critical patent/WO2001055085A1/fr
Priority to NO20023566A priority patent/NO20023566L/no

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • 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
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
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    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

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, hypertriglycehdaemia 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.
  • 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.
  • A is aryl or heteroaryl and wherein A is optionally substituted with one or more substituents selected from hydroxy, halogen, perhalomethyl, perhalomethoxy, acyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, methylenedioxy, aralkenyl, aralkynyl, heteroary- loxy, heteroaralkoxy, aralkyl, heteroaralkyl, arylamino, or A is optionally substituted with C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxycarbonyl or carboxy, or
  • A is optionally substituted with C 1-6 -alkoxy, C 1-6 -alkylthio or C 2-6 -alkenyloxy each of which is optionally substituted with one or more halogens, or A is optionally substituted with aryloxy, arylthio or aralkoxy each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxy, nitro, carboxy or C 1-6 - alkoxycarbonyl; and X-i and X 2 independently are hydrogen, aryl or heteroaryl each of which is optionally substituted with one or more substituents selected from hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy, C 1-6 -alkoxy, C 1-6 - alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, amino
  • A is selected from the ring systems consisting of
  • FIG. 1 wherein the attachment point of A to the remaining part of the structure of formula (I) is as indicated on the chemical structures in Figure 1 , and wherein A is optionally substituted with one or more substituents selected from C 1-6 -aIkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkyIthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, C 1-6 - dialkylamino, arylamino or methylenedioxy; and wherein X ⁇ and X 2 are hydrogen; and
  • R 5 is hydrogen or C 1-6 -aIkyl
  • Y is hydrogen, or Y is C 1-12 -alkyl, C 2- i 2 -alkenyl, C 2- ⁇ 2 -alkynyl, C 4-12 -alkenynyl, aralkyl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C 1-6 - alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and
  • Z is hydrogen, halogen, hydroxy, or Z is C 1-6 -alkyl or C -6 -alkoxy each of which is optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C 1-6 -alkoxy; and Q is O, S or NR 6 , wherein R 6 is hydrogen, C 1-6 -alkyI, C 2-6 -alkenyl, C 2- 6-alkynyl, C 4-6 -alkenynyl, aralkyl, heteroaralkyl and wherein R 6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 -alkoxy, amino or carboxy; and
  • Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C 1-6 -alkyl, aryl or C 1-6 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; and
  • Ri is hydrogen, hydroxy or halogen; or R ⁇ forms a bond together with R 2 ;
  • R is hydrogen or C 1-6 -alkyl; or R 2 forms a bond together with R-i;
  • R 3 is hydrogen, or
  • R 3 is C 1-6 -alkyl, C 2- 6-alkenyl, C 2-6 -alkynyl, C ⁇ e-alkenynyl, aryl, aralkyl, C 1-6 -alkoxyC 1-6 alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy or cyano; and
  • R 4 is hydrogen, C -6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C -6 -alkenynyl or aryl;
  • n is an integer ranging from 0 to 3;
  • n is an integer ranging from 0 to 1 ;
  • A is aryl or heteroaryl and wherein A is optionally substituted with one or more substituents selected from hydroxy, halogen, perhalomethyl, perhalomethoxy, acyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, methylenedioxy, aralkenyl, aralkynyl, heteroary- loxy, heteroaralkoxy, aralkyl, heteroaralkyl, arylamino, or
  • A is optionally substituted with C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxycarbonyl or carboxy, or A is optionally substituted with C 1-6 -alkoxy, C 1-6 -alkylthio or C 2-6 -alkenyloxy each of which is optionally substituted with one or more halogens, or
  • A is optionally substituted with aryloxy, arylthio or aralkoxy each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxy, nitro, carboxy or C 1-6 - alkoxycarbonyl; and Xi and X 2 independently are hydrogen, aryl or heteroaryl each of which is optionally substituted with one or more substituents selected from hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy, C 1-6 -alkoxy, C 1-6 - alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaral- kyl, cyano, amino, C 1-6 -alkylamino, C ⁇ -6 -dialkylamino, arylamino or methylenedioxy, or aryl or heteroaryl each of which is optionally substituted with one
  • attachment point of A to the remaining part of the structure of formula (I) is as indicated on the chemical structures in Figure 1 , and wherein A is optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alky!amino, C 1-6 - dialkylamino, arylamino or methylenedioxy; and wherein Xi and X 2 are hydrogen; and
  • R 5 is hydrogen or C 1-6 -aIkyl
  • Y is hydrogen, or
  • Y is d- 12 -alkyl, C 2- ⁇ 2 -alkenyl, C 2 - ⁇ 2 -alkynyl, C 4-12 -alkenynyl, aralkyl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C h alky!, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and Z is hydrogen, halogen, hydroxy, or
  • Z is C 1-6 -alkyI or C 1-6 -alkoxy each of which is optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C 1-6 -alkoxy;
  • Q is O, S or NR 6 , wherein R 6 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aralkyl, heteroaralkyl and wherein R 6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 -alkoxy, amino or carboxy; and
  • Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C 1-6 -alkyl, aryl or C 1-6 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; and
  • Ri is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R ;
  • R 2 is hydrogen or C 1-6 -alkyl; or R 2 forms a bond together with R ⁇ and
  • R 3 is hydrogen, or
  • R 3 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C ⁇ e-alkenynyl, aryl, aralkyl, C 1-6 -alkoxyC 1-6 alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy or cyano; and
  • R 4 is hydrogen, C 1-6 -alkyl, C 2 - 6 -alkenyl, C 2-6 -alkynyl, C ⁇ e-alkenynyl or aryl;
  • n is an integer ranging from 1 to 3;
  • m 1 ;
  • A is aryl or heteroaryl and wherein A is optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, C ⁇ - dialkylamino, arylamino or methylenedioxy, and
  • X-i and X independently are hydrogen, aryl or heteroaryl optionally substituted with one or more substituents selected from C ⁇ -6 -alkyl, C 2- 6-alkenyl, C 2-6 -aIkyny(, hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, d-e-dialkylamino, arylamino or methylenedioxy; or
  • A is selected from the ring systems consisting of
  • attachment point of A to the remaining part of the structure of formula (I) is as indicated on the chemical structures in Figure 1 , and wherein A is optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2 . 6-alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C -6 -alkoxy, C ⁇ -6 -alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, arylamino or methylenedioxy, and wherein X.
  • R 5 is hydrogen or C 1-6 -alkyl
  • Y is hydrogen, C 1-12 -alkyl, C 2- ⁇ 2 -alkenyl, C 2-12 -alkynyl, C ⁇ -alkenynyl, aralkyl or heteroaralkyl optionally substituted with one or more substituents selected from halogen, C 1-6 -aIkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and
  • Z is hydrogen, halogen, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C 1-6 -alkoxy; and Q is O, S or NR 6 , wherein R 6 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2- 6-alkynyl, C 4-6 -alkenynyl, aralkyl, heteroaralkyl and wherein R 6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C ⁇ -6 -alkoxy, amino or carboxy; and
  • Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C-i-e-alkyl, aryl or C 1-6 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; and
  • Ri is hydrogen, hydroxy or halogen; or R forms a bond together with R 2 ;
  • R 2 is hydrogen or C 1-6 -alkyl; or R 2 forms a bond together with R ⁇ and
  • R 3 is hydrogen, C 1-6 -alkyI, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aryl, aralkyl, C 1-6 - alkoxyC 1-6 alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy or cyano; and
  • R 4 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl or aryl;
  • n is an integer ranging from 0 to 3;
  • n is an integer ranging from 0 to 1.
  • the present invention is concerned with compounds of formula (I)
  • A is aryl or heteroaryl and wherein A is optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2 .6-alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, C 1-6 - dialkylamino, arylamino or methylenedioxy; or
  • Xi and X 2 is hydrogen
  • A is selected from the ring systems consisting of
  • A is optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2- 6-alkenyl, C 2 . 6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C ⁇ -6 -alkylamino, C 1-6 -dialkylamino, arylamino or methylenedioxy; and
  • R 5 is hydrogen or C 1-6 -alkyl
  • Xi and X 2 independently are hydrogen, aryl or heteroaryl optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy, C 1-6 -alkoxy, d- ⁇ -alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, amino, d ⁇ -alkylamino, C 1-6 -dialkylamino, arylamino or methylenedioxy; and
  • Y is hydrogen, d_ ⁇ 2 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C ⁇ -alkenynyl, aralkyl or heteroaralkyl optionally substituted with one or more substituents selected from halogen, C 1-6 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and
  • Z is hydrogen, halogen, hydroxy, C 1-6 -alkyl or d -6 -alkoxy optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C 1-6 -alkoxy; and Q is O, S or NR 6 , wherein R 6 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4 . 6 -alkenynyl, aralkyl, heteroaralkyl and wherein R 6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 -alkoxy, amino or carboxy; and
  • Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C 1-6 -alkyl, aryl or C 1-6 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; and
  • Ri is hydrogen, hydroxy or halogen; or R forms a bond together with R 2 ;
  • R is hydrogen or C 1-6 -alkyl; or R 2 forms a bond together with R ⁇ and
  • R 3 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aryl, aralkyl, C 1-6 - alkoxyC 1-6 alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy or cyano; and
  • n is an integer ranging from 0 to 3;
  • n is an integer ranging from 0 to 1.
  • the present invention is concerned with compounds of formula I wherein A is aryl or heteroaryl optionally substituted with one or more substituents selected from from C 1-6 -alkyI, C 2-6 -alkenyI each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxycarbonyl or carboxy, or A is optionally substituted with aryloxy optionally substituted with one or more C 1-6 -alkoxy, or A is optionally substituted with aralkoxy optionally substituted with one or more substituents selected from C 1-6 -alkoxy, nitro, carboxy or C 1-6 -aIkoxycarbonyl, or A is optionally substituted with C 1-6 -alkoxy optionally substituted with one or more halogens, or
  • A is optionally substituted with aralkenyl, C 2-6 -alkenyloxy, aralkynyl, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl or methylenedioxy.
  • the present invention is concerned with compounds of formula I wherein A is aryl, heteroaryl or
  • aryloxy optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, d-e-alkoxy, C 1-6 -aIkylthio, halogen, perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
  • the present invention is concerned with compounds of formula I wherein A is aryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, d- ⁇ -alkylthio, halogen, perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
  • the present invention is concerned with compounds of formula I wherein A is aryl optionally substituted with one or more substituents selected from from C 1-6 -alkyl, C 2-6 -alkenyl each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxycarbonyl or carboxy, or A is optionally substituted with aryloxy optionally substituted with one or more C 1-6 -alkoxy, or A is optionally substituted with aralkoxy optionally substituted with one or more substituents selected from C 1-6 -alkoxy, nitro, carboxy or C 1-6 -alkoxycarbonyl, or A is optionally substituted with C 1-6 -alkoxy optionally substituted with one or more halogens, or A is optionally substituted with aralkenyl, C 2-6 -alkenyloxy, aralkynyl, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl
  • the present invention is concerned with compounds of formula I wherein A is aryl optionally substituted with one or more substituents selected from from C 1-6 -alkyl, or
  • A is optionally substituted with aryloxy optionally substituted with one or more C 1-6 -aIkoxy, A is optionally substituted with aralkoxy optionally substituted with one or more substituents selected from C 1-6 -alkoxy, or
  • A is optionally substituted with C 1-6 -alkoxy optionally substituted with one or more halogens, or
  • A is optionally substituted with aralkenyl, aralkynyl, halogen, perhalomethyl, perhalomethoxy or aralkyl.
  • the present invention is concerned with compounds of formula I wherein A is heteroaryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, halogen, perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
  • the present invention is concerned with compounds of formula I wherein A is heteroaryl.
  • the present invention is concerned with compounds of formula I wherein A is
  • the present invention is concerned with compounds of formula I wherein A is
  • the present invention is concerned with compounds of formula I wherein X ⁇ and X 2 independently are hydrogen, aryl or heteroaryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, halogen, perha- lomethyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
  • the present invention is concerned with compounds of formula I wherein Xi and X 2 independently are hydrogen, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, acyl, aryl, or aryl or heteroaryl optionally substituted with one or more substituents selected from C h alky!, C 2-6 -alkynyl each of which is optionally substituted with hydroxy.
  • the present invention is concerned with compounds of formula I wherein X 1 and X 2 independently are hydrogen, or aryl or heteroaryl optionally substituted with one or more substituents selected from halogen.
  • the present invention is concerned with compounds of formula I wherein X ⁇ and X 2 independently are hydrogen or aryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, halogen, perhalomethyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
  • the present invention is concerned with compounds of formula I wherein X ⁇ and X 2 independently are hydrogen, aryl optionally substituted with one or more substituents selected from halogen, acyl, aryl, or aryl optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkynyl each of which is optionally substituted with hydroxy.
  • the present invention is concerned with compounds of formula I wherein X and X 2 independently are hydrogen, or phenyl optionally substituted with one or more substituents selected from halogen.
  • the present invention is concerned with compounds of formula I wherein X ! and X 2 independently are hydrogen or heteroaryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, halogen, perhalomethyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
  • the present invention is concerned with compounds of formula I wherein Xi and X 2 independently are hydrogen or heteroaryl.
  • the present invention is concerned with compounds of formula I wherein X ⁇ and X 2 is hydrogen.
  • the present invention is concerned with compounds of for- mula I wherein Y is hydrogen or C 1-12 -alkyl.
  • the present invention is concerned with compounds of formula I wherein Y is hydrogen or methyl.
  • the present invention is concerned with compounds of formula I wherein Z is hydrogen or C 1-6 -aIkoxy.
  • the present invention is concerned with compounds of formula I wherein Z is hydrogen or C 1-6 -alkyl.
  • the present invention is concerned with compounds of formula I wherein Z is hydrogen.
  • the present invention is concerned with compounds of for- mula I wherein Q is O.
  • the present invention is concerned with compounds of formula I wherein Ar is arylene optionally substituted with one or more substituents selected from d-e-alkyl or C 1-6 -alkoxy each of which can be optionally substituted with carboxy.
  • the present invention is concerned with compounds of formula I wherein Ar is arylene.
  • the present invention is concerned with compounds of formula I wherein Ri is hydrogen or Ri forms a bond together with R 2 .
  • the present invention is concerned with compounds of formula I wherein Ri is hydrogen.
  • the present invention is concerned with compounds of formula I wherein R 2 is hydrogen or R 2 forms a bond together with R-i.
  • the present invention is concerned with compounds of for- mula I wherein R 2 is hydrogen.
  • the present invention is concerned with compounds of formula I wherein R 3 is C 1-6 -alkyl or aralkyl.
  • the present invention is concerned with compounds of formula I wherein R 3 is C -6 -alkyl.
  • the present invention is concerned with compounds of formula I wherein R is hydrogen, C 1-3 -alkyl.
  • the present invention is concerned with compounds of formula I wherein R* is hydrogen.
  • the present invention is concerned with compounds of for- mula 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 alkyl is methyl, ethyl, n-propyl, iso-propyl, butyl, tert-butyl, pentyl, hexyl, cyclopropyl or cyclopentyl.
  • the present invention is concerned with compounds of formula I wherein alkenyl is vinyl or 1-propenyl.
  • the present invention is concerned with compounds of formula I wherein alkynyl is ethynyl, 1-propynyl and 2-propynyI.
  • the present invention is concerned with compounds of formula I wherein alkoxy is methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy or cyclopentyloxy.
  • the present invention is concerned with compounds of formula I wherein alkylthio is methylthio, ethylthio, propylthio or cyclopentylthio.
  • the present invention is concerned with compounds of formula I wherein aryl is phenyl optionally substituted with halogen.
  • the present invention is concerned with compounds of formula I wherein arylene is phenylene optionally substituted with halogen.
  • the present invention is concerned with compounds of formula I wherein halogen is fluorine or chlorine.
  • the present invention is concerned with compounds of formula I wherein perhalomethyl is trifluoromethyl.
  • the present invention is concerned with compounds of formula I wherein acyl is acetyl.
  • the present invention is concerned with compounds of formula I wherein heteroaryl is furan, thiophene, pyrrole, imidazole, pyrazole, pyridine, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole or benzofuran.
  • the present invention is concerned with compounds of formula I wherein heteroaryl is furan, pyrrole, indole or benzofuran.
  • the present invention is concerned with compounds of formula I wherein heteroarylene is furan, thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine or pyridazine.
  • the present invention is concerned with compounds of formula I wherein aralkyl is benzyl or phenethyl.
  • the present invention is concerned with compounds of formula I wherein aryloxy is phenoxy.
  • the present invention is concerned with compounds of formula I wherein aralkoxy is benzyloxy.
  • the present invention is concerned with compounds of formula I wherein n is an integer ranging from 1 to 3 and m is 1.
  • the present invention is concerned with compounds of formula I wherein the substituents Z and Y are arranged in a trans-configuration.
  • the present invention is concerned with compounds of formula I wherein the substituents Z and Y are arranged in a cis-configuration.
  • Preferred compounds of the invention are:
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric forms.
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric forms.
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric forms.
  • C ⁇ -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 C 1-12 -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, cyclob- utyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like, especially preferred is methyl, ethyl, n-propyl, iso-propyl, butyl, tert-butyl, pentyl, hexyl, cyclopropyl and cyclopentyl.
  • C 2-12 -alkenyl 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-propenyI, 2- propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like, especially preferred is vinyl and 1-propenyI.
  • C 2-12 -alkynyl represent an unsaturated branched or straight group having from 2 to the specified number of carbon atoms and at least one triple bond.
  • groups include, but are not limited to ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like, especially preferred is ethynyl, 1- propynyl and 2-propynyl.
  • C 4-12 -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.
  • C 1-6 -alkoxy as used herein, alone or in combination is intended to include those d_g- 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, especially preferred is methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy.
  • Examples of branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy and the like, especially preferred is isopropoxy.
  • cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, especially preferred is cyclopentyloxy.
  • C 1-6 -alkylthio refers to a straight or branched or cyclic monovalent substituent comprising a C 1-6 -alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 6 carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio and the like, especially preferred is methylthio, ethylthio and propylthio.
  • Examples of cyclic alkylthio are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, especially preferred is cyclopentylthio.
  • d-e-alkylamino refers to a straight or branched or cyclic monovalent substituent comprising a C 1-6 -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.
  • 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.
  • C 1-6 -alkoxyC ⁇ -6 -alkyl refers to a C 1-6 -alkyl as defined herein whereto is attached a C 1-6 -alkoxy as defined herein, e.g. methoxy methyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like.
  • aryl is intended to include a bicyclic aromatic ring, such as carbocyclic aromatic rings selected from the group consisting of phenyl and naphthyl, (1-naphthyl or 2-naphthyl), optionally substituted with halogen, amino, hydroxy, C 1-6 -alkyl, C 1-6 -alkoxy, carboxy or C 1-6 -alkylester and the like, especially preferred is halogen.
  • arylene is intended to include divalent aromatic rings, such as carbocyclic aromatic rings selected from the group consisting of phenylene, naphthylene and the like optionally substituted with halogen, amino, hydroxy, C ⁇ -alkyl, C 1-6 -alkoxy, carboxy or C 1-6 -alkylester and the like.
  • halogen means fluorine, chlorine, bromine or iodine, especially preferred is fluorine and chlorine.
  • perhalomethyl means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl, especially preferred is trifluoromethyl.
  • C 1-6 -dialkylamino refers to an amino group wherein the two hydrogen atoms independently are substituted with a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms; such as 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 C 1-6 -alkyl group linked through a carbonyl group; such as e.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and the like, especially preferred is acetyl.
  • 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
  • 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, especially preferred is benzyl and phenethyl.
  • aryloxy refers to phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like, especially preferred is phenoxy.
  • aralkoxy refers to a C 1-6 -aIkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1- naphthyl)ethoxy and the like, especially preferred is benzyloxy.
  • heteroarylkyl 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.
  • heteroaralkoxy refers to a heteroaralkyl 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-methyI-1-(2- pyrimidyl)ethyl linked to oxygen, 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 C 1-6 -alkyl, halogen, hydroxy or C ⁇ -alkoxy; e.g. phenylthio, (4-methylphenyl)-thio, (2-chlorophenyl)thio 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 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 divalent heterocyclic group means a divalent saturated or unsaturated 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.
  • 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
  • treatment includes treatment, prevention and management of such condition.
  • 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, hy- drobromic, 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, g
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • Exam- pies of 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 like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of sol- vents 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, DimmerDeD acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, pal- mitic 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, DimmerDeD acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic
  • 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, lac- tic 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 compound of formula I may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols 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 compound of formula I may be prepared by hydro- lysing 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 cool- ing 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 Prolifera- tor-Activated Receptors (PPAR).
  • PPAR Peroxisome Prolifera- tor-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 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.
  • PCOS polycystic ovarian syndrome
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredi- ent, 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.
  • the method comprises: a)
  • L is a leaving group such as p-toluenesulfonate, methanesulfonate, halogen , triflate and the like and wherein A, X ⁇ X 2 , Y, Z and t are defined as above with a compound of formula V
  • A, X ⁇ and X 2 are defined as above, through a Friedel-Crafts acylation with in example CIOCCHZ(CH 2 ) n R7 (wherein n and Z is defined as above and R 7 are halogen or OH), in the presence of a Friedel-Crafts catalysts such as aluminium trichloride and the like, to give a compound of formula VIII
  • A, Xi, X 2 , Y, Z, Q, Ar, R ⁇ R 2 , R 3 , R 4 , n and m are defined as above, except that R is not H, to obtain a compound of formula I, wherein A, X 1? X 2 , Y, Z, Q, Ar, Ri, R 2 , Rs, R ⁇ n and m are defined as above, except that R 4 is H.
  • 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 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 transfection to give a confluency of 50-80 % at transfection. A total of 0,8 ⁇ g DNA containing 0,64 ⁇ g pM1 ⁇ / ⁇ LBD, 0,1 ⁇ g pCMV ⁇ Gal, 0,08 ⁇ g pGL2Gal4DBD and 0,02 ⁇ g pADVANTAGE was transfected per well using FuGene transfection 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 liver and adipose tissue respectively. 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) and fused to the DNA binding domain (DBD) of the yeast transcription factor GAL4 by subcloning fragments in frame into the vector pM1 generating the plasmids pMl ⁇ LBD and pMl ⁇ LBD.
  • LBD ligand binding domain
  • the reporter was constructed by inserting an oligonucleotide encoding five repeats of the GAL4 recognition sequence (5 x CGGAGTACTGTCCTCCG(AG)) 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. 1mM Mg++ and Ca++ was added to each well. The luciferase assay was performed using the Lu- cLite kit according to the manufacturers instructions (Packard Instruments). Light emission was quantified by counting SPC mode on a Packard Instruments top-counter. To measure ⁇ - galactosidase activity 25 ⁇ l supernatant from each transfection lysate was transferred to a new microplate. ⁇ -galactosidase assays were performed in the microwell plates, using a kit from Promega and read in a microplate reader. The ⁇ -galactosidase data were used to nor- malize (transfection efficiency, cell growth etc.) the luciferase data.
  • 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, 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 (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 leptin.
  • 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 (glucagons 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 antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), compounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potas- sium 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 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, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihyperlipidemic 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 dtstearate, 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, trarisdermal orparenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, in- tranasal,. ophthalmic solution or an ointment, the oral route being preferred.
  • oral nasal, pulmonary, trarisdermal orparenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, 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 cap- sules 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. For example, in the treatment of adult humans, 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. In choosing a regimen for patients it may frequently be necessary to begin with a dosage of from about 2 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 0.1 to about 10 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.
  • DIBAL-H diisobutylaluminum hydride
  • CDCI 3 deuterated chloroform
  • Diethyl azodicarboxylate (0.346 ml, 2.2 mmol) was added at 0°C to a stirred solution of triphenyl- phosphine (0.656 g, 2.2 mmol) and (£J-3-biphenyl-4-yl-but-2-en-1-ol (0.270 g, 1.2 mmol) in dry THF (20 ml) and the mixture stirred for 5 min.
  • a solution of (S -ethyl 2-ethoxy-3- (4-hydroxy-phenyl)-propionate (0.238 g, 1.0 mmol) in dry THF (10 ml) was added, the mixture allowed to warm to room temperature, and stirring continued for 48 h.
  • the title compound was prepared from (£)-3-(4'-bromo-biphenyl-4-yl)-but-2-en-1-ol (0.364 g, 1.2 mmol), triphenylphosphine (0.328 g, 1.3 mmol), diethyl azodicarboxylate (0.173 ml, 1.1 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.238 g, 1.0 mmol) by a pro- 0 cedure analogous to that described in example 1c, yielding 0.180 g (34%) of (£)-(S)-3- ⁇ 4-[3- (4'-bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl ⁇ -2-ethoxy-propionic acid ethyl ester.
  • the title compound was prepared from (£J-(S)-3- ⁇ 4-[3-(4'-bromo-biphenyl-4-yl)-but-2- enyloxy]-phenyl ⁇ -2-ethoxy-propionic acid ethyl ester (example 3) (0.150 g, 0.29 mmol) and 5 sodium hydroxide (1 M, 0.45 ml, 0.45 mmol) by a procedure analogous to that described in example 2 yielding 0.180 g (34%) of (£)-(S)-3- ⁇ 4-[3-(4'-bromo-biphenyl-4-yl)-but-2-enyloxy]- phenyl ⁇ -2-ethoxy-propionic acid ethyl ester.
  • the title compound was prepared from 4-phenoxyacetophenone (12.0 g, 0.056 mol) by a sequence analogous to that described in example 3, yielding 0.190 g (41%) of (£ -(S)-2-ethoxy- 3- ⁇ 4-[3-(4-phenoxy-phenyl)-but-2-enyloxy]-phenyl ⁇ -propionic acid ethyl ester.
  • the title compound was prepared from (£)-(S)-2-ethoxy-3- ⁇ 4-[3-(4-phenoxy-phenyl)-but-2- enyloxy]-phenyl ⁇ -propionic acid ethyl ester (example 5) (0.170 g, 0.37 mmol) and sodium hydroxide (1 M, 0.74 ml, 0.74 mmol) by a procedure analogous to that described in example 2 yielding 0.136 g (85%) of (£ (S)-2-ethoxy-3- ⁇ 4-[3-(4-phenoxy-phenyl)-but-2-enyloxy]- phenyl ⁇ -propionic acid.
  • the title compound was prepared from 4-(4-methoxyphenoxy)acetophenone (2.63 g, 0.01.1 mol) by a sequence analogous to that described in example 3 yielding 0.200 g (41%) of (£)- (S)-2-ethoxy-3-(4- ⁇ 3-[4-(4-methoxy-phenoxy)-phenyl]-but-2-enyloxy ⁇ -phenyl)-propionic acid ethyl ester.
  • the title compound was prepared from (£ -(S)-2-ethoxy-3- ⁇ 4-[3-(9H-fluoren-2-yl)-but-2- enyloxy]-phenyl ⁇ -propionic acid ethyl ester (example 9) (0.230 g, 0.504 mol) and sodium hydroxide (1 M, 1.008 ml, 1.008 mmol) by a procedure analogous to that described in example 2 yielding 0.140 g (84%) of (£)-(S)-2-ethoxy-3- ⁇ 4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl ⁇ - propionic acid.
  • the title compound was prepared from 3,4-dimethoxyacetophenone (10.00 g, 0.055 mol) by a sequence analogous to that described in example 3 yielding 0.160 g (31%) of (£)-(S)-3- ⁇ 4- [3-(3,4-dimethoxy-phenyl)-but-2-enyloxy]-phenyl ⁇ -2-ethoxy-propionic acid ethyl ester.
  • the title compound was prepared from (£)-(S)-3- ⁇ 4-[3-(3,4-dimethoxy-phenyl)-but-2-enyloxy]- phenyl ⁇ -2-ethoxy-propionic acid ethyl ester (example 11) (0.150 g, 0.350 mmol) and sodium hydroxide (1M, 1.05 ml, 1.05 mmol) by a procedure analogous to that described in example 2 yielding 0.120 g (86%) of (£)-(S)-3- ⁇ 4-[3-(3,4-dimethoxy-phenyl)-but-2-enyloxy]-phenyl ⁇ -2- ethoxy-propionic acid.
  • the title compound was prepared from 3,5-bis(trifluoromethyl)acetophenone (5.12 g, 0.02 mol) by a sequence analogous to that described in example 3 yielding 0.370 g (73%) of (£)- (S)-3- ⁇ 4-[3-(3,5-bis-trifluoromethyl-phenyI)-but-2-enyloxy]-phenyl ⁇ -2-ethoxy-propionic acid ethyl ester.
  • the title compound was prepared from (£)-(S)-3-[4-(3-biphenyl-4-yl-allyloxy)-phenyl]-2- ethoxy-propionic acid ethyl ester (example 15) (0.200 g, 0.464 mmol) and sodium hydroxide (1 M, 0.928 ml, 0.928 mmol) by a procedure analogous to that described in example 2 yield- ing 0.043 g (23%) of (£)-(S)-3-[4-(3-biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid.
  • the title compound was prepared from 2-acetonaphthone (10.0 g, 0.06 mol) by a sequence analogous to that described in example 3 yielding 0.190 g (38%) of (£)-(S)-2 ⁇ ethoxy-3-[4-(3- naphthalen-2-yl-but-2-enyloxy)-phenyl]-propionic acid ethyl ester.
  • the title compound was prepared from (£)-(S)-2-ethoxy-3-[4-(3-naphthalen-2-yl-but-2- enyloxy)-phenyl]-propionic acid ethyl ester (example 17) (0.165 g, 0.394 mmol) and sodium hydroxide (1 M, 0.789 ml, 0.789 mmol) by a procedure analogous to that described in exam- pie 2 yielding 0.030 g (19%) of (£)-(S)-2-ethoxy-3-[4-(3-naphthalen-2-yl-but-2-enyloxy)- phenylj-propionic acid.
  • the title compound was prepared from (£)-(S)-2-ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)- phenylj-propionic acid ethyl ester (example 19) (0.220 g, 0.595 mmol) and sodium hydroxide (1 M, 1.19 ml, 1.19 mmol) by a procedure analogous to that described in example 2 yielding 0.200 g (98%) of (£)-(S)-2-ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionic acid.
  • the title compound was prepared from 3,5-dibenzyloxyacetophenone (6.64 g, 0.02 mol) by a sequence analogous to that described in example.3 yielding 0.460 g (53%) of (£)-(S)-3- ⁇ 4-[3- (3,5-bis-benzyloxy-phenyl)-but-2-enyloxy]-phenyl ⁇ -2-ethoxy-propionic acid ethyl ester.
  • the title compound was prepared from (£)-(S)-3- ⁇ 4-[3-(3,5-bis-benzyloxy-phenyl)-but-2- enyloxy]-phenyl ⁇ -2-ethoxy-propionic acid ethyl ester (example 21) (0.430 g, 0.741 mmol) and sodium hydroxide (1 M, 1.5 ml, 1.5 mmol) by a procedure analogous to that described in example 2 yielding 0.300 g (73%) of (£)-(S)-3- ⁇ 4-[3-(3,5-bis-benzyloxy-phenyl)-but-2-enyloxy]- phenyl ⁇ -2-ethoxy-propionic acid.
  • Triethyl phosphonoacetate (8.9 g, 40.0 mmol) was added at 0°C over a period of 10 min. to a stirred suspension of sodium hydride (60% in oil, 1.44 g, 36.0 mmol) in dry THF (145 mL). After stirring at 0°C for 15 min. a solution of 2-naphthaldehyde (3.12 g, 20.0 mmol) in dry THF (15 mL) was added, the mixture slowly warmed to room temperature, and stirring con- tinued for 16h. The reaction mixture was quenched with water (100 mL) and acidified to pH 6 with 1N hydrochloric acid.
  • the title compound was prepared from 3-phenoxybenzaldehyde (4.0 g, 20.0 mmol) by a sequence analogous to that described in example 23.
  • the title compound was prepared from 4-benzyloxybenzaldehyde (21.2 g, 0.1 mol) by a sequence analogous to that described in example 23.
  • the title compound was purified on HPLC, using ethyl acetate/heptane (20:80) as eluent.
  • the title compound was prepared from piperonal (3.0 g, 20 mmol) by a sequence analogous to that described in example 23.
  • the title compound was purified on HPLC, using ethyl acetate/heptane (10:90) as eluent.
  • the title compound was prepared from benzofuran-7-carboxaldehyde (1.46 g, 10 mmol) by a sequence analogous to that described in example 23.
  • the title compound was prepared from 2,3-methylenedioxybenzaldehyde (1.5 g, 10 mmol) by a sequence analogous to that described in example 23.
  • the title compound was prepared from fluorene-2-carboxaldehyde (9.7 g, 50 mmol) by a sequence analogous to that described in example 23.
  • the title compound was prepared from phenanthrene-9-carboxaldehyde (4.1 g, 20.0 mmol) by a sequence analogous to that described in example 23.
  • Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (0.74 ml, 0.61 g, 3.0 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)- propionate (0.500 g, 2.10 mmol) and (£)-3-(4-bromophenyl)-but-2-en-1-ol (0.454 g, 2.0 mmol) in dry benzene (20 ml), the mixture warmed to room temperature, and stirred for 2.5 days.
  • Tetrakis(triphenylphoshine)palladium(0) (0.26 g, 0.22 mmol, 4 mol%) was added, under nitrogen, to a stirred solution of (£)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.5 g, 5.57 mmol) ⁇ prepared as detailed in example 50 a ⁇ in DME (70 ml), and the resulting orange coloured solution stirred at room temperature for 10 min.
  • Azodicarboxylic dipiperidide (0.731 g, 2.9 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (0.71 ml, 0.58 g, 2.9 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)- propionate (0.483 g, 2.03 mmol) and (£)-3-(4'-chloro-biphenyl-4-yl)-but-2-en-1-ol (0.500 g, 1.93 mmol) in dry benzene (15 ml), the mixture warmed to room temperature, and stirred for 3 h.
  • Tetrakis(triphenylphoshine)palladium(0) (0.20 g, 0.18 mmol, 4 mol%) was added, under nitrogen, to a stirred solution of (£)-3-(4-bromophenyl)-but-2-en-1-ol (1.0 g, 4.40 mmol) ⁇ prepared as detailed in example 50 b ⁇ in DME (55 ml), and the resulting orange coloured solution stirred at room temperature for 10 min.
  • Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5°C to a stirred solution of tributylphosphine (0.74 ml, 0.61 g, 3.0 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)- propionate (0.50 g, 2.10 mmol) and 3-(5'-isopropyl-2'-methoxy-biphenyl-4-yl)-but-2-en-1-oI (0.593 g, 2.0 mmol) in dry benzene (15 ml), the mixture warmed to room temperature, and stirred for 4 h.
  • the resulting mixture was diluted with water (100 ml) and ethyl acetate (50 ml), the aqueous layer collected and further extracted with ethyl acetate (50 ml). The organic layers were combined, washed with brine, dried (MgSO 4 ) and evaporated.
  • the title compound (0.54 g, 61% yield) was prepared from (£)-3-(5'-chloro-2'-methoxy- biphenyl-4-yl)-but-2-en-1-ol (0.50 g, 1.73 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)- propionate (0.433 g, 1.82 mmol) by a procedure analogous to that described in example 52 c.
  • the title compound (0.41 g, 80% yield) was prepared from (£)-3-(2',3'-dichloro-biphenyl-4- yl)-but-2-en-1-ol (0.293 g, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) by a procedure analogous to that described in example 52 c.
  • the title compound (0.41 g, 80% yield) was prepared from (£)-3-(2',6'-dimethoxy-biphenyl-4- yl)-but-2-en-1-ol (0.50 g, 1.76 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.44 g, 1.85 mmol) by a procedure analogous to that described in example 52 c.
  • the title compound (0.83 g, 87% yield) was prepared from (£)-3-(4-bromophenyl)-2-methyl- but-2-en-1-ol (0.50 g, 2.07 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol) by a procedure analogous to that described in example 52c.
  • the title compound (0.91 g, 95% yield) was prepared from (Z)-3-(4-bromophenyl)-2-methyI- but-2-en-1-ol (0.50 g, 2.07 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol) by a procedure analogous to that described in example 52 c.
  • the title compound (0.41 g, 80% yield) was prepared from (£)-3-[1 ,1';3',1"]terphenyl-4"-yl- but-2-en-1-ol (0.30 g, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) by a procedure analogous to that described in example 52 c.
  • the title compound was prepared from (£)-(S)-2-ethoxy-3- ⁇ 4-[3-(3'-methyl-biphenyl-4-yl)-but- 2-enyloxy]-phenyl ⁇ -propionate (example 68) (0.225 g, 0.49 mmol) and sodium hydroxide (1 M, 0.98 ml, 0.98 mmol) by a procedure analogous to that described in example 51 ; giving (£)- (S)-2-ethoxy-3- ⁇ 4-[3-(3'-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl ⁇ -propionic acid as a gum; 0.20 g (95%).
  • This solid was recrystallised from aqueous ethanol to give a first crop of very pure (£)-3-(3'-acetyl- biphenyl-4-yl)-but-2-en-1-ol as colourless platelets; 2.78 g (41%) and a second crop of (£)-3- (3'-acetyl-biphenyl-4-yl)-but-2-en-1-ol as an amorphous off-white solid; 2.53 g (37%).
  • the title compound (0.16 g, 65% yield) was prepared from (£)-3-(3'-acetyl-biphenyl-4-yl)-but- 2-en-1-ol (0.133 g, 0.50 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-pr ⁇ pionate (0.125 g, 0.525 mmol) by a procedure analogous to that described in example 52 c.
  • the title compound was prepared from (£)-3-(5'-isopropyl-2'-methoxy-biphenyl-4-yl)-prop-2- en-1-ol by a procedure analogous to that described in 52 c.
  • Bu 4 NBr 2.0 g, 6.3 mmol
  • K 2 CO 3 7.8 g, 56.7 mmol
  • Pd(Oac) 2 250 mg, 1.1 mmol
  • styrene 20 mL, 175 mmol
  • 3,5- dibromobenzaldehyde 5.0 g, 18.9 mmol
  • dry DMF 5.0 mL
  • the reaction mixture was diluted with ethyl acetate (20 mL) and the solution filtered. The filtrate was diluted with water and extracted with ethyl acetate (3 x 50 mL).
  • the title compound was prepared from 3-(3,5-bis-phenylethynyl-phenyl)-acrylic acid ethyl ester by a sequence analogous to that described in example 23b-c.
  • the title compound was prepared from 3,5-diphenethyl-benzaldehyde by a sequence analo- gous to that described in example 23.
  • Tetrakis(triphenylphoshine)palIadium(0) (0.69 g, 0.60 mmol, 6 mol%) was added, under nitrogen, to a stirred solution of (£)-ethyl 3-(4-iodophenyI)-but-2-enoate (3.16 g, 10.0 mmol) in DME (100 ml), and the resulting orange coloured 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 furan-2-boronic acid (2.25 g, 20.11 mmol) was added, and the reaction mixture heated to 80°C for 20 h, under reflux.
  • the title compound (678 mg, 77%) was prepared from (£)-3-(4-furan-2-yl-phenyl)-but-2-en-1- ol (430 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (526 mg, 2.21 mmol) by a procedure analogous to that described in example 52c.
  • the title compound (1.80 g, 78%) was prepared as a colourless oil from (£)-3-(2'-methyl- biphenyl-4-yl)-but-2-en-1-ol (1.19 g, 4.99 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)- propionate (1.31 g, 6.48 mmol) by a procedure analogous to that described in example 52c.
  • the colourless gum (£)-3-(2',5'-dimethoxy-biphenyl-4-yl)-but-2-en-1-oI was prepared by DIBAL-H reduction of (£)-ethyl 3-(2',5'-dimethoxy-biphenyl-4-yl)-but-2-enoate by a procedure analogous to that described in example 52b.
  • the title compound (0.765 g, 61%) was prepared as a colourless gum from (£)-3-(2',5'- dimethoxy-biphenyI-4-yl)-but-2-en-1-ol (0.711 g, 2.50 mmol) and (S)-ethyl 2-ethoxy-3-(4- hydroxyphenyl)-propionate (0.655 g, 2.75 mmol) by a procedure analogous to that described in example 52c.
  • the title compound (843 mg, 89%) was prepared from (£)-3-(4-bromophenyl)-2-ethyl-but-2- en-1-ol (510 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
  • the title compound was prepared from (£)-(S)-ethyl 3- ⁇ 4-[3-(4-bromophenyl)-2-ethyI-but-2- enyloxy]-phenyl ⁇ -2-ethoxy-propionate (Example 96) (0.78 g, 1.64 mmol) and sodium hydroxide (1M, 3.3 ml, 3.3 mmol) by a procedure analogous to that described in example 51, yielding (£)-(S)-3- ⁇ 4-[3-(4-bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl ⁇ -2-ethoxy-propionic acid (0.703 g, 96%) as a pale yellow oil, which contained a small amount of dichloromethane; 0.703 g (96%).
  • the title compound (535 mg, 81%) was prepared from (Z)-3-(4-bromophenyl)-2-ethyl-but-2- en-1-ol (prepared as described in example 96b) (355 mg, 1.39 mmol) and (S)-ethyl 2-ethoxy- 3-(4-hydroxyphenyl)-propionate (348 mg, 1.46 mmol) by a procedure analogous to that described in example 52c.

Abstract

L'invention concerne des composés correspondant à la formule générale (I). Ces composés sont utiles dans le traitement et/ou la prévention d'états induits par des récepteurs nucléaires, notamment par les récepteurs activés de la prolifération des peroxysomes (PPAR).
PCT/DK2001/000058 2000-01-28 2001-01-26 Derives de l'acide propionique et leur utilisation dans le traitement du diabete et de l'obesite WO2001055085A1 (fr)

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KR1020027009463A KR20020070508A (ko) 2000-01-28 2001-01-26 프로피온산 유도체 및 당뇨병 및 비만의 치료에 그것의 사용
BR0107901-8A BR0107901A (pt) 2000-01-28 2001-01-26 Composto, composição farmacêutica, método para o trtamento de enfermidade, para o trtamento e/ou prevenção de condições mediadas por receptores nucleares, e para o tratamento e/ou prevenção de diabetes e/ou obesidade, uso de um composto, e, método para tratar diabetes de tipo i, diabetes de tipo ii, tolerância à gligose prejudicada, resistência à insulina ou obesidade
PL01357010A PL357010A1 (en) 2000-01-28 2001-01-26 Propionic acid derivatives and their use in the treatment of diabetes and obesity
JP2001555028A JP2003520838A (ja) 2000-01-28 2001-01-26 新規化合物、それらの製造および使用。
AU28319/01A AU2831901A (en) 2000-01-28 2001-01-26 Propionic acid derivatives and their use in the treatment of diabetes and obesity
IL15026001A IL150260A0 (en) 2000-01-28 2001-01-26 Propionic acid derivatives and their use in the treatment of diabetes and obesity
CA002395298A CA2395298A1 (fr) 2000-01-28 2001-01-26 Derives de l'acide propionique et leur utilisation dans le traitement du diabete et de l'obesite
EP01946844A EP1254101A1 (fr) 2000-01-28 2001-01-26 Derives de l'acide propionique et leur utilisation dans le traitement du diabete et de l'obesite
MXPA02007286A MXPA02007286A (es) 2000-01-28 2001-01-26 Derivados de acido propionico y su uso en el tratamiento de diabetes y obesidad.
HU0204574A HUP0204574A3 (en) 2000-01-28 2001-01-26 Propionic acid derivatives and their use in the treatment of diabetes and obesity, pharmaceutical compositions containing them and their preparation
NO20023566A NO20023566L (no) 2000-01-28 2002-07-26 Propionsyrederivater og deres anvendelse ved behandling av sukkkersyke og fedme

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WO2004037775A1 (fr) 2002-10-28 2004-05-06 Novo Nordisk A/S Nouveaux composes traitant les maladies mediees par le ppar
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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US7067530B2 (en) 2001-07-30 2006-06-27 Novo Nordisk A/S Compounds, their preparation and use
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JP2007523064A (ja) * 2004-01-23 2007-08-16 ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア 面に対して両親媒性のポリアリール及びポリアリールアルキニルのポリマー及びオリゴマー並びにそれらの使用
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US7378427B2 (en) 2004-06-18 2008-05-27 Wyeth Processes for preparing 6-alkyl-5-arylsulfonyl-dihydrophenanthridines
US7943613B2 (en) 2005-12-22 2011-05-17 High Point Pharmaceuticals, Llc Compounds, their preparation and use
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JP2003520838A (ja) 2003-07-08
MXPA02007286A (es) 2002-11-29
KR20020070508A (ko) 2002-09-09
AU2831901A (en) 2001-08-07
IL150260A0 (en) 2002-12-01
NO20023566D0 (no) 2002-07-26
BR0107901A (pt) 2002-11-05
CN1396903A (zh) 2003-02-12
NO20023566L (no) 2002-09-25
HUP0204574A2 (en) 2003-05-28
CA2395298A1 (fr) 2001-08-02
HUP0204574A3 (en) 2003-08-28
EP1254101A1 (fr) 2002-11-06
PL357010A1 (en) 2004-07-12

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