US20080287409A1 - Phenyl and pyridinyl-1,2,4-oxadiazolone derivatives, processes for their preparation and their use as pharmaceutical compositions - Google Patents

Phenyl and pyridinyl-1,2,4-oxadiazolone derivatives, processes for their preparation and their use as pharmaceutical compositions Download PDF

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US20080287409A1
US20080287409A1 US12/055,793 US5579308A US2008287409A1 US 20080287409 A1 US20080287409 A1 US 20080287409A1 US 5579308 A US5579308 A US 5579308A US 2008287409 A1 US2008287409 A1 US 2008287409A1
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alkylene
alkyl
substituted
mono
phenyl
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Patrick Bernardelli
Stefanie Keil
Matthias Urmann
Hans Matter
Wolfgang Wendler
Maike GLIEN
Karen Chandross
Lan Lee
Corinne Terrier
Herve Minoux
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Sanofi Aventis France
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Sanofi Aventis France
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Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Assigned to SANOFI-AVENTIS reassignment SANOFI-AVENTIS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BERNARDELLI, PATRICK, MINOUX, HERVE, TERRIER, CORINNE, GLIEN, MAIKE, WENDLER, WOLFGANG, MATTER, HANS, URMANN, MATTHIAS, KEIL, STEFANIE, LEE, LAN, CHANDROSS, KAREN
Publication of US20080287409A1 publication Critical patent/US20080287409A1/en
Priority to US12/474,838 priority Critical patent/US7851493B2/en
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Definitions

  • the present invention relates generally to pharmaceutical compositions for the treatment of metabolic disorders and the diseases and the physiological manifestations resulting therefrom. More specifically, the present invention relates to phenyl- and pyridinyl-1,2,4-oxadiazolone derivatives and their salts which are able to therapeutically modulate lipid and/or carbohydrate metabolism in mammals and are thus suitable for the prevention and/or treatment of diseases such as type-2 diabetes, atherosclerosis, cardiovascular disorders and the like. More specifically, the inventive compounds of the present invention are also useful in the treatment of the de-myelinating and other neurodegenerative disorders of the central and peripheral nervous systems.
  • the present invention is directed to pharmaceutical compounds and compositions which are able to therapeutically modulate lipid and/or carbohydrate metabolism for the treatment of metabolic disorders and the diseases as well as de-myelinating and other neurodegenerative disorders of the central and peripheral nervous system.
  • inventive compounds of the present invention are comprised of phenyl and pyridinyl-1, 2,4-oxadiazolone derivatives and their physiologically acceptable salts and functional derivatives that are shown to provide peroxisome proliferator activator receptor (PPAR) delta agonist activity.
  • PPAR peroxisome proliferator activator receptor
  • PPARdelta agonists have been described in the prior art. (e.g. WO 01/00603 and WO 02/092590 to Keil et. al., WO 2003/074495, WO2004/093879, WO2004/080943, WO2005/054213 and WO2005/097786).
  • Compounds comprising an oxadiazolone component have been disclosed as inhibitors of factor Xa and described in DE 101 12 768 A1 and also as orally administrable hypoglycemic agents in WO 96/13264.
  • WO 97/40017 teaches oxadiazolone compounds having a phenyl group linked to Heterocyclic rings and these are disclosed as modulators of those molecules that comprise phosphotyrosine recognition units.
  • Benzene derivatives of oxadiazolone compounds are known to be useful as inhibitors of squalene synthase and protein farnesyltransferase and these are described in WO96/34851.
  • the present invention is directed to pharmaceutical compounds and compositions comprised of phenyl and pyridinyl-1,2,4-oxadiazolone derivatives and their physiologically acceptable salts and functional derivatives showing that exhibit peroxisome proliferator activator receptor (PPAR) delta agonist activity.
  • PPARdelta agonists have are well in the biochemical and pharmaceutical arts. Phenyl derivatives of oxadiazalones are described as agents for the therapeutic treatment of thromboembolic disorders as described in WO 02/057236. Benzene derivatives of oxadiazalone have also been shown to inhibitor squalene synthase and protein farnesyltransferase as described in WO96/34851. See also U.S. Pat. No. 6,200,995 to De La Brouse-Elwood et. al. as well as WO 03/043997 and WO 02/092590 to Johnston et. al.
  • the peroxisome proliferator-activated receptors are transducer proteins belonging to the steroid/thyroid/retinoid receptor superfamily.
  • the PPAR receptors were originally identified as orphan receptors without known ligands, but were known for their ability to mediate the pleiotropic effects of fatty acid peroxisome proliferators.
  • the target genes encode enzymes involved in a number of metabolic and cell growth/cell proliferation/cell differentiation inductions. These then act as targets for the development of therapeutic agents for the treatment of metabolic and central nervous system disorders, among others.
  • the present invention comprises derivatives of 2-aminothiazoles and 2-amino-oxazole compounds and the salts thereof as well as pharmaceutical compositions comprising them for the treatment of metabolic disorders and more particularly, those insulin-related metabolic disorders of the blood such as hyperlipidemia, diabetes, insulin-resistance and the like
  • the compounds also effectively modulate lipid and/or carbohydrate metabolism and are thus suitable for the prevention and/or treatment of diseases such as type-2 diabetes, atherosclerosis and neurological disorders comprising de-myelinating and other neurodegenerative disorders of the central and peripheral nervous systems.
  • PPAR peroxisome proliferator-activated receptor
  • the present invention comprises compounds and compositions for the treatment of metabolic disorders and more particularly, those insulin-related metabolic disorders of the blood such as hyperlipidemia, diabetes and the like comprising arylcycloalkyl-substituted alkanoic acid derivatives and their salts.
  • those insulin-related metabolic disorders of the blood such as hyperlipidemia, diabetes and the like comprising arylcycloalkyl-substituted alkanoic acid derivatives and their salts.
  • PPAR peroxisome proliferator-activated receptors
  • the invention relates to compounds of formula I
  • the present invention comprises a class of compounds, which therapeutically modulate lipid and/or carbohydrate metabolism and are thus suitable for the prevention and/or treatment of diseases such as type-2 diabetes, atherosclerosis and the diverse physiological manifestations thereof.
  • the compounds are also effective in the treatment of de-myelinating and other neurodegenerative disorders of the central and peripheral nervous systems.
  • the present invention then, comprises a series of compounds which modulate the activity of PPAR receptor agonists has been found.
  • the compounds are suitable in particular for activating PPARdelta or PPARdelta and PPARalpha, however it being possible for the extent of the relative activation to vary depending on the compounds.
  • Another embodiment according to the invention are compounds of the formula I, wherein
  • Another embodiment according to the invention are compounds of the formula I, wherein
  • Another embodiment according to the invention are compounds of the formula I, wherein
  • Another embodiment according to the invention are compounds of the formula I, wherein
  • R5 is selected from the group consisting of SO2(C1-C4)alkyl, SO2(C1-C4)alkylene-(C3-C13)cycloalkyl, SO2(C1-C4)alkylene-(C6C10)aryl, SO2(C1-C4)alkylene-(C3-C15)heterocycloalkyl, SO2(C1-C4)alkylene-(C3-C15)heterocycloalkenyl, SO2(C1-C4)alkylene-(C5-C15)heteroaryl, SO2N((C1-C4)alkylene-H)—(C1-C4)alkylene-(C6-C10)aryl, SO2N((C1-C4)alkylene-H)—(C1-C4)alkylene-H, SO2N((C1-C4)alkylene-H)—(C1-C4)alkylene-H, SO2N((C1-C4)al
  • Z is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—CH 2 —, —CH ⁇ CH—.
  • R5 is (C1-C4)alkyl mono-, di- or tri-substituted by F, CO—(C1-C3)alkyl, (C1-C3)alkylene-(C3-C6)cycloalkyl, (C1-C3)alkylene-(C3-C7)heterocycloalkyl, (C1-C3)alkylene-(C5-C8)heteroaryl; or
  • R5 is selected from the group consisting of (C1-C4)alkyl mono-, di- or tri-substituted by F, CO—(C1-C3)alkyl, (C1-C3)alkylene-(C3-C6)cycloalkyl, (C1-C3)alkylene-(C3-C7)heterocycloalkyl, (C1-C3)alkylene-(C5-C8) heteroaryl; or
  • R5 is selected from the group consisting of (C1-C8)alkyl, (C1-C4) alkylene-(C3-C13)cycloalkyl, (C1-C4)alkylene-(C6-C12)aryl, (C1-C4)alkylene-(C3-C15)heterocycloalkyl, (C1-C4)alkylene-(C3-C15)heterocycloalkenyl, (C1-C4)alkylene-(C5-C15) heteroaryl, CO—(C1-C4)alkyl, CO—O—(C6-C10)aryl, wherein alkyl and alkylene can be mono-, di- or tri-substituted by F, S—(C1-C4) alkyl, SO—(C1-C4)alkyl, N((C1-C4)alkylene-H)—(C1-C4) alkylene-H, CO—O(C1-C4)alkyl and O
  • Z is —CH2—, —CH2—CH2—, —CH2—O—CH2—, —CH ⁇ CH—.
  • R5 is selected from the group consisting of H, (C1-C4)alkyl, (C1-C3)alkylene-(C3-C7)cycloalkyl, (C1-C3)alkylene-phenyl, (C1-C3)alkylene-(C3-C7)heterocycloalkyl, (C1-C4)alkylene-(C4-C7)heterocycloalkenyl, (C1-C3)alkylene-(C5-C6)heteroaryl, CO—(C1-C3)alkyl, CO—O-phenyl, wherein alkyl and alkylene can be mono-, di- or tri-substituted by F, S—(C1-C3)alkyl, SO—(C1-C3)alkyl, SO2 (C1-C3)alkyl, N((C1-C3)alkylene-H)—(C1-C3)alkylene-H and CO—O(C1-C3)alkyl and
  • R5 is (C1-C3)alkyl or (C1-C3)alkylene-(C3-C6)cycloalkyl, wherein alkyl is un-substituted or mono-, di- or tri-substituted by F;
  • alkyl is to be understood in the broadest sense to mean saturated hydrocarbon residues which can be linear, i. e. straight-chain, or branched. If not otherwise defined alkyl has 1 to 8 carbon atoms.
  • Examples of, “—(C1-C8)-alkyl” are alkyl residues containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl, the n-isomers of all these residues, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert-pentyl.
  • —(C1-C8)-alkyl is a hydrocarbon residue containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term “—C1-alkyl” is a covalent bond. All these statements apply also to the term alkylene.
  • alkenyl is to be understood in the broadest sense to mean hydrocarbon residues which has 1 to 4 double bonds and can be linear, i. e. straight-chain, or branched. If not otherwise defined alkenyl has 2 to 8 carbon atoms.
  • alkynyl is to be understood in the broadest sense to mean hydrocarbon residues, which has 1 to 4 triple bonds and can be linear, i. e. straight-chain, or branched. If not otherwise defined alkynyl has 2 to 8 carbon atoms.
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene are un-substituted or mono, di- or tri-substituted independently of one another by suitable groups such as, for example: F, Cl, Br, I, CF 3 , NO 2 , CN, COOH, CO—O—(C1-C4) alkylene-(C6-C10)aryl, CO—O—(C1-C4)alkyl, CO—O—(C1-C4)alkylene-(C3-C13)cycloalkyl, CO—O—(C1-C4)alkylene-(C3-C15)heterocycle, CO—N((C1-C4)alkylene-H)—(C1-C4)alkylene-(C6-C10)aryl, CO—N((C1-C4)alkylene-H)—(C1-C4)alkylene-H, CO—N((C1-C4)alkylene
  • cycloalkyl is to be understood to mean saturated hydrocarbon cycle containing from 3 to 13 carbon atoms in a mono- or bicyclic, fused, bridged or spirocyclic ring.
  • Examples of (C3-C13)-cycloalkyl cyclic alkyl residues are cycloalkyl residues containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or cyclododecyl.
  • the term cycloalkyl also includes bicyclic groups in which any of the above cycloalkyl ring is fused to a benzene ring, for example indane and 1,2,3,4-tetrahydronaphthalene.
  • cycloalkenyl is to be understood to mean unsaturated hydrocarbon cycle containing from 3 to 8 carbon atoms in a mono- or bicyclic, fused or bridged ring, wherein the one, two or three double bonds are not located within a cyclic alkyl group in such a manner that an aromatic system results.
  • unsaturated cycloalkenyl groups are cyclopentenyl or cyclohexenyl, which can be bonded via any carbon atom.
  • cycloalkenyl also includes bicyclic groups in which any of the above cycloalkenyl ring is fused to a benzene ring, for example 1,2-dihydronaphthalene, 1,4-dihydronaphthalene and 1H-indene.
  • cycloalkyl or cycloalkenyl are un-substituted or mono, di- or tri-substituted independently of one another by suitable groups such as, for example: F, Cl, Br, I, CF3, NO2, CN, COOH, CO—O—(C1-C4)alkylene-(C6-C10)aryl, CO—O—(C1-C4) alkyl, CO—O—(C1-C4)alkylene-(C3-C13)cycloalkyl, CO—O—(C1-C4)alkylene-(C3-C15)heterocycle, CO—N((C1-C4)alkylene-H)—(C1-C6)alkylene-H, CO—N((C1-C4) alkylene-H)—(C1-C6)cycloalkyl, CON((C1-C4)alkylene-H)—(C1-C4)alkylene-(C6-C12)-aryl,
  • aryl is understood to mean aromatic hydrocarbon ring containing from 6 to 14 carbon atoms in a mono- or bicyclic ring.
  • Examples of (C6-C14)-aryl rings are phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl, biphenyl, for example 2-biphenyl, 3-biphenyl and 4-biphenyl, anthryl or fluorenyl.
  • Biphenyl rings, naphthyl ring and, in particular, phenyl ring are further embodiments of aryl ring.
  • heterocycle is understood to mean saturated (heterocycloalkyl), partly unsaturated (heterocycloalkenyl) or unsaturated (heteroaryl) hydrocarbon rings containing from 3 to 15 carbon atoms in a mono- or bicyclic, fused, bridged or spirocyclicring in which 1 to 5 carbon atoms of the 3 to 15 ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur in which further the heteroatoms can be oxidized, for example N ⁇ O, S ⁇ O, SO2.
  • heterocycles are acridinyl, azaindole (1H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrochinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-diox
  • heterocyclic rings are un-substituted or mono-, di- or tri-substituted by suitable groups such as, for example: F, Cl, Br, I, CF3, NO2, CN, COOH, CO—O—(C1-C4) alkylene-(C6-C10)aryl, CO—O—(C1-C4)alkyl, CO—O—(C1-C4)alkylene-(C3-C13) cycloalkyl, CO—O—(C1-C4)alkylene-(C3-C15)heterocycle, CO—N((C1-C4)alkylene-H)—(C1-C6)alkylene-H, CO—N((C1-C4)alkylene-H)—(C1-C6)cycloalkyl, CON((C1-C4) alkylene-H)—(C1-C4)alkylene-(C6-C12)-aryl, (C1-C4)alkylene-(C3-C
  • R5 and R6 together with the nitrogen atom to which they are bonded can form a (C3-C9)-heterocycle which for example can contain additionally 1 to 3 heteroatoms” refer to structures of heterocycles which can be derived from compounds such as for example pyrrolidine, morpholine, thiomorpholine, piperidine, piperazine, azetidine, 2,3-dihydro-1H-isoindole, piperazin-2-one, azetidine, isoindoline, 2,5-diazabicyclo[2.2.1]heptane, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, piperidin-4-one, piperidin-3-one, homopiperidine, homopiperazine, homomorpholine, 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one, 4-oxazolidine, aze
  • oxo-residue or “ ⁇ O” refers to residues such as carbonyl (—CO—), nitroso (—N ⁇ O), sulfinyl (—SO—) or sulfonyl (— SO2 )—.
  • Halogen is a fluorine, chlorine, bromine or iodine moiety.
  • Optically active carbon atoms present in the compounds of the formula I can independently of each other have R configuration or S configuration.
  • the compounds of the formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and/or diastereomers, for example in the form of racemates.
  • the present invention relates to pure enantiomers and mixtures of enantiomers as well as to pure diastereomers and mixtures of diastereomers.
  • the invention comprises mixtures of two or of more than two stereoisomers of the formula I and it comprises all ratios of the stereoisomers in the mixtures.
  • the invention relates both to pure E isomers and pure Z isomers and to E/Z mixtures in all ratios.
  • the invention also comprises all tautomeric forms of the compounds of the formula I.
  • Diastereomers including E/Z isomers, can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary methods, for example by chromatography on chiral phases or by resolution, for example by crystallization of diastereomeric salts obtained with optically active acids or bases. Stereochemically uniform compounds of the formula I can also be obtained by employing stereochemically uniform starting materials or by using stereoselective reactions.
  • the compounds of the formula I may exist in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and mixtures of diastereomers as well in their tautomeric forms.
  • the present invention encompasses all these isomeric and tautomeric forms of the compounds of the formula I. These isomeric forms can be obtained by known methods even if not specifically described in some cases.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid.
  • inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid
  • organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.
  • Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
  • physiologically functional derivative refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.
  • Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.
  • the compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.
  • This invention relates further to the use of compounds of the formula I and their pharmaceutical compositions as Peroxisome Proliferater Activator Receptor (PPAR) ligands.
  • PPAR Peroxisome Proliferater Activator Receptor
  • the PPAR ligands of the invention are suitable as modulators of PPAR activity.
  • Peroxisome proliferator-activated receptors are transcription factors which can be activated by ligands and belong to the class of nuclear hormone receptors. There are three PPAR isoforms, PPARalpha, PPARgamma and PPARdelta (identical to PPARbeta), which are encoded by different genes (Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Motojima K., Cell Struct Funct., 1993, 18(5), 267-77).
  • PPARgamma exists in three variants, PPARgamma 1 , gamma 2 , and gamma 3 , which are the result of alternative use of promoters and differential mRNA splicing.
  • Different PPARs have different tissue distribution and modulate different physiological functions.
  • the PPARs play a key role in various aspects of the regulation of a large number of genes, the products of which genes are directly or indirectly crucially involved in lipid and carbohydrate metabolism.
  • the PPARalpha receptor plays an important part in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARgamma is crucially involved for example in regulating adipose cell differentiation.
  • PPARs are also involved in the regulation of many other physiological processes, including those which are not directly connected with carbohydrate or lipid metabolism.
  • the activity of different PPARs can be modulated by various fatty acids, fatty acid derivatives and synthetic compounds to varying extents.
  • Berger, J. et al. Annu. Rev. Med., 2002, 53, 409-435; Wilson, T. et al., J. Med. Chem., 2000, 43 (4), 527-550; Kliewer, S. et al., Recent Prog Horm Res., 2001, 56, 239-63; Moller, D. E. and Berger, J. P., Int J Obes Relat Metab Disord., 2003, 27 Suppl 3, 17-21; Ram, V. J., Drugs Today, 2003, 39(8),609-32).
  • the potent and selective PPARdelta ligand GW501516 raises HDL-cholesterol, decreases plasma LDL-cholesterol, triglycerides and insulin levels (Oliver, W. et al., Proc. Natl. Acad. Sci., 2001, 98, 5306-5361).
  • the dual PPARdelta/PPARalpha agonist YM-1 6638 significantly lowers plasma lipids in rhesus and cynomolgus monkeys (Goto, S. et al., Br. J. Pharm., 1996, 118, 174-178) and acts in a similar manner in two weeks clinical trials in healthy volunteers (Shimokawa, T.
  • PPARdelta is an important target for the treatment of dyslipidemia, insulin resistance, type 2 diabetes, atherosclerosis and syndrom X (Wang, Y-X. et al., Cell, 2003, 113, 159-170; Luquet, S. et al., FASEB J., 2003, 17, 209-226; Tanaka, T. et al., PNAS, 2003, 100, 15924-15929; Hoist, D. et al., BioChem. Biophys. Acta, 2003, 1633, 43-50; Dressel, U. et al., Mol. Endocrin., 2003, 17, 2477-2493; Lee, C. H. et al., Science, 2003, 302, 453-457).
  • PPARdelta Besides its actions as a regulator of the lipid-, glucose- and cholesterol-metabolism PPARdelta is known to play a role in embryonic development, implantation and bone formation (Lim, H. and Dey, S. K., Trends Endocrinol Metab., 2000, 11(4),137-42; Ding, N. Z. et al., Mol Reprod Dev., 2003, 66(3), 218-24; Mano, H. et al., J Biol Chem., 2000, 275(11), 8126-32).
  • PPARdelta appears to be significantly expressed in the CNS; however much of its function there still remains undiscovered. Of singular interest however, is the discovery that PPARdelta was expressed in rodent oligodendrocytes, the major lipid producing cells of the CNS (J. Granneman, et al., J. Neurosci. Res., 1998, 51, 563-573). Moreover, it was also found that a PPARdelta selective agonist was found to significantly increase oligodendroglial myelin gene expression and myelin sheath diameter in mouse cultures (I. Saluja et al., Glia, 2001, 33, 194-204).
  • PPARdelta activators may be of use for the treatment of de-myelinating and dysmyelinating diseases.
  • the use of peroxisome proliferator activated receptor delta agonists for the treatment of MS and other demyelynating diseases can be shown as described in WO2005/097098.
  • De-myelinating conditions are manifested in loss of myelin—the multiple dense layers of lipids and protein which cover many nerve fibers. These layers are provided by oligodendroglia in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS).
  • CNS central nervous system
  • PNS peripheral nervous system
  • demyelination may be irreversible; it is usually accompanied or followed by axonal degeneration, and often by cellular degeneration. Demyelination can occur as a result of neuronal damage or damage to the myelin itself—whether due to aberrant immune responses, local injury, ischemia, metabolic disorders, toxic agents, or viral infections (Prineas and McDonald, De-myelinating Diseases.
  • central demyelination occurs in several conditions, often of uncertain etiology, that have come to be known as the primary de-myelinating diseases. Of these, multiple sclerosis (MS) is the most prevalent.
  • Other primary de-myelinating diseases include adrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolar myelopathy, HTLV-associated myelopathy, Leber's hereditary optic atrophy, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis, Guillian-Barre syndrome and tropical spastic paraparesis.
  • ALD adrenoleukodystrophy
  • adrenomyeloneuropathy AIDS-vacuolar myelopathy
  • HTLV-associated myelopathy HTLV-associated myelopathy
  • Leber's hereditary optic atrophy progressive multifocal leukoencephalopathy (PML),
  • demyelination can occur in the CNS, e.g., acute disseminated encephalomyelitis (ADEM) and acute viral encephalitis.
  • ADAM acute disseminated encephalomyelitis
  • acute transverse myelitis a syndrome in which an acute spinal cord transection of unknown cause affects both gray and white matter in one or more adjacent thoracic segments, can also result in demyelination.
  • disorders in which myelin forming glial cells are damaged including spinal cord injuries, neuropathies and nerve injury.
  • the present invention relates to compounds of the formula I suitable for modulating the activity of PPARs, especially the activity of PPARdelta and PPARalpha.
  • the compounds of the formula I are suitable for the treatment, control and prophylaxis of the indications described hereinafter, and for a number of other pharmaceutical applications connected thereto (see, for example, Berger, J., et al., Annu. Rev. Med., 2002, 53, 409-435; Wilson, T. et al., J. Med. Chem., 2000, 43(4), 527-550; Kliewer, S. et al., Recent Prog Horm Res., 2001, 56, 239-63; Fruchart, J. C.
  • Compounds of this type are particularly suitable for the treatment and/or prevention of:
  • the amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient.
  • the daily dose is generally in the range from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg) per day and per kilogram of bodyweight, for example 0.1-10 mg/kg/day.
  • An intravenous dose may be, for example, in the range from 0.001 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute.
  • Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter.
  • Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
  • ampules for injections may contain, for example, from 1 mg to 100 mg
  • single-dose formulations which can be administered orally, such as, for example, capsules or tablets may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg.
  • the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health.
  • the carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Other pharmaceutically active substances may likewise be present, including other compounds of formula 1.
  • the pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
  • compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case.
  • Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • Suitable pharmaceutical preparations for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contain a defined amount of the compound of formula l; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact.
  • the compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary.
  • a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients.
  • Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one (or more) surface-active/dispersing agent(s) in a suitable machine.
  • Molded tablets can be produced by molding the compound, which is in powder form and is moistened with an inert liquid diluent, in a suitable machine.
  • compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastlles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula 1, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.
  • compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil.
  • Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances.
  • the active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.
  • compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis.
  • Such plasters suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active ingredient concentration is about 1 % to 35%, preferably about 3% to 15%.
  • a particular possibility is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 368 (1986).
  • the compounds of the formula I are distinguished by favorable effects on metabolic disorders. They beneficially influence lipid and sugar metabolism, in particular they lower the triglyceride level and are suitable for the prevention and treatment of type II diabetes and atheriosclerosis and the diverse sequalae thereof.
  • the compounds of the invention can be administered alone or in combination with one or more further pharmacologically active substances.
  • the compounds of the invention can be administered in combination with active ingredients having a similar pharmacological action.
  • they can be administered in combination with active ingredients which have favorable effects on metabolic disturbances or disorders frequently associated therewith. Examples of such medicaments are
  • Administration of the active ingredient combination can take place either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.
  • Particularly suitable further active ingredients for the combination preparations are: All antidiabetic pharmaceuticals mentioned in the Rote Liste 2006, Chapter 12; all slimming agents/appetite suppressants mentioned in the Rote Liste 2006, Chapter 1; all lipid-lowering agents mentioned in the Rote Liste 2006, Chapter 58. They can be combined with the compound of the formula I according to the invention in particular for a synergistic enhancement of activity.
  • the active compound combination can be administered either by separate administration of the active compounds to the patient or in the form of combination preparations in which a plurality of active compounds are present in a pharmaceutical preparation. Most of the active compounds listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
  • Antidiabetic compounds include insulin and insulin derivatives, such as, for example, Lantus® (see www.lantus.com) or HMR 1964 or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see U.S. Pat. No.
  • inhalable insulins such as, for example, Exubera® or oral insulins, such as, for example, IN-105 (Nobex) or Oral-lynTM (Generex Biotechnology), GLP-1 derivatives, such as, for example, Exenatide, Liraglutide or those disclosed in WO 98/08871 or WO2005027978 by Novo Nordisk A/S, in WO 01/04156 by Zealand or in WO 00/34331 by Beaufour-Ipsen, pramlintide acetate (Symlin; Amylin Pharmaceuticals), and also orally effective hypoglycemic active ingredients.
  • GLP-1 derivatives such as, for example, Exenatide, Liraglutide or those disclosed in WO 98/08871 or WO2005027978 by Novo Nordisk A/S, in WO 01/04156 by Zealand or in WO 00/34331 by Beaufour-Ipsen, pramlintide acetate (Symlin; Amylin Pharmaceutical
  • the active compounds preferably include
  • the compound of the formula I is administered in combination with a HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin or L-659699.
  • a HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin or L-659699.
  • the compound of the formula I is administered in combination with a cholesterol resorption inhibitor, such as, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692), MD-0727 (Microbia Inc., WO2005021497) or with compounds as described in WO2002066464 (Kotobuki Pharmaceutical Co. Ltd.), WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZeneca AB).
  • a cholesterol resorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692), MD-0727 (Microbia Inc., WO2005021497) or with compounds as described in WO2002066464 (K
  • the compound of the formula I is administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483 or CS-011 (rivoglitazone).
  • a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483 or CS-011 (rivoglitazone).
  • the compound of the formula I is administered in combination with a PPAR alpha agonist, such as, for example, GW9578, GW-590735, K-111, LY-674, KRP-101 or DRF-10945.
  • a PPAR alpha agonist such as, for example, GW9578, GW-590735, K-111, LY-674, KRP-101 or DRF-10945.
  • the compound of the formula I is administered in combination with a mixed PPAR alpha/gamma agonist, such as, for example, muraglitazar, tesaglitazar, naveglitazar, LY-510929, ONO-5129, E-3030 or as described in WO00/64888, WO00/64876, WO03/020269, WO2004075891, WO2004076402, WO2004075815, WO2004076447, WO2004076428, WO2004076401, WO2004076426, WO2004076427, WO2006018118, WO2006018115, and WO2006018116 or in J. P. Berger et al., TRENDS in Pharmacological Sciences 28(5), 244-251, 2005.
  • a mixed PPAR alpha/gamma agonist such as, for example, muraglitazar, tesaglitazar, naveglitazar, LY-510929, ONO-5129, E
  • the compound of the formula I is administered in combination with a PPAR delta agonist, such as, for example, GW-501516 or as described in WO2005097762, WO2005097786, WO2005097763, and WO2006029699.
  • a PPAR delta agonist such as, for example, GW-501516 or as described in WO2005097762, WO2005097786, WO2005097763, and WO2006029699.
  • the compound of the formula I is administered in combination with metaglidasen or with MBX-2044 or other partial PPAR gamma agonists/antagonists.
  • the compound of the formula I is administered in combination with a fibrate, such as, for example, fenofibrate, clofibrate or bezafibrate.
  • a fibrate such as, for example, fenofibrate, clofibrate or bezafibrate.
  • the compound of the formula I is administered in combination with an MTP inhibitor, such as, for example, implitapide, BMS-201038, R-103757 or those described in WO2005085226.
  • an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757 or those described in WO2005085226.
  • the compound of the formula I is administered in combination with a CETP inhibitor, such as, for example, torcetrapib or JTT-705.
  • a CETP inhibitor such as, for example, torcetrapib or JTT-705.
  • the compound of the formula I is administered in combination with a bile acid resorption inhibitor (see, for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 or WO00/61568), such as, for example, HMR 1741 or those described in DE 10 2005 033099.1 and DE 10 2005 033100.9.
  • a bile acid resorption inhibitor see, for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 or WO00/61568
  • HMR 1741 such as, for example, HMR 1741 or those described in DE 10 2005 033099.1 and DE 10 2005 033100.9.
  • the compound of the formula I is administered in combination with a polymeric bile acid adsorber, such as, for example, cholestyramine or colesevelam.
  • a polymeric bile acid adsorber such as, for example, cholestyramine or colesevelam.
  • the compound of the formula I is administered in combination with an LDL receptor inducer (see U.S. Pat. No. 6,342,512), such as, for example, HMR1171, HMR1586 or those described in WO2005097738.
  • an LDL receptor inducer see U.S. Pat. No. 6,342,512
  • the compound of the formula I is administered in combination with Omacor® (omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).
  • Omacor® omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid.
  • the compound of the formula I is administered in combination with an ACAT inhibitor, such as, for example, avasimibe.
  • an ACAT inhibitor such as, for example, avasimibe.
  • the compound of the formula I is administered in combination with an antioxidant, such as, for example, OPC-14117, probucol, tocopherol, ascorbic acid, ⁇ -carotene or selenium.
  • an antioxidant such as, for example, OPC-14117, probucol, tocopherol, ascorbic acid, ⁇ -carotene or selenium.
  • the compound of the formula I is administered in combination with a vitamin, such as, for example, vitamin B6 or vitamin B12.
  • a vitamin such as, for example, vitamin B6 or vitamin B12.
  • the compound of the formula I is administered in combination with a lipoprotein lipase modulator, such as, for example, ibrolipim (NO-1886).
  • a lipoprotein lipase modulator such as, for example, ibrolipim (NO-1886).
  • the compound of the formula I is administered in combination with an ATP-citrate lyase inhibitor, such as, for example, SB-204990.
  • the compound of the formula I is administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494 or as described in WO2005077907.
  • a squalene synthetase inhibitor such as, for example, BMS-188494 or as described in WO2005077907.
  • the compound of the formula I is administered in combination with a lipoprotein(a) antagonist, such as, for example, gemcabene (C1-1027).
  • a lipoprotein(a) antagonist such as, for example, gemcabene (C1-1027).
  • the compound of the formula I is administered in combination with an HM74A receptor agonists, such as, for example, nicotinic acid.
  • the compound of the formula I is administered in combination with a lipase inhibitor, such as, for example, orlistat or cetilistat (ATL-962).
  • a lipase inhibitor such as, for example, orlistat or cetilistat (ATL-962).
  • the compound of the formula I is administered in combination with insulin.
  • the compound of the formula I is administered in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.
  • a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.
  • the compound of the formula I is administered in combination with a biguanide, such as, for example, metformin.
  • a biguanide such as, for example, metformin.
  • the compound of the formula I is administered in combination with a meglitinide, such as, for example, repaglinide or nateglinide.
  • a meglitinide such as, for example, repaglinide or nateglinide.
  • the compound of the formula I is administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 by Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
  • a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 by Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedi
  • the compound of the formula I is administered in combination with an ⁇ -glucosidase inhibitor, such as, for example, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose.
  • the compound of the formula I is administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • the compound of the formula I is administered in combination with more than one of the compounds mentioned above, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • the compound of the formula I is administered in combination with an inhibitor of glycogen phosphorylase, such as, for example, PSN-357 or FR-258900 or those described in WO2003084922, WO2004007455, WO2005073229-31 or WO2005067932.
  • an inhibitor of glycogen phosphorylase such as, for example, PSN-357 or FR-258900 or those described in WO2003084922, WO2004007455, WO2005073229-31 or WO2005067932.
  • the compound of the formula I is administered in combination with glucagon receptor antagonists, such as, for example, A-770077, NNC-25-2504 or such as in WO2004100875 or WO2005065680.
  • glucagon receptor antagonists such as, for example, A-770077, NNC-25-2504 or such as in WO2004100875 or WO2005065680.
  • the compound of the formula I is administered in combination with activators of glucokinase, such as, for example, RO-4389620, LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those described, for example, by Prosidion in WO2004072031, WO2004072066, WO 05103021 or WO 06016178, by Roche in WO 00058293, WO 00183465, WO 00183478, WO 00185706, WO 00185707, WO 01044216, GB 02385328, WO 02008209, WO 02014312, WO 0246173, WO 0248106, DE 10259786, WO 03095438, U.S.
  • activators of glucokinase such as, for example, RO-4389620, LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those described, for example, by Pro
  • the compound of the formula I is administered in combination with an inhibitor of gluconeogenesis, such as, for example, FR-225654.
  • the compound of the formula I is administered in combination with inhibitors of fructose-1,6-bisphosphatase (FBPase), such as, for example, CS-917.
  • FBPase fructose-1,6-bisphosphatase
  • the compound of the formula I is administered in combination with modulators of the glucose transporter 4 (GLUT4), such as, for example, KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).
  • GLUT4 glucose transporter 4
  • the compound of the formula I is administered in combination with inhibitors of glutamine:fructose-6-phosphate amidotransferase (GFAT), as described, for example, in W02004101528.
  • GFAT glutamine:fructose-6-phosphate amidotransferase
  • the compound of the formula I is administered in combination with inhibitors of dipeptidylpeptidase IV (DPP-IV), such as, for example, vildagliptin (LAF-237), sitagliptin (MK-0431), saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X or as described in WO2003074500, WO2003106456, WO200450658, WO2005058901, WO2005012312, WO2005/012308, PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002, PCT/EP2005/008004, PCT/EP2005/008283, DE 10 2005 012874.2 or DE 10 2005 012873.4.
  • DPP-IV dipeptidylpeptidase IV
  • the compound of the formula I is administered in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11 ⁇ -HSD1), such as, for example, BVT-2733 or those described, for example, in WO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744, WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896, WO2005016877 or WO2005097759.
  • 11 ⁇ -HSD1 11-beta-hydroxysteroid dehydrogenase-1
  • the compound of the formula I is administered in combination with inhibitors of protein tyrosine phosphatase 1B (PTP1 B), as described, for example, in WO200119830-31, WO200117516, WO2004506446, WO2005012295, PCT/EP2005/005311, PCT/EP2005/005321, PCT/EP2005/007151, PCT/EP2005/or DE 10 2004 060542.4.
  • PTP1 B protein tyrosine phosphatase 1B
  • the compound of the formula I is administered in combination with modulators of the sodium/glucose cotransporter 1 or 2 (SGLT1, SGLT2), such as, for example, KGA-2727, T-1095 and SGL-0010 or as described, for example, in WO2004007517, WO200452903, WO200452902, WO2005121161, WO2005085237, JP2004359630 or by A. L. Handlon in Expert Opin. Ther. Patents (2005) 15(11), 1531-1540.
  • modulators of the sodium/glucose cotransporter 1 or 2 SGLT1, SGLT2
  • the compound of the formula I is administered in combination with inhibitors of hormone-sensitive lipase (HSL), such as those described, for example, in WO01/17981, WO01/66531, WO2004035550, WO2005073199 or WO03/051842.
  • HSL hormone-sensitive lipase
  • the compound of the formula I is administered in combination with inhibitors of acetyl-CoA carboxylase (ACC) such as those described, for example, in WO199946262, WO200372197, WO2003072197 or WO2005044814.
  • ACC acetyl-CoA carboxylase
  • the compound of the formula I is administered in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), such as those described, for example, in WO2004074288.
  • PPCK phosphoenolpyruvate carboxykinase
  • the compound of the formula I is administered in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), such as those described, for example, in US2005222220, WO2004046117, WO2005085230, WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727 or WO2004046117.
  • GSK-3 beta glycogen synthase kinase-3 beta
  • the compound of the formula I is administered in combination with an inhibitor of protein kinase C beta (PKC beta), such as, for example, ruboxistaurin.
  • PLC beta protein kinase C beta
  • the compound of the formula I is administered in combination with an endothelin-A receptor antagonist, such as, for example, avosentan (SPP-301).
  • an endothelin-A receptor antagonist such as, for example, avosentan (SPP-301).
  • the compound of the formula I is administered in combination with inhibitors of “I-kappaB kinase” (IKK inhibitors), such as those described, for example, in WO2001000610, WO2001030774, WO2004022553 or WO2005097129.
  • IKK inhibitors such as those described, for example, in WO2001000610, WO2001030774, WO2004022553 or WO2005097129.
  • the compound of the formula I is administered in combination with modulators of the glucocorticoid receptor as described, for example, in WO2005090336.
  • the compound of the formula I is administered in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9), 554-558); NPY antagonists such as, for example, ⁇ 4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl ⁇ naphthalene-1-sulfonamide hydrochloride (CGP 71683A); peptide YY 3-36 (PYY3-36) or analogous compounds, such as, for example, CJC-1682 (PYY3-36 conjugated with human serum albumin via Cys34), CJC-1643 (derivative of PYY3-36 which conjugates in vivo to serum albumin) or those described in WO2005080424;
  • CART modulators see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety
  • cannabinoid receptor 1 antagonists such as, for example, rimonabant, SR147778 or those described, for example, in EP 0656354, WO 00/15609, WO 02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069, U.S. Pat. No.
  • MC4 agonists for example [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-1-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxamide; (WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or those described in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793, WOUS20050222014, US20050176728, US20050164914, US20050124636, US20050130988,
  • orexin receptor antagonists for example 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride (SB-334867-A) or those described, for example, in WO200196302, WO200185693, WO2004085403 or WO2005075458;
  • histamine H3 receptor agonists for example 3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-propan-1-one oxalic acid salt (WO 00/63208) or those described in WO200064884, WO2005082893);
  • CRF antagonists for example [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585));
  • CRF BP antagonists for example urocortin
  • P3 agonists such as, for example, 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol hydrochloride (WO 01/83451));
  • MSH melanocyte-stimulating hormone
  • MCH (melanin-concentrating hormone) receptor antagonists such as, for example, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or those compounds described in WO2003/15769, WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2006018280, WO2006018279, WO2004039780, WO2003033476, WO2002006245, WO2002002744, WO2003004027 or FR2868780);
  • CCK-A agonists such as, for example, ⁇ 2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl ⁇ acetic acid trifluoroacetic acid salt (WO 99/15525), SR-146131 (WO 0244150) or SSR-125180);
  • serotonin reuptake inhibitors for example dexfenfluramine
  • 5-HT receptor agonists for example 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111);
  • 5-HT2C receptor agonists such as, for example, APD-356, BVT-933 or those described in WO200077010, WO20077001-02, WO2005019180, WO2003064423, WO200242304 or WO2005082859;
  • 5-HT6 receptor antagonists such as described, for example, in WO2005058858;
  • growth hormone for example human growth hormone or AOD-9604.
  • growth hormone releasing compounds tert-butyl 6-benzyloxy-1-(2-diisopropylamino-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695));
  • growth hormone secretagog receptor antagonists such as, for example, A-778193 or those described in WO2005030734;
  • TRH agonists see, for example, EP 0 462 884
  • leptin agonists see for example Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881);
  • DA agonists bromocriptine or Doprexin
  • lipase/amylase inhibitors as described, for example, in WO 00/40569;
  • DGATs diacylglycerol O-acyltransferases
  • FAS fatty acid synthase
  • thyroid hormone receptor agonists such as, for example, KB-2115 or those described in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421 or WO2005092316.
  • the further active ingredient is leptin; see for example “Perspectives in the therapeutic use of leptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.
  • the further active ingredient is dexamphetamine or amphetamine.
  • the further active ingredient is fenfluramine or dexfenfluramine.
  • the further active ingredient is sibutramine.
  • the further active ingredient is mazindol or phentermine.
  • the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (September-October 2001), 18(5), 230-6).
  • Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hbchst, 65926 Frankfurt/Main).
  • Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®.
  • Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.
  • the compound of the formula I is administered in combination with PDE (phosphodiesterase) inhibitors, as described, for example, in WO2003/077949 or WO2005012485.
  • PDE phosphodiesterase
  • the compound of the formula I is administered in combination with NAR-1 (nicotinic acid receptor) agonists as described, for example, in WO2004094429.
  • NAR-1 neurotinic acid receptor
  • the compound of the formula I is administered in combination with CB2 (cannabinoid receptor) agonists as described, for example, in US2005/143448.
  • CB2 cannabinoid receptor
  • the compound of the formula I is administered in combination with histamine 1 agonists as described, for example, in WO2005101979.
  • the compound of the formula I is administered in combination with bupropion, as described in WO2006017504.
  • the compound of the formula I is administered in combination with opioid antagonists as described, for example, in WO2005107806 or WO2004094429.
  • the compound of the formula I is administered in combination with neutral endopeptidase inhibitors as described, for example, in WO200202513, WO2002/06492, WO 2002040008, WO2002040022 or WO2002047670.
  • the compound of the formula I is administered in combination with NPY inhibitors (neuropeptide Y) as described, for example, in WO2002047670.
  • the compound of the formula I is administered in combination with sodium/hydrogen exchange inhibitors as described, for example, in WO2003092694.
  • the compound of the formula I is administered in combination with modulators of the glucocorticoid receptor as described, for example, in WO2005090336.
  • the compound of the formula I is administered in combination with nicotine receptor agonists as described, for example, in WO2004094429.
  • the compound of the formula I is administered in combination with NRIs (norepinephrine reuptake inhibitors) as described, for example, in WO2002053140.
  • NRIs nervepinephrine reuptake inhibitors
  • the compound of the formula I is administered in combination with MOA (E-beta-methoxyacrylate), such as, for example, segeline, or as described, for example, in WO2002053140.
  • MOA E-beta-methoxyacrylate
  • the compound of the formula I is administered in combination with antithrombotic active ingredients, such as, for example, clopidogrel.
  • HEK human embryo kidney
  • pdeltaM-GAL4-Luc-Zeo a luciferase reporter element
  • GR-GAL4-humanPPARalpha-LBD PPARalpha fusion protein
  • the stably and constitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD binds in the cell nucleus of the PPARalpha reporter cell line via the GAL4 protein portion to the GAL4 DNA binding motifs 5′-upstream of the luciferase reporter element which is stably integrated in the genome of the cell line.
  • cs-FCS fatty acid-depleted fetal calf serum
  • PPARalpha ligands bind and activate the PPARalpha fusion protein and thereby stimulate the expression of the luciferase reporter gene.
  • the luciferase which is formed can be detected by means of chemiluminescence via an appropriate substrate.
  • the PPARalpha reporter cell line was prepared in two stages. Firstly, the luciferase reporter element was constructed and stably transfected into HEK cells. For this purpose, five binding sites of the yeast transcription factor GAL4 (Accession #AF264724) were cloned in 5′-upstream of a 68 bp-long minimal MMTV promoter (Accession #V01175). The minimal MMTV promoter section contains a CCMT box and a TATA element in order to enable efficient transcription by RNA polymerase II. The cloning and sequencing of the GAL4-MMTV construct took place in analogy to the description of Sambrook J. et. al.
  • zeocin-containing medium 0.5 mg/ml was used to select a suitable stable cell clone which showed very low basal expression of the luceriferase gene.
  • the PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD was introduced into the stable cell clone described.
  • the cDNA coding for the N-terminal 76 amino acids of the glucocorticoid receptor (Accession #P04150) was linked to the cDNA section coding for amino acids 1-147 of the yeast transcription factor GAL4 (Accession #P04386).
  • the cDNA of the ligand-binding domain of the human PPARalpha receptor (amino acids S167-Y468; Accession #S74349) was cloned in at the 3′-end of this GR-GAL4 construct.
  • the fusion construct prepared in this way (GR-GAL4-humanPPARalpha-LBD) was recloned into the plasmid pcDNA3 (Invitrogen) in order to enable constitutive expression therein by the cytomegalovirus promoter.
  • This plasmid was linearized with a restriction endonuclease and stably transfected into the previously described cell clone containing the luciferase reporter element.
  • the finished PPARalpha reporter cell line which contains a luciferase reporter element and constitutively expresses the PPARalpha fusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by selection with zeocin (0.5 mg/ml) and G418 (0.5 mg/ml).
  • the activity of PPARalpha agonists is determined in a 3-day assay, which is described below:
  • the PPARalphareporter cell line is cultivated to 80% confluence in DMEM (#41965-039, Invitrogen) which is mixed with the following additions: 10% cs-FCS (fetal calf serum; #SH-30068.03, Hyclone), 0.5 mg/ml zeocin (#R250-01, Invitrogen), 0.5 mg/ml G418 (#10136-027, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen).
  • 10% cs-FCS fetal calf serum
  • #SH-30068.03, Hyclone fetal calf serum
  • zeocin fetal calf serum
  • G418 0.5 mg/ml G418
  • penicillin-streptomycin solution #15140-122, Invitrogen
  • the cultivation takes place in standard cell culture bottles (#353612, Becton Dickinson) in a cell culture incubator at 37° C. in the presence of 5% CO 2 .
  • the 80%-confluent cells are washed once with 15 ml of PBS (#14190-094, Invitrogen), treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37° C. for 2 min, taken up in 5 ml of the DMEM described and counted in a cell counter. After dilution to 500.000 cells/ml, 35,000 cells are seeded in each well of a 96 well microtiter plate with a clear plastic base (#3610, Corning Costar). The plates are incubated in the cell culture incubator at 37° C. and 5% CO 2 for 24 h.
  • PPARalpha agonists to be tested are dissolved in DMSO in a concentration of 10 mM.
  • This stock solution is diluted in DMEM (#41965-039, Invitrogen) which is mixed with 5% cs-FCS (#SH-30068.03, Hyclone), 2 mM L-glutamine (#25030-024, Invitrogen) and the previously described antibiotics (zeocin, G418, penicillin and streptomycin).
  • Test substances are tested in 11 different concentrations in the range from 10 ⁇ M to 100 ⁇ M. More potent compounds are tested in concentration ranges from 1 ⁇ M to 10 ⁇ M or between 100 nM and 1 ⁇ M.
  • the medium of the PPARalpha reporter cell line seeded on day 1 is completely removed by aspiration, and the test substances diluted in medium are immediately added to the cells.
  • the dilution and addition of the substances is carried out by a robot (Beckman FX).
  • the final volume of the test substances diluted in medium is 100 ⁇ l per well of a 96 well microtiter plate.
  • the DMSO concentration in the assay is less than 0.1% v/v in order to avoid cytotoxic effects of the solvent.
  • Each plate was charged with a standard PPARalpha agonist, which was likewise diluted in 11 different concentrations, in order to demonstrate the functioning of the assay in each individual plate.
  • the assay plates are incubated in an incubator at 37° C. and 5% CO 2 for 24 h.
  • the PPARalpha reporter cells treated with the test substances are removed from the incubator, and the medium is aspirated off.
  • the cells are lyzed by pipetting 50 ⁇ l of Bright Glo reagent (from Promega) into each well of a 96 well microtiter plate. After incubation at room temperature in the dark for 10 minutes, the microtiter plates are measured in the luminometer (Trilux from Wallac). The measuring time for each well of a microtiter plate is 1 sec.
  • the raw data from the luminometer are transferred into a Microsoft Excel file.
  • Dose-effect plots and EC50 values of PPAR agonists are calculated using the XL.Fit program as specified by the manufacturer (IDBS).
  • the PPARalpha EC50 values for the compounds of Examples 1 to 112 in this assay are in the range from 5 nM to >10 ⁇ M.
  • Compounds of the invention of the formula I activate the PPARalpha receptor.
  • HEK human embryo kidney
  • the PPARdelta reporter cell line also contains two genetic elements, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARdelta fusion protein (GR-GAL4-humanPPARdelta-LBD) which mediates expression of the luciferase reporter element depending on a PPARdelta ligand.
  • the stably and constitutively expressed fusion protein GR-GAL4-humanPPARdelta-LBD binds in the cell nucleus of the PPARdelta reporter cell line via the GAL4 protein portion to the GAL4 DNA binding motifs 5′-upstream of the luciferase reporter element which is stably integrated in the genome of the cell line.
  • cs-FCS fatty acid-depleted fetal calf serum
  • PPARdelta ligands bind and activate the PPARdelta fusion protein and thereby stimulate expression of the luciferase reporter gene.
  • the luciferase which is formed can be detected by means of chemiluminescence via an appropriate substrate.
  • the production of the stable PPARdelta reporter cell line is based on a stable HEK-cell clone which was stably transfected with a luciferase reporter element. This step was already described above in the section “construction of the PPARalpha reporter cell line”.
  • the PPARdelta fusion protein (GR-GAL4-humanPPARdelta-LBD was stably introduced into this cell clone.
  • the cDNA coding for the N-terminal 76 amino acids of the glucocorticoid receptor accesion #P04150
  • the cDNA of the ligand-binding domain of the human PPARdelta receptor (amino acids S139-Y441; Accession #L07592) was cloned in at the 3′-end of this GR-GAL4 construct.
  • the fusion construct prepared in this way (GR-GAL4-humanPPARdelta-LBD) was recloned into the plasmid pcDNA3 (Invitrogen) in order to enable constitutive expression by the cytomegalovirus promoter.
  • This plasmid was linearized with a restriction endonuclease and stably transfected into the previously described cell clone containing the luciferase reporter element.
  • the resulting PPARdelta reporter cell line which contains a luciferase reporter element and constitutively expresses the PPARdelta fusion protein (GR-GAL4-human PPARdelta-LBD) was isolated by selection with zeocin (0.5 mg/ml) and G418 (0.5 mg/ml).
  • the activity of PPARdelta agonists is determined in a 3-day assay in exact analogy to the procedure already described for the PPARalpha reporter cell line except that the PPARdelta reporter cell line and a specific PPARdelta agonist was used as a standard to control test efficacy.
  • PPARdelta EC50 values in the range from 0.2 nM to >10 ⁇ M were measured for the PPAR agonists of Examples 1 to 112 described in this application.
  • Compounds of the invention of the formula I activate the PPARdelta receptor.
  • a dotted line means the point of attachment.
  • PPARdelta PPARalpha Example EC50 ( ⁇ M) EC50 ( ⁇ M) 1 0.056 0.830 9 0.056 0.729 15 0.153 >10 19 0.171 1.19 33 0.299 1.41 51 0.228 1.21 55 0.003 0.319 56 0.358 2.19 68 0.661 1.20 77 0.003 0.530 83 0.012 0.398 89 0.153 2.62 94 0.018 0.664 100 0.008 0.315 102 0.022 1.780 103 0.008 0.483
  • a compound of general formula A-2 where X′ is —OH, —SH, —CH2OH or —CH2SH and R1, R2, R3, B as defined above is either reacted with a compound of general formula A-1 where R is halide (I, Br, Cl) or a sulfonate (O SO2 CH 3 , O SO2 C 6 H 4 CH 3 ) and R5, R7, R8, U, V, W, Y and Z are as defined above in the presence of a base as cesium carbonate or sodium hydride in a solvent as dimethylformamide or with an alcohol of general formula A-1 where R ⁇ OH and R5, R7, R8, U, V, W, Y and Z are as defined above under Mitsunobu reaction conditions (triphenylphosphine, diethylazodicarboxylate for instance) in an apolar solvent as dichloromethane to give a compound of general formula A-4 where X ⁇ O, S, —OCH 2 — or —SCH 2
  • This process can be applied to a compound of general formula A-3 where R is halide (I, Br, Cl) or a sulfonate (O SO2 CH 3 , O SO2 PhCH 3 ) and R5, R7, R8, U, V, W, Y and Z are as defined above or with an alcohol of general formula A-3 where R ⁇ OH and R5, R7, R8, U, V, W, Y and Z are as defined above under reaction conditions as previously described to lead to a compound of general formula A-4 where X ⁇ —CH 2 O— or —CH 2 O—.
  • the compound of general formula A-4 is reacted with hydroxylamine hydrochloride in the presence of a base as triethylamine in a solvent as tetrahydrofuran and methanol to obtain a compound of general formula A-5.
  • This reaction can be facilitated by heating the reaction mixture under microwave irradiation.
  • This compound of general formula A-5 is converted to the product of general formula A-6 by reaction with phenylchloroformate in the presence of a base as pyridine or diisopropylethylamine followed by heating the reaction mixture with microwave irradiation to allow cyclization or alternatively isolating the resulting intermediate and treating it with a base as 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent as acetonitrile.
  • a base as pyridine or diisopropylethylamine
  • a compound of general formula B-1 where X is O, S, CH 2 O or CH 2 S and R5, R7, R8, U, V, W, Y and Z are as defined above is reacted with a fluoro-nitrile of general formula B-2 where B, R1, R2 and R3 are as defined above in the presence of a base such as cesium carbonate, sodium hydride or potassium tert-butoxide in a solvent such as dimethylformamide to give a compound of general formula B-3.
  • This reaction can be performed by heating the reaction mixture at 60° C. under microwave irradiation.
  • compound B-3 is treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine in a solvent as tetrahydrofuran and methanol to obtain a compound of general formula B-4.
  • a base such as triethylamine
  • a solvent such as tetrahydrofuran and methanol
  • Compound B-4 is converted to the product of general formula B-5 by reaction with phenylchloroformate in the presence of a base as pyridine or diisopropylethylamine followed by heating the reaction mixture under microwave irradiation to allow cyclization or alternatively isolating the resulting intermediate and treating it with a base as 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent as acetonitrile.
  • a base as pyridine or diisopropylethylamine
  • Examples 1-15, 94-98 and example 100 were obtained according to process B.
  • a compound of general formula C-1 where R1 ⁇ F and B, R2, R3, R5, R7, R8, U, V, W, Y and Z are as defined above is reacted with a nucleophile, e.g. sodium methylate, to obtain a compound of general formula C-2.
  • a compound of general formula C-2 is reacted with hydroxylamine hydrochloride in the presence of a base as triethylamine in a solvent as tetrahydrofuran and methanol to obtain a compound of general formula C-3. This reaction can be facilitated by heating the reaction mixture under microwave irradiation.
  • a compound of general formula C-3 is converted to the product of general formula C-4 by reaction with phenylchloroformate in the presence of a base as pyridine or diisopropylethylamine followed by heating the reaction mixture with microwave irradiation to allow cyclization or alternatively isolating the resulting intermediate and treating it with a base as 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent as acetonitrile.
  • a base as pyridine or diisopropylethylamine
  • Example 99 was obtained according to process C.
  • a compound of general formula D-1 where PG is a protecting group and R1, R2, R3, R7, R8, B, U, V, W, Y and X are as defined above is deprotected under appropriate reaction conditions depending on Y and its protecting group according to methods known by the person skilled of the art to give the compound of general formula D-2. If Y ⁇ N, the compound of formula D-2 can be reacted with an electrophile such as an alkyl halide or an acyl halide in the presence of a base such as diisopropyl ethyl amine in a polar solvent such dimethylformamide to obtain the compound of general formula D-3 where Y ⁇ N.
  • an electrophile such as an alkyl halide or an acyl halide in the presence of a base such as diisopropyl ethyl amine in a polar solvent such dimethylformamide
  • the compound of formula D-2 can be reacted with an electrophile such as an alkyl halide or an acyl halide in the presence of a stronger base such as sodium methoxide in a polar solvent such dimethylformamide to obtain the compound of general formula D-3 where Y ⁇ S.
  • an electrophile such as an alkyl halide or an acyl halide in the presence of a stronger base such as sodium methoxide in a polar solvent such dimethylformamide
  • the compound of general formula D-4 is reacted with a nucleophile, for example a primary or secondary amine or a sodium salt of a thiol or an alcohol, in a polar solvent such a dimethylformamide to obtain the compound of general formula D-5.
  • This reaction can be facilitated by heating the reaction mixture under microwave irradiation.
  • Example 16 42-46, 85-91, 101-112 were obtained according to process D.
  • a compound of general formula E-1 where PG is a protecting group and R1, R2, R3, R7, R8, B, U, V, W, Y and X are as defined above is deprotected under appropriate reaction conditions depending on Y and its protecting group according to methods known by the person skilled in the art to give the compound of general formula E-2.
  • the amine of formula E-2 can be transformed into an amine of general formula E-3 by reductive amination following either a two-step procedure involving imine formation with an aldehyde and triethylamine in a solvent such as methanol then reduction by adding a reducing agent such as sodium borohydride, or a one-step procedure using an aldehyde and a reducing agent such as sodium triacetoxyborohydride in a solvent as dichloromethane.
  • a reducing agent such as sodium borohydride
  • a reducing agent such as sodium triacetoxyborohydride
  • the corresponding primary alcohol of formula E-4 can be oxidized to an aldehyde of general formula E-5 with one of the methods known by the person skilled of the art such as treatment with Dess-Martin periodinane in a solvent as dichloromethane or dimethylformamide.
  • the compound of general formula E-5 is converted into an amine of general formula E-6 by reductive amination following either a two-step procedure involving imine formation with a primary or secondary amine and triethylamine in a solvent such as methanol then reduction by adding a reducing agent such as sodium borohydride, or a one-step procedure using a primary or secondary amine and a reducing agent such as sodium triacetoxyborohydride in a solvent as dichloromethane.
  • a compound of general formula F-1 where WYR5 ⁇ CH3 and R1, R2, R3, R7, R8, B, U, V and X are as defined above is reacted with N-bromosuccinimide or bromine in an inert solvent such as carbon tetrachloride (an inert polar co-solvent such as hexafluoroisopropanol may be added to help solubilize the starting material) in the presence of a radical initiator such as AIBN or a peroxide to obtain the compound of general formula F-2.
  • the resulting bromide of general formula F-2 is displaced with a nucleophile, for example a primary or secondary amine, in a polar solvent such a dimethylformamide to give a compound of general formula F-3.
  • a compound of general formula G-1 where B ⁇ C(R4), WYR5 ⁇ CH3, V ⁇ N, X ⁇ O or OCH 2 and R1, R2, R3, R4, R7, R8 and U are as defined above is reacted with an oxidant such as meta-chloroperbenzoic acid MCPBA in a solvent such as dichloromethane (a polar co-solvent such as hexafluoroisopropanol may be added to help solubilize the starting material) to give the N-oxide of general formula G-2.
  • the compound of general formula G-2 is subjected to a Polonovsky-type rearrangement by heating it with acetic anhydride to lead to an acetate of general formula G-3.
  • This acetate can be hydrolyzed to the corresponding alcohol of general formula G-4 with for instance lithium hydroxide in water and an organic solvent such as methanol or tetrahydrofuran.
  • the compound of general formula G-5 is reacted with a nucleophile, for example a primary or secondary amine, to obtain the compound of general formula G-6.
  • the alcohol of general formula G-4 can be oxidized to an aldehyde of general formula G-7 with one of the methods known by the person skilled of the art such as treatment with manganese dioxide in a solvent as dichloromethane or dimethylformamide or with Dess-Martin periodinane.
  • the compound of general formula G-7 is converted into an amine of general formula G-8 by reductive amination following either a two-step procedure involving imine formation with a primary or secondary amine and triethylamine in a solvent such as methanol then reduction by adding a reducing agent such as sodium borohydride, or a one-step procedure using a primary or secondary amine and a reducing agent such as sodium triacetoxyborohydride in a solvent as dichloromethane.
  • Examples 33-34 were obtained according to process G.
  • a 3-oxo-carboxylic acid methyl- or ethyl ester of general formula H-1 where R5, Y and W are as defined above is reacted with sulfuryl chloride or chlorine to yield the corresponding chloride of general formula H-2.
  • This compound of general formula H-2 is reacted with a benzamide or thiobenzamide of general formula H-3, where U is S or O and R7, R8 and Z are as defined above to obtain a phenylthiazole or phenyloxazole ester of general formula H-4.
  • the ester of general formula H-4 is reduced with a reducing agent, for example lithium aluminum hydride, to the alcohol of general formula H-5.
  • the alcohol of general formula H-5 is reacted with methanesulfonyl chloride in the presence of a base as triethylamine in a solvent as dichloromethane to obtain the building block of general formula H-6, where R5, R7, R8, U, W, Y and Z are as defined above.
  • This process is used for synthesizing the building blocks I-4, which corresponds to general formula A-1 of process A, where R ⁇ OH, W is CH2, R9 and R10 are H, Z is bond, (C2-C6)alkyl, —CH ⁇ CH—, —C—C— and U, V, Y, R5, R7 and R8 are as defined and, I-5 which corresponds to general formula A-3 of process A, where R ⁇ Cl, W is CH2, R9 and R10 are H, Z is bond, (C2-C6)alkyl, —CH ⁇ CH—, —C ⁇ C— and U, V, Y, R5, R7 and R8 are as defined.
  • Z is (C2-C6)alkyl
  • the carbon atom directly attached to the oxazole or thiazole ring is brominated as well.
  • the brominated product of general formula I-2 is reacted with a nucleophile Y—R5 where Y is OH or Y is NH(R6) and R5 is as defined in a polar solvent like tetrahydrofuran in the presence of a base like DBU to obtain a compound of general formula I-3.
  • a nucleophile Y—R5 where Y is OH or Y is NH(R6) and R5 is as defined in a polar solvent like tetrahydrofuran in the presence of a base like DBU
  • a base like DBU
  • Z is —CH2—CH2— the elimination takes place under the bromination conditions.
  • the double bond can be hydrogenated with hydrogen in the presence of a palladium catalyst in a polar solvent as ethanol or methanol.
  • the ester of general formula I-3 is reduced with a reducing agent, e.g. lithium aluminum hydride, to the alcohol of general formula I-4.
  • a reducing agent e.g. lithium aluminum hydride
  • the alcohol of general formula I-4 is reacted with methanesulfonyl chloride in the presence of a base as triethylamine in a solvent as dichloromethane to obtain the building block of general formula I-5.
  • a compound of the general formula J-1 where R′ is alkyl as methyl or ethyl, and U, V, R8 and R7 are as defined above is brominated upon treatment with N-bromosuccinimide in an apolar solvent as tetrachloromethane to obtain a compound of general formula J-2.
  • the bromide of general formula J-2 is converted into the alcohol of general formula J-3 upon treatment with silver trifluoroacetate in a solvent as dimethylformamide and subsequent heating of the resulting trifluoroacetate in a solvent as ethanol.
  • the hydroxyl group of the compound of general formula J-2 is protected for example as a tetrahydropyranylether by treatment with 3,4-dihydro-2H-pyran in a solvent as dichloromethane in the presence of an acid as pyridinium para-toluenesulfonate to obtain a compound of general formula J-4.
  • the ester of the compound of general formula J-4 is reduced with an agent as lithium aluminum hydride in a solvent as tetrahydrofuran to obtain the compound of general formula J-5, where R is OH.
  • the hydroxyl group can be converted into a chlorine by treatment with methanesulfonylchloride in the presence of a base as triethylamine in a solvent as dichloromethane to obtain a compound of general formula J-6, where R is Cl.
  • the compound of general formula K-2 is cyclyzed to obtain a compound of general formula K-3 upon treatment with triphenylphosphine and iodine in an apolar solvent as dichloromethane.
  • the compound of the general formula K-3 is brominated upon treatment with N-bromosuccinimide in an apolar solvent as tetrachloromethane to obtain a compound of general formula K-4.
  • the bromide of general formula K-4 is converted into the alcohol of general formula K-5 upon treatment with silver trifluoroacetate in a solvent as dimethylformamide and subsequent heating of the resulting trifluoroacetate in a solvent as ethanol.
  • the hydroxyl group of the compound of general formula K-5 is protected for example as a tetrahydropyranylether by treatment with 3,4-dihydro-2H-pyran in a solvent as dichloromethane in the presence of an acid as pyridinium para-toluenesulfonate to obtain a compound of general formula K-6.
  • the ester of the compound of general formula K-6 is reduced with a reducing agent as lithium aluminum hydride in a solvent as tetrahydrofuran to obtain the compound of general formula K-7.
  • the hydroxyl group can be converted into a mesylate by treatment with methanesulfonylchloride in the presence of a base as triethylamine in a solvent as dichloromethane to obtain a compound of general formula K-8.
  • a compound of the general formula L-1 (which can be synthesized according to process A, where the substituent W—Y—R5 of building blocks A-1 is —CH2—OPG; synthesis of this building block is described in process J and K ) where B, U, V, X, R1, R2, R3 , R4, R7 and R8 are as defined and PG means a protecting group as for example a tetrahydropyranylether.
  • the protecting group of the compound of the general formula L-1 is removed, in case PG is a tetrahydropyranylether for example by treatment with an acid in polar solvent as methanol to obtain a compound of general formula I-2.
  • the hydroxyl group of the compound of general formula L-2 is converted into a leaving group (LG) for example a mesylate or chloride by treatment with methanesulfonylchloride in the presence of a base as triethylamine in a solvent as dichloromethane to obtain a compound of general formula L-3.
  • the compound of general formula L-3 is reacted with an nucleophile Y-R5 where Y is OH or Y is NH(R6) and R5 is as defined in a polar solvent like tetrahydrofuran in the presence of a base like DBU to obtain a compound of general formula L-4.
  • the compound of the general formula L-4 is reacted with hydroxylamine hydrochloride in the presence of a base as triethylamine in a solvent as tetrahydrofuran and methanol to obtain a compound of the general formula L-5.
  • a compound of the general formula L-5 is converted to the product of general formula L-6 by reaction with phenylchloroformate in the presence of a base as pyridine and treating this intermediate with a base as 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent as acetonitrile.
  • Examples 60-83 were obtained according to process L.
  • This process is used for synthesizing the building blocks M-2, which corresponds to general formula B-2 of process B, where B ⁇ C(R4), R1 ⁇ OR, R is (C1-C4)alkyl or (C1-C2)alkylene-(C3-C6)cycloalkyl wherein alkyl and alkylene are un-substituted or mono, di- or trisubstituted by F, and where R2, R3 and R4 are H.
  • 2,4-Difluoro-benzonitrile of formula M-1 is treated with an alcohol ROH in a solvent such as tetrahydrofuran in presence of a base such as potassium tert-butoxide at 0-5° C. to give the ether of general formula M-2 where R is (C1-C4)alkyl or (C1-C2)alkylene-(C3-C6)cycloalkyl wherein alkyl and alkylene are un-substituted or mono, di- or trisubstituted by F.
  • R is (C1-C4)alkyl or (C1-C2)alkylene-(C3-C6)cycloalkyl wherein alkyl and alkylene are un-substituted or mono, di- or trisubstituted by F.
  • This process is used for synthesizing the building blocks N-3, which corresponds to general formula B-2 of process B, where B ⁇ C(R4), R1 ⁇ OR, R is (C1-C4)alkyl or (C1-C2)alkylene-(C3-C6)cycloalkyl wherein alkyl and alkylene are un-substituted or mono, di- or trisubstituted by F, and where R2, R3 and R4 are as defined above.
  • the aryl methyl ether of general formula N-1 where R2, R3 and R4 are as defined above, is demethylated by the treatment with aluminum trichloride in refluxing dichloroethane to give the phenol of general formula N-2.
  • the phenol of general formula N-2 is reacted with an electrophile RX where X is a leaving group such as halide or a sulfonate in a polar solvent like dimethylformamide in the presence of a base like potassium carbonate to obtain a compound of general formula N-3.
  • RX is a leaving group such as halide or a sulfonate
  • a polar solvent like dimethylformamide in the presence of a base like potassium carbonate
  • methyl chlorodifluororacetate is used as electrophile and the reaction mixture is heated to 60-120° C. in a solvent such as dimethylformamide or dimethylacetamide, the compound of general formula N-3 where R is CHF2 is obtained.
  • the crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 50/50) followed by washing of the collected solid with diisopropyl ether to give 355 mg of 4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester.
  • [4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [4-(4-methyl-piperazin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol was obtained from 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and 1-methyl-piperazine.
  • [4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [4-pyrrolidin-1-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol was obtained from 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and pyrrolidine.
  • [4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [4-(4-fluoro-piperidin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol was obtained from 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and 4-fluoro-piperidine.
  • racemic [2-(4-trifluoromethyl-phenyl)-4-(3-trifluoromethyl-pyrrolidin-1-ylmethyl)-thiazol-5-yl]-methanol was obtained from 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and racemic 4-trifluoromethyl-pyrrolidine.
  • racemic [4-[([1,4]dioxan-2-ylmethyl-methyl-amino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol was obtained from 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and racemic [1,4]dioxan-2-ylmethyl-methyl-amine.
  • [4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [4-(4-ethyl-piperazin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol was obtained from 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and 1-piperazin-1-yl-ethanone.
  • the amide function in the piperazine group is reduced to the corresponding amine in the reduction step.
  • This building block could also be prepared starting from 4-ethyl-piperazine.
  • [4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [4-cyclopropylaminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol was obtained from 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and cyclopropylamine.
  • reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 4.0 g 5-chloromethyl-4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole as an oil which was used without further purification.
  • 5-chloromethyl-4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole 5-chloromethyl-2-(4-methoxy-benzyl)-4-methyl-oxazole was obtained from 4-methoxyphenylacetamide and ethyl 2-chloroacetoacetate.
  • 5-chloromethyl-4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole 5-chloromethyl-4-methoxymethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-thiazole was obtained from 4-(trifluoromethyl)cinnamide and 2-chloro-4-methoxy-3-oxo-butyric acid methyl ester.
  • Chlorine was bubbled through 10.0 g ethyl 4,4-difluoroacetoacetate for fifteen minutes at room temperature. Then argon was bubbled through. 11.67 g 2-Chloro-4,4-difluoro-3-oxo-butyric acid ethyl ester were obtained as crude material which was used without further purification.
  • reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 2.5 g of 5-chloromethyl-2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole as an oil which was used without further purification.
  • 4-Fluoro-2-methoxy-benzonitrile was prepared according to a previous publication: 4 To a solution of 1 g of 4-fluoro-2-methoxy-benzonitrile in 15 mL of dichloroethane was added 1.1 g of aluminum trichloride. The resulting mixture was refluxed for 1 day then poured slowly into water and extracted with ethyl acetate. The organic extracts were washed twice with 10% aqueous solution of sodium hydroxide. The combined basic layers were washed twice with ethyl acetate, acidified with concentrated aqueous solution of hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with water, with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.78 g of 4-fluoro-2-hydroxy-benzonitrile as a white solid. 4 JP0143139
  • the crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 80/ethyl acetate 20) to give 0.42 g of 2-difluoromethoxy-4,5-difluoro-benzonitrile as a yellowish liquid.
  • the crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 90/ethyl acetate 10) to give 640 mg of 4-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzonitrile as a white solid.
  • 4-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzonitrile 4-fluoro-2-isopropoxy-benzonitrile was obtained from 2,4-difluoro-benzonitrile and isopropanol.
  • 2-cyclopropylmethoxy-4-fluoro-benzonitrile was obtained from 2,4-difluoro-benzonitrile and cyclopropylmethanol.
  • the crude product was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 95/methanol 5) to give 154 mg of N-hydroxy-2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzamidine.
  • the crude product was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10) to give 105 mg of 3- ⁇ 2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one.
  • racemic 3- ⁇ 2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(3-trifluoromethyl-pyrrolidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from racemic [2-(4-trifluoromethyl-phenyl)-4-(3-trifluoromethyl-pyrrolidin-1-ylmethyl)-thiazol-5-yl]-methanol and commercially available 4-fluoro-2-methoxybenzonitrile.
  • racemic 3- ⁇ 4-[4-[([1,4]dioxan-2-ylmethyl-methyl-amino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from racemic [4-[([1,4]dioxan-2-ylmethyl-methyl-amino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol and commercially available 4-fluoro-2-methoxybenzonitrile.
  • cyclopropyl-[5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl]-carbamic acid phenyl ester was obtained from [4-cyclopropylaminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol and commercially available 4-fluoro-2-methoxybenzonitrile.
  • the secondary cyclopropylamine reacted with phenyl chloroformate to give the cited phenyl carbamate.
  • 3- ⁇ 2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2,6-difluoro-phenyl4H-[1,2,4]oxadiazol-5-one was obtained from 3- ⁇ 2-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazole-5-one and 4,4-difluoro-piperidine hydrochloride.
  • 3- ⁇ 2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 2-fluoro-4-[4- ⁇ [(2-hydroxy-ethyl)-methyl-amino]-methyl ⁇ -2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 3- ⁇ 2-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl)-4H-[1,2,4]oxadiazole-5-one and 2-methylaminoethanol.
  • 3- ⁇ 2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 2-fluoro-4-[4-(4-methyl-piperazin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl) thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 3- ⁇ 2-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazole-5-one and 4-methyl-piperazine.
  • 3- ⁇ 2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 2-fluoro-4-[4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 3- ⁇ 2-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazole-5-one and morpholine.
  • 3- ⁇ 2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 2-fluoro-4-[4-[(4-fluoro-benzylamino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 3- ⁇ 2-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazole-5-one and 4-fluoro-benzylamine.
  • 3- ⁇ 2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 2-fluoro-4-[4-[(3-methylsulfanyl-propylamino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 3- ⁇ 2-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazole-5-one and 3-methylsulfanyl-propylamine.
  • 3- ⁇ 2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 2-fluoro-4-[4-[(4-methoxy-benzylamino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 3- ⁇ 2-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazole-5-one and 4-methoxy-benzylamine.
  • 3- ⁇ 2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 5-bromo-2-methoxy-4-[4-piperidin-1-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 3- ⁇ 2-methoxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 6 and piperidine.
  • the crude product was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 80/methanol 20) to give 164 mg of a 1/1 mixture of 3- ⁇ 5-fluoro-2-methoxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one and starting material which was used in the next step without further purification.
  • 3- ⁇ 5-fluoro-2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 5-fluoro-2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 3- ⁇ 5-fluoro-2-methoxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one and 4-trifluoromethyl-piperidine.
  • the solid was filtered and washed with ethyl acetate to give 0.48 g of a first crop of desired product as a white solid.
  • the filtrate was concentrated and recrystallized in methanol to provide an additional 0.19 g of desired product as a white solid.
  • the mother liquor was concentrated and purified by column chromatography on silica gel (heptane 1/ethyl acetate 3 then dichloromethane 95/methanol 5).
  • the crude product was purified by column chromatography on silica gel (gradient from heptane 4/ethyl acetate 1 to heptane 1/ethyl acetate 1) to give 180 mg of acetic acid 5-[3-fluoro-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester as a beige solid.
  • 3-(2-methoxy-4- ⁇ 2-(4-trifluoromethyl-phenyl)-4-[(3,3,3-trifluoro-propylamino)-methyl]-thiazol-5-ylmethoxy ⁇ -phenyl)-4H-[1,2,4]oxadiazol-5-one 3- ⁇ 4-[4-[(cyclopropylmethyl-amino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde and cyclopropylmethyl amine.
  • 3-(2-methoxy-4- ⁇ 2-(4-trifluoromethyl-phenyl)-4-[(3,3,3-trifluoro-propylamino)-methyl]-thiazol-5-ylmethoxy ⁇ -phenyl)-4H-[1,2,4]oxadiazol-5-one 3- ⁇ 4-[4-cyclobutylaminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde and cyclobutylamine.
  • 3- ⁇ 4-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 4-[4- ⁇ [bis-(2-hydroxy-ethyl)-amino]-methyl ⁇ -2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from methanesulfonic acid 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester and diethanolamine.
  • 3- ⁇ 4-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one 3- ⁇ 2-methoxy-4-[4-thiomorpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from methanesulfonic acid 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester and thiomorpholine.
  • 3- ⁇ 2-methyl-4-[4-propylaminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one in example 47 3- ⁇ 2-methyl-4-[4-[(2-pyrrolidin-1-yl-ethylamino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 5-[3-methyl-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde and N-(2-aminoethyl)pyrrolidine. The compound was obtained as its trifluoroacetate salt.
  • 3- ⁇ 2-methyl-4-[4-propylaminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one in example 47 3- ⁇ 2-methyl-4-[4-[(2-morpholin-4-yl-ethylamino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 5-[3-methyl-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde and N-(2-aminoethyl)-morpholine. The compound was obtained as its trifluoroacetate salt.
  • 3- ⁇ 2-methyl-4-[4-propylaminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one in example 47 3- ⁇ 2-methyl-4-[4-[(2-piperidin-1-yl-ethylamino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl ⁇ -4H-[1,2,4]oxadiazol-5-one was obtained from 5-[3-methyl-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde and 1-(2-aminoethyl)piperidine. The compound was obtained as its trifluoroacetate salt.

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UY29829A1 (es) 2007-04-30
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