EP1578716A1 - Dicarbonsäurederivate alsppar-agonisten - Google Patents

Dicarbonsäurederivate alsppar-agonisten

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Publication number
EP1578716A1
EP1578716A1 EP03779752A EP03779752A EP1578716A1 EP 1578716 A1 EP1578716 A1 EP 1578716A1 EP 03779752 A EP03779752 A EP 03779752A EP 03779752 A EP03779752 A EP 03779752A EP 1578716 A1 EP1578716 A1 EP 1578716A1
Authority
EP
European Patent Office
Prior art keywords
methyl
ethoxy
ethyl
phenyl
phenoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03779752A
Other languages
English (en)
French (fr)
Inventor
Per Sauerberg
Lone Jeppesen
Zdenek Polivka
Karel Sindelar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP1578716A1 publication Critical patent/EP1578716A1/de
Withdrawn legal-status Critical Current

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    • C07D213/02—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
    • 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
    • C07D213/60—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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • 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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    • C07C323/52—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 atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • 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
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to novel dimeric dicarboxylic acid derivatives, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising 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), in particular the PPAR ⁇ subtype.
  • 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 PPARoc- 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.
  • 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 hy- pertriglyceridaemia associated with these syndromes as well as alleviation of hyperglycae- mia.
  • C 1-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.
  • Examples of such groups include, but are not limited to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, ferf-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
  • Ca-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 1-n . divalent saturated carbon chain and "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. Examples of such groups include, but are not limited to methylene, ethylene, trimethylene, tetramethylene, propylene, ethylethylene, methylpropylene, ethylpropylene and the like.
  • C -n .-cycloalkyIene 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.
  • C 2-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 ⁇ 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 ⁇ 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 specified 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.
  • 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., - CH 2 CH 2 C ⁇ C-, -CH 2 CsC-CH 2 -), and the like.
  • C ⁇ 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 ⁇ n -divalent unsaturated carbon chain wherein n' can be from 4 through 9, as used herein, represent an divalent unsaturated branched or straight hydrocarbon group having from 3 to the specified number of carbon atoms and at least one double bound (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 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 1- rv --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 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.
  • Examples of such groups include, but are not limited to methylthio, ethylthio, propylthio, butylthio, pentylthio and the like.
  • C3. r rcycl0alkylt.hi0 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, fluorenyl 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, fluorenylene 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.
  • Examples of such bi-, ter- and quaterarylylene having 2 through 4 identical aryl ring systems include, but are not limited to biphenylylene, binaphthylylene, terphenylylene, temaphthylylene, 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 ⁇ _ 5 -aIkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenyIpropoxy, 1-naphthylmethoxy, 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 C 1-3 -alkylene which is optionally substituted with one or more substituents se- lected from
  • R 3 represents C 1-6 -alkyIene, C 2-6 -alkenyIene, C 4-6 -cycloalkylene, C ⁇ e- cycloalkenylene, or arylene optionally substituted with one or more halogens; o represents aryl optionally substituted with one or more halogens; or
  • A is -O-A' or -S-A' wherein -O- or -S- is linked to X in formula (I) and wherein A' is C 1-3 - alkylene which is optionally substituted with one or more substituents selected from
  • B is C 1-3 -alkyIene which is optionally substituted with one or more substituents selected from
  • halogen or • C 1-3 -alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, C -6 -alkyIthio, C 3-6 -cycloalkylthio or aralkoxy each of which is optionally substituted with one or more halogens; or
  • B is -O-B' or -S-B' wherein -O- or -S- is linked to Y in formula (I) and wherein B' is C 1-3 - alkylene which is optionally substituted with one or more substituents selected from
  • D is H, C 1-6 -alkyl or C 3-6 -cycloalkyl
  • E is H, C 1-6 -alkyl or C 3-6 -cycloaIkyl
  • L and M are independently -O- or -S-;
  • T is C 1-6 divalent saturated carbon chain optionally substituted with one or more substituents selected from
  • T is -NR-i-T' wherein -NR r is linked to Z in formula (I) and wherein T' is C 1-6 alkylene which is optionally substituted with one or more halogen and R 1 represents hydrogen or C 1-3 alkyl; and
  • U is C 1-6 divalent saturated carbon chain optionally substituted with one or more substituents selected from
  • U is -NRrU' wherein -NR r is linked to Z in formula (I) and wherein U' is C 1-6 alkylene which is optionally substituted with one or more halogen and Ri represents hydrogen or C 1-3 alkyl; and
  • X is arylene or heteroarylene each of which is optionally substituted with one or more substituents selected from
  • Z is arylene, heteroarylene or a divalent polycyclic ringsystem 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 C 1-3 -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 C 1-3 -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 A is -O-A' wherein -O- or is linked to X in formula (I) and wherein A' is methylene or ethylene.
  • the present invention is concerned with compounds of formula (I) 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 for- mula (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 1-3 -alkylene which is optionally substituted with one or more substituents selected from • halogen or
  • the present invention is concerned with compounds of for- mula (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 B is -O-B' wherein -O- is linked to Y in formula (I) and wherein B' is methyl- ene or ethylene.
  • the present invention is concerned with compounds of formula (I) wherein D is H.
  • the present invention is concerned with compounds of formula (I) wherein D is methyl. In another embodiment, the present invention is concerned with compounds of formula (I) wherein D is ethyl.
  • the present invention is concerned with compounds of formula (I) wherein D is isopropyl.
  • the present invention is concerned with compounds of for- mula (I) wherein E is H.
  • the present invention is concerned with compounds of formula (I) wherein E is methyl.
  • the present invention is concerned with compounds of formula (I) wherein E is ethyl. In another embodiment, the present invention is concerned with compounds of formula (I) wherein E is isopropyl.
  • the present invention is concerned with compounds of formula (I) wherein L is -O-. In another embodiment, the present invention is concerned with compounds of formula (I) wherein L is -S-.
  • the present invention is concerned with compounds of formula (I) wherein M is -O-.
  • the present invention is concerned with compounds of for- mula (I) wherein M is -S-.
  • the present invention is concerned with compounds of formula (I) wherein T is C 1-6 divalent saturated carbon chain optionally substituted with one or more substituents selected from phenyl, benzyloxy or C 1-3 -alkoxy which is optionally substituted with halogen.
  • the present invention is concerned with compounds of formula (I) wherein T is an unsubstituted C 1-6 divalent saturated carbon chain.
  • the present invention is concerned with compounds of formula (I) wherein T is methylene.
  • the present invention is concerned with compounds of for- mula (I) wherein T is ethylene.
  • the present invention is concerned with compounds of formula (I) wherein T is propylene.
  • the present invention is concerned with compounds of formula (I) wherein T is -NR T' wherein -NR is linked to Z in formula (I) and wherein T' is C 1-6 alkylene which is optionally substituted with one or more halogen and Ri represents hydrogen or C ⁇ -3 alkyl.
  • the present invention is concerned with compounds of formula (I) wherein T is -NR T' wherein -NR is linked to Z in formula (I) and wherein T is C 1-3 alkylene and R ⁇ represents hydrogen or C 1-3 alkyl.
  • the present invention is concerned with compounds of formula (I) wherein T is -NR T' wherein -NR is linked to Z in formula (I) and wherein T' is ethylene and Ri is methyl.
  • the present invention is concerned with compounds of formula (I) wherein U is C 1-6 divalent saturated carbon chain optionally substituted with one or more substituents selected from phenyl, benzyloxy or C 1-3 -alkoxy which is optionally substituted with halogen.
  • the present invention is concerned with compounds of formula (I) wherein U is an unsubstituted C 1-6 divalent saturated carbon chain. In another embodiment, the present invention is concerned with compounds of formula (I) wherein U is methylene.
  • the present invention is concerned with compounds of formula (I) wherein U is ethylene.
  • the present invention is concerned with compounds of for- mula (I) wherein U is propylene.
  • the present invention is concerned with compounds of formula (I) wherein U is -NRrU' wherein -NRr is linked to Z in formula (I) and wherein U' is C 6 alkylene which is optionally substituted with one or more halogen and R ⁇ represents hydrogen or C 1-3 alkyl.
  • the present invention is concerned with compounds of formula (I) wherein U is -NRrU' wherein -NR is linked to Z in formula (I) and wherein U' is C L 3 alkylene and R 1 represents hydrogen or C 1-3 alkyl.
  • the present invention is concerned with compounds of formula (I) wherein U is -NRrU' wherein -NRr is linked to Z in formula (I) and wherein U' is ethylene and R-, is methyl.
  • 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
  • halogen or • C 1-6 -alkyl, aryl each of which is optionally substituted with one or more halogen.
  • the present invention is concerned with compounds of formula (I) wherein X is arylene optionally substituted with one or more substituents selected from • halogen; or
  • 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
  • the present invention is concerned with compounds of formula (I) wherein X is phenylene optionally substituted with one or more halogen, methyl or phenyl.
  • the present invention is concerned with compounds of formula (I) wherein X is phenylene optionally substituted with one or more trifluoromethyl or methoxy.
  • 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
  • halogen or • C 1-6 -aIkyl, aryl each of which is optionally substituted with one or more halogen.
  • 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 formula (I) wherein Y is phenylene optionally substituted with one or more halogen, methyl or phenyl.
  • the present invention is concerned with compounds of formula (I) wherein Y is phenylene optionally substituted with one or more trifluoromethyl or methoxy.
  • 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: which is optionally substituted with one or more substituents selected from
  • 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 formula (I) wherein Z is selected among the following groups:
  • the present invention is concerned with compounds of formula (I) wherein Z is:
  • the present invention is concerned with compounds of formula (I) wherein Z is:
  • the present invention is concerned with compounds of formula (I) wherein Z is:
  • the present invention is concerned with compounds of formula (I) wherein Z is:
  • the present invention is concerned with compounds of formula (I) wherein Z is:
  • the present invention is concerned with compounds of the present invention having a fS)-configuration when possible.
  • 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 ⁇ 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. In another embodiment, 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-(2- ⁇ [6-( ⁇ 2-[4-(2-ethoxy-2-methoxycarbonyl-ethyl)-phenylsulfanyl]-ethyl ⁇ -methyl- amino)-pyridin-2-yl]-methyl-amino ⁇ -ethylsulfanyl)-phenyl]-propionic acid;
  • 3-oxo-3-phenyl-propenylamino)-propionic acid 3- ⁇ 4-[2-( ⁇ 6-[(2- ⁇ 4-[2-Carboxy-2-(1-methyl-3-oxo-3-phenyl-propenylamino)-ethyl]-phenoxy ⁇ - ethyl)-methyl-amino]-pyridin-2-yl ⁇ -methyl-amino)-ethoxy]-phenyl ⁇ -2-(1-methyl-3-oxo-3-phenyl- propenylamino)-propionic acid;
  • 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
  • inorganic or organic acid addition salts include the pharmaceutically accept- able 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, so- dium 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.
  • a base such as sodium hydroxide, sodium methoxide, so- dium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like
  • solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc.
  • Organic bases like lysine, arginine, diethanolamine
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, ni- trie 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, ni- trie acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid
  • 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)-phenyIethylamine, 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 may be prepared by crystallization of compound of the invention under different conditions. For example, using different solvents commonly used or their mixtures for recrystalliza- tion; 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 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. Furthermore, the invention relates to the use of compounds of the present invention 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 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 prepara- tion 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 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, hypergly- caemia, atherosclerosis, hyperlipidemia, coronary artery disease, myocardial ischemia and other cardiovascular disorders.
  • Type 2 diabetes Type 2 diabetes
  • impaired glucose tolerance disorders related to Syndrome X such as hypertension, obesity, insulin resistance, hypergly- caemia, 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 the use of the present compounds, which after administration lower the bio-markers of atherosclerosis like, but not limited to, c-reactive protein (CRP), TNF ⁇ and IL-6.
  • 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 serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone
  • the antiobesity agent is leptin. In another embodiment the antiobesity agent is dexamphetamine or amphetamine.
  • the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine.
  • antiobesity. agent is orlistat.
  • the antiobesity agent is mazindol or phentermine.
  • Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, 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 antihypieripidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), compounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potassium channel of the ⁇ -cells.
  • the present compounds are administered in combination with insulin.
  • the present compounds are administered in combination with a sulphonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
  • the present compounds are administered in combination with a biguanide 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 antihypieripidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-518674, LY-519818, MK-767, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, cerivastin, acipimox, ezetimibe, probucol, dextrothyroxine or nicotinic acid.
  • an antihypieripidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-518674, LY-519818, MK-7
  • the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone or rosiglitazone.
  • a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone or rosiglitazone.
  • the present compounds are administered in combination with more than one of the above-mentioned compounds eg. in combination with a sulphony- lurea 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 stereoisomers, 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 ex- cipients 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.
  • the pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, 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 suspen- sions 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 factors 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.
  • 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 co-solvent to give a compound of formula (
  • Step C Reacting a compound of formula (c), wherein P, Z and P' are as defined above, with a reducing agent such as NaBH or LiBH 4 to give a compounds of formula (d)
  • Step D and E may be carried out in one step giving a compound of formula (I), wherein A and B are identical, D and E are identical, L and M are identical and X and Y are identical.
  • Step A Converting the -OH functionality in the compound of formula (d), 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, mecanice III, 6/1b, 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)
  • Step C Reacting the compound of formula (i) wherein Q is a leaving group such as p- toluenesulfonate, methanesulfonate, halogen, triflate and the like and wherein A, D, L, Q, T, U, X, and Z are defined as above with a compound of formula (g), wherein B, M, Y and E are defined as above except that E is not hydrogen, to give 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.
  • Q is a leaving group such as p- toluenesulfonate, methanesulfonate, halogen, triflate and the like and wherein A, D, L, Q, T, U, X, and Z are defined as above with a compound of formula (g), wherein B, M, Y and E are defined as above except that E is not hydrogen
  • Step B and C may be carried out in one step giving a compound of formula (I), wherein A and B are identical, D and E are identical, L and M are identical and X and Y are identical.
  • A, B, D, E, L, M, T', Ri, U', X, Y and Z are defined as above, except that D and E are not hydrogen.
  • Step D and E may be carried out in one step giving a compound of formula (n), wherein A and B are identical, D and E are identical, L and M are identical and X and Y are identical.
  • Step 1 o-Cresol (100 g, 0.925 mol) was dissolved in 2-butanone (1200 ml), potassium car- bonate (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 (ca 200 g) was distilled in vacuo. This afforded 161.9 g (90.1 %) of (2- methyl-phenoxy)-acetic acid ethyl ester, b.p. 120-130 °C/2 kPa.
  • Chlorosulfonic acid (180.9 g, 104 ml, 1.553 mol) was cooled to -2 - 0 °C and then the above (2-methyl-phenoxy)-acetic acid ethyl ester (75.35 g, 0.388 mol) was added drop- wise under stirring at such rate that the temperature of the reaction mixture did not exceed 0 °C (20 min).
  • the mixture was left to warm to ambient temperature (1 h) and then poured on crushed ice (1 kg).
  • the crystalline product was filtered off, washed with water (500 ml) and dried on air to constant weight.
  • Step 3 To the mixture of above sulfochloride (97.7 g, 0.333 mol), tin (189.9 g, 1.59 mol) and methanol (170 ml) concentrated hydrochloric acid was added dropwise under vigorous stirring during 20 min. The reaction became exothermic and began to reflux spontaneously.
  • Step l
  • Step 4 A stream of gaseous hydrogen chloride was introduced to the solution of above acid (56.1 g, 0.248 mol) in methanol (450 ml) and benzene (90 ml) at 30 -35 °C for 6 h.
  • the reaction mixture was left to stand overnight, diluted with benzene (400 ml) and poured to crushed ice (500 g).
  • the benzene layer was separated and the water layer was extracted with diethyl ether (2 x 200 m). Collected organic layers were washed with water (4 x 150 ml), dried over MgSO 4 , filtrated through silica gel (60 g) and evaporated. The residue vas distilled in vacuo to yield 48.4 g (81.2 %) of the title compound.
  • B.p.130 °C/200 Pa
  • Step l
  • Step 3 To the mixture of above sulfochloride (36.6 g, 0.114 mol), tin (65.4 g, 0.55 gat) and methanol (60 ml) concentrated hydrochloric acid was added dropwise under vigorous stirring during 20 min. The reaction became exothermic and began to reflux spontaneously. The reaction mixture was further heated to reflux for 3 hours, then cooled and poured to crushed ice (1 kg). The mixture was extracted with dichloromethane (2 x 200 ml), organic layer was washed with water (2 x 80 ml), dried over MgSO and evaporated in. vacuo.
  • Step 1
  • 2,2 ' -Bistrifluoromethyl-4,4 ' -diaminobiphenyl (42,6 g, 133 mmol; prepared as described in J.Chem.Soc 1951 , 3459) was dissolved in acetic acid (300 ml) and concentrated sulphuric acid (50 ml) was added.
  • the resulted suspension was diazotized with NaNO 2 (20.2 g, 293 mmol) in 50 ml water at 5 °C for 1 h, then filtered and poured into a solution of Kl (220 g, 1.35 mol) in 800 ml water.
  • 2,2 ' -Bistrifluoromethylbiphenyl-4,4 ' -diacrylic acid dimethyl ester (11.5 g, 25.1 mmol) was dissolved in 200 ml polyethylene glycol (PEG 400) and sodium borohydride (6.5 g, 172 mmol) was added gradually during 30 min at 130 °C. The mixture was heated at this temperature for 6 h. After cooling water was added, the mixture was extracted with chloroform, dried (MgSO 4 ) and evaporated to give a residue which was submitted to chromatography on silica gel. Elution with ethyl acetate afforded 3.57 g (35 %) of the title compound as an oil.
  • Step C A mixture of sodium borohydride (3.7 g, 98 mmol) and lithium chloride (4.2 g, 101 mmol) in ethanol (70 ml) was stirred at 5 °C for 15 min, 9H-fluorene-2,7-diacrylic acid dimethyl ester (5.0 g, 15 mmol) in diglyme (150 ml) was added portionwise at 20-50 °C and the mixture was refluxed for 18 h. Diluted hydrochloric acid was added dropwise after cooling and the mixture was extracted with diethyl ether. Organic layer was separated, dried (MgSO 4 ) and evaporated to give a residue, which was purified by chromatography on silica gel. Elution with ethyl acetate afforded 1.85 g (44 %) of the title compound as white crystals. M.p. 160-180 °C.
  • Step l
  • Acetanhydride (600 ml) was added dropwise to the solution of above diester (110.5 g, 0.191 mol) in pyridine (600 ml) during 1.5 h and the reaction mixture was stirred at 95 °C for 2 h. The dark solution was cooled to 80 °C, water (325 ml) was added dropwise at such a rate that the mixture refluxed vigorously (30 min), warmed to reflux for the next 30 min and left to stand overnight.
  • reaction mixture was acidified with 10% hydrochloric acid (1800 ml), extracted with ethyl acetate (1000 ml, 2 x 500 ml), collected extracts were washed with water (200 ml), dried MgSO 4 and evaporated in vacuo to yield 97.1 g (88.8 %) of crude 3-[3- (1-benzyloxycarbonylmethyl-2-oxo-propylcarbamoyl)-benzoyIamino]-4-oxo-pentanoic acid benzyl ester as an oil which was used directly to next step.
  • Step l L-Aspartic acid 4-benzylester (78.1 g, 0.35 mol) was suspended in dioxane (1000 ml), the solution of sodium carbonate (56 g, 0.52 mol) in water (1200 ml) and the mixture was stirred for 1 h.
  • Step 4 The solution of above diester (6.0 g, 14.8 mmol) in tefrahydrofuran (500 ml) was added drop-wise to a suspension of lithium aluminum hydride (1.12 g, 29.7 mmol) in diethyl ether (150 ml) at 5 °C during 60 min. The mixture was stirred the next 2 h at the same temperature, and 2 h at ambient temperature. The reaction mixture was decomposed by successive addling water (1.1 ml), 15% solution of sodium hydroxide (1.1 ml) and water (3.5 ml).
  • Step 2 The above ester (97.8 g, 0.334 mol) was dissolved in ethanol (450 mL), 5%Pd/C
  • Step 3 The above diethyl ester (20.0 g, 358 mmol) was dissolved in dimethylacetamide (100 mL), sodium borohydride (3.5 g, 926 mmol) was added portionwise at 5°C and the mixture was stirred for 60 min. Acetone (20 mL) and benzene (300 mL) were added, the mixture was washed with water and the organic layer was evaporated. The residue was fractionated at reduced pressure to yield the title compound (7.5 g, 37%), b.p. 72 °C/5 Pa. A considerable amount of high-boiling material remained (starting diethyl ester). R F (SiO 2 , chloroform/methanol 9:1): 0.69.
  • Step l A mixture of 2-chloro-4-nitrophenol (63.6 g, 0.367 mol), ethyl bromoacetate (67.0 g,
  • Step l 4-Amino-2-chloro-phenylthioacetic acid hydrate (109.3 g, 0.49 mol, prepared according FR Pat. 1489916) was added to the mixture of cone, hydrochloric acid (100 mL) and water (200 mL) and the mixture was cooled to 5°C. A solution of sodium nitrite (34.5 g, 0.5 mol) in water (150 mL) was added dropwise together with cracked ice to keep the tempera- ture below 5°C. This takes about 5 min.
  • Step l To a solution of (2-methoxy-4-nitrophenoxy)acetic acid ethyl ester (107.0 g, 0.42 mol, prepared as described in J.Chem.Soc. 1955, 3681) in ethanol (800 mL) a slurry of 5% palladium (5.0 g) on carbon in ethanol (50 mL) was added. The mixture was hydrogenated in a Parr apparatus for 3 h. Removal of the catalyst and solvent left oily crude (4-amino-2- methoxyphenoxy)acetic acid ethyl ester. Yield: 93.7 g, 99%.
  • Step 2 The above crude ester (91.7 g, 0.405 mol) was added to a mixture of cone, hydrochloric acid (78 mL) and water (195 mL) and the resulting mixture was cooled to 5°C. A solution of sodium nitrite (27.0 g, 0.391 mol) in water (100 mL) was added dropwise together with cracked ice to keep the reaction temperature below 5°C (5 min). The solution of diazo com- pound was stirred for 30 min and then added dropwise to a solution of potassium ethyl xan- thogenate (90 g, 0.56 mol) in water (100 mL) maintaining the reaction temperature between 45 and 50°C.
  • Step l
  • Step A-B A mixture of the above sulfide (49.7 g, 86.6 mmol), triphenylphosphine (1.8 g, 6.9 mmol), palladium(ll)acetate (0.6 g, 2.67 mmol), methyl acrylate (22.1 g, 257 mmol) and triethylamine (17 g, 168 mmol) in 80 mL dimethylformamide was stirred and heated to 110°C for 9 h. After standing overnight water and benzene were added, the organic layer was sepa- rated, washed with water, evaporated and the residue was purified by chromatography on silica gel (Fluka, 300 g, benzene and chloroform).
  • Step C Step l :
  • step A from (5'- ⁇ 2-[(6- ⁇ [2-(2'- ethoxycarbonylmethoxy-[1 , 1 ';3 ⁇ 1 "]terphenyl-5'-yloxy)-ethyl]-methyl-amino ⁇ -pyridin-2-yl)- methyl-amino]-ethoxy ⁇ -[1 ,1 ';3',1 "]terphenyl-2'-yloxy)-acetic acid ethyl ester (example 3) in 15 mg (60%) yield.
  • Step C-D Was synthesized as described under example 1 , step C-D, using (S)-2-(2-benzoyl- phenylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester (J. Med. Chem. 1998, 41, 5020-5036) (154 mg, 0.41 mmol) in stead of 2-ethoxy-3-(4-mercapto-phenyl)-propionic acid methyl ester giving the title compound in 46 mg (29%) yield.
  • Step A Was synthesized as described under example 2, step A from (S,S)-2-(2-benzoyl- phenylamino)-3- ⁇ 4-[2-( ⁇ 6-[(2- ⁇ 4-[2-(2-benzoyl-phenylamino)-2-methoxycarbonyl-ethyl]- phenoxy ⁇ -ethyl)-methyl-amino]-pyridin-2-yl ⁇ -methyI-amino)-ethoxy]-phenyl ⁇ -propionic acid methyl ester (example 5) in 42 mg (93%) yield.
  • step A from (3-chloro-4- ⁇ 2-[(6- ⁇ [2- (2-chloro-4-ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino ⁇ -pyridin-2-yl)-methyl-amino]- ethoxy ⁇ -phenyl)-acetic acid ethyl ester (example 7) in 90 mg (73%) yield.
  • step A using (3- ⁇ 2-[(6- ⁇ [2-(3- ethoxycarbonyImethyl-phenoxy)-ethyl]-methyl-amino ⁇ -pyridin-2-yl)-methyl-amino]-ethoxy ⁇ - phenyl)-acetic acid ethyl ester (example 9) in 26 mg (88%) yield.
  • step A using (S,S)-2-ethoxy-3-[4- (2- ⁇ [6-( ⁇ 2-[4-(2-ethoxy-2-ethoxycarbonyI-ethyl)-phenoxy]-ethyl ⁇ -methyl-amino)-pyridin- 2-yl]- methyl-amino ⁇ -ethoxy)-phenyl]-propionic acid ethyl ester (example 11) in 91 mg (93%) yield.
  • step C-A was synthesized as described under example 13 step C-A using 3-[4'-(3-hydroxy- propyl)-3,3'-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol (intermediate 6) (102 mg, 0.25 mmol) instead of 3-[4'-(3-hydroxy-propyl)-2,2'-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol giving the title compound in 205 mg (93 %) yield.
  • Step A Was synthesized as described under example 14 step A using (S,S)-3- ⁇ 3-bromo-4-
  • azodicarboxylic dipiperidine (253 mg, 1.0 mmol) was added to a solution of 3-[4'-(3-hydroxy-propyl)-2,2 , -bis-trifluoromethyl-biphenyl-4-yl]-propan-1 -ol (interme- diate 5) (102 mg, 0,25 mmol) and tributylphosphine (203 mg, 1.0 mmol) in THF (10 ml) at 0 °C. The reaction mixture was stirred for 10 min after which (4-mercapto-2-methyl-phenoxy)- acetic acid methyl ester (intermediate 1) (213 mg, 1.0 mmol) was added prop wise over 5 min.
  • Step A To a solution of [4-(3- ⁇ 4'-[3-(4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)- propyl]-2,2'-bis-trifluoromethyl-biphenyl-4-yl ⁇ -propylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester (example 25) (102 mg, 0.12 mmol) in ethanol (5 ml) was added aqueous 1 N NaOH (0.5 ml). The reaction mixture was stirred for 3 hours at room temperature and the evaporated.
  • Step D-E Was synthesized as described under example 25 step D-E using 3-[4'-(3-hydroxy- propyl)-3,3'-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol (intermediate 6) (102 mg, 0.25 mmol) instead of 3-[4'-(3-hydroxy-propyl)-2,2'-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol to give the title compound in 130 mg (65%) yield.
  • Step D-E Was synthesized as described under example 25 step D-E using 3-[7-(3-hydroxy- propyl)-9H-fluoren-2-yl]-propan-1-ol (Intermediate 8) (85mg, 0.3 mmol) instead of 3-[4'-(3- hydroxy-propyl)-2,2'-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol to give the title compound in 34 mg (17%) yield after a second column purification using heptane:ethyl acetate (5:2) as eluent.
  • Step A Was synthesized as described under example 26 step A using (S,S)-2-ethoxy-3-[4-
  • Example 37 [4-(3- ⁇ 4 , -[3-(4-Carboxymethylsulfanyl-3-chloro-phenylsulfanyl)-propyl]-3,3'-bis-rifluoromethyl- biphenyl-4-yl ⁇ -propylsulfanyI)-2-chloro-phenylsulfanyl]-acetic acid
  • Step A-B (2-Chloro-4-mercapto-phenylsulfanyl)-acetic acid ethyl ester (intermediate 13) (3.7 g, 7 mmol) was dissolved in dimethylacetamide (20 mL). Sodium borohydride (0.5 g, 13.2 mmol) was added portionwise at 5°C and the mixture was stirred for 30 min.
  • Step A 3-[4'-(3-Hydroxy-propyl)-biphenyl-4-yl]-propan-1-ol (intermediate 14) (5.0 g,18.5 mmol) was dissolved in dichloromethane (100 mL) and triethylamine (6.0 g, 59 mmol) and subsequently methanesulfonyl chloride (4.6 g, 40 mmol) were added dropwise. The mixture was stirred overnight, washed with water (30 mL), evaporated in vacuo and the residue crystallized from benzene giving 4,4'-biphenyldipropanol bismethanesulfonate. Yield: 6.8 g (87%). M.p. 155.5-157°C.
  • Step A To a solution of 3-[4'-(3-hydroxy-propyl)-3,3 , -bis-trifluoromethyl-biphenyl-4-yl]- propan-1-ol (intermediate 6) (5.4 g, 13.3 mmol) in dichloromethane (40 mL) triethylamine (2.5 g, 24.7 mmol) and methanesulfonyl chloride (2.7g, 23.6 mmol) were added dropwise. The mixture was stirred overnight, diluted with dichloromethane (50 mL) and washed with water (2x15 mL). Evaporation of the organic solution gave 3,3 ' -bistrifluoromethyl-4,4 ' -biphenyl- dipropanol bismethanesulfonate. Yield: 6.6 g (88%).
  • 4,4 '-Dithiobis(2-chlorophenoxyacetic acid diethyl ester) (intermediate 12) (3.7 g, 7.5 mmol) was dissolved in N,N-dimethylacetamide (50 mL), sodium borohydride (0.55 g, 14.5 mmol) was added portionwise at 5°C and the mixture was stirred for 30 min.
  • a solution of the above bismethanesulfonate (3.25 g, 5.8 mmol) in 2-butanone (15 mL) and potassium car- bonate (1.4 g, 10 mmol) were added to the mixture and the resulting suspension was stirred overnight at ambient temperature and subsequently refluxed for 3 h.
  • Step A The above diethyl ester (2.8 g, 3.5 mmol) was dissolved in ethanol (30 mL) and tefrahydrofuran (30 mL). 20% Aqueous solution of sodium hydroxide (7 mL) was added, the mixture was left to stand for 48 h and then evaporated in vacuo. The residue was dissolved in water and the title product was precipitated with hydrochloric acid. The solid mass was filtered, washed with water and dried. Yield: 2.3 g (85%). M.p. 143-152°C.
  • 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.
  • 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 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 pGL2(Gal4) 5 and 0,02 ⁇ g pADVANTAGE was transfected per well using FuGene transfection reagent accord- ing 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 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; 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 con- structed 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 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 Labsystems Ascent Multiscan reader. The ?-galactosidase data were used to normalize (transfection 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.

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  • Child & Adolescent Psychology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
EP03779752A 2002-12-20 2003-12-18 Dicarbonsäurederivate alsppar-agonisten Withdrawn EP1578716A1 (de)

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DK200201966 2002-12-20
DKPA200201966 2002-12-20
PCT/DK2003/000895 WO2004056740A1 (en) 2002-12-20 2003-12-18 Dicarboxylic acid derivatives as ppar-agonists

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CA2588953A1 (en) 2004-11-30 2006-06-08 Plexxikon, Inc. Ppar active compounds
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KR20090094125A (ko) 2006-12-08 2009-09-03 엑셀리시스, 인코포레이티드 Ｌｘｒ 및 ｆｘｒ 조절자
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JP2006510687A (ja) 2006-03-30

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