WO2006091047A1 - Derives de thiazole utilises comme ligands ppar delta et processus de fabrication de ceux-ci - Google Patents

Derives de thiazole utilises comme ligands ppar delta et processus de fabrication de ceux-ci Download PDF

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WO2006091047A1
WO2006091047A1 PCT/KR2006/000663 KR2006000663W WO2006091047A1 WO 2006091047 A1 WO2006091047 A1 WO 2006091047A1 KR 2006000663 W KR2006000663 W KR 2006000663W WO 2006091047 A1 WO2006091047 A1 WO 2006091047A1
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formula
compound
group
atom
halogen
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PCT/KR2006/000663
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Heonjoong Kang
Jungyeob Ham
Hoosang Hwang
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Heonjoong Kang
Jungyeob Ham
Hoosang Hwang
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Priority to CA2599281A priority Critical patent/CA2599281C/fr
Priority to CN2006800090529A priority patent/CN101146784B/zh
Priority to BRPI0606232-6A priority patent/BRPI0606232A2/pt
Priority to US11/816,925 priority patent/US20090054493A1/en
Priority to JP2007556978A priority patent/JP5191744B2/ja
Priority to EP06716113A priority patent/EP1856072A4/fr
Priority claimed from KR1020060018360A external-priority patent/KR100797798B1/ko
Publication of WO2006091047A1 publication Critical patent/WO2006091047A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel thiazole derivatives represented by Formula I, as peroxisome proliferator-activated receptor ⁇ (PPAR ⁇ ) -activating ligands, which can be used for the treatment of obesity, hyperlipidemia, arteriosclerosis and diabetes, as well as their intermediates and preparation methods thereof:
  • PPAR ⁇ peroxisome proliferator-activated receptor ⁇
  • A is hydrogen, R 2 or " ORe
  • a peroxisome proliferator- activated receptor includes three subtypes: PPAR ⁇ , PPAR ⁇ , PPAR ⁇ ⁇ Nature, 1990, 347, p645-650., Proc. Natl. Acad. Sci. USA 1994, 91, p7335-7359).
  • PPAR ⁇ , PPAR ⁇ and PPAR ⁇ have functions distinguished according to in vivo tissues and are expressed in different sites.
  • PPAR ⁇ is expressed mainly in the human heart, kidneys, skeletal muscle and colon ⁇ Mol. Pharmacol. 1998, 53, pl4-22., Toxicol. Lett. 1999, 110, pll9- 127., J. Biol. Chem.
  • PPAR ⁇ is known to be expressed weakly in a skeletal muscle, but expressed largely in fat tissue, and thus involved in the differentiation of fat cells, the storage of energy in the form of fat, and the regulation of homeostasis of insulin and sugar ⁇ Moll. Cell. 1999, 4, p585-594., p597-609., p ⁇ ll-617).
  • PPAR ⁇ has been evolutionally conserved in Vertebrata, such as mammals, including human beings, rodents and Ascidiacea. Those found so far have been known as PPAR ⁇ in Xenopus laevis ⁇ Cell 1992, 68, p879-887), and as NUCI ⁇ Mol. Endocrinol. 1992, 6, pl634 ⁇ 1641), PPAR ⁇ (Proc. Natl. Acad. Sci. USA 1994, 91, p7355- 7359), NUCI ⁇ Biochem. Biophys . Res. Commun. 1993, 196, p671- 677), FAAR (J. Bio. Chem.
  • PPAR ⁇ is known to be present in chromosome 6 ⁇ 21. l-p21.2, whereas, in rats, the mRNA of PPAR ⁇ is found in the cells of various sites, but the amount thereof is shown to be lower than that of PPARcx and PPAR ⁇ ⁇ Endocrinology 1996, 137, p354-366., J. Bio. Chem. 1995, 270, p2367-2371., Endocrinology 1996, 131, p354-366) .
  • PPAR ⁇ is known to play an important in an expression process ⁇ Genes Dev. 1999, 13, pl561-1574. ) , and to perform physiological functions, including the differentiation of nervous cells in the central nervous system (CNS) (J. Chem. Neuroanat 2000, 19, p225-232), and wound healing by anti-inflammatory effect ⁇ Genes Dev. 2001, 15, p3263-3277., Proc. Natl. Acad. Sci. USA 2003, 100, p6295- 6296) .
  • CNS central nervous system
  • PPAR ⁇ is associated with the differentiation of fat cells and the metabolism of fat (Proc. Natl. Acad. Sci. USA 2002, 99, p303-308., MoJ.
  • PPAR ⁇ activates the expression of key genes associated with ⁇ -oxidation and uncoupling proteins (UCPs) associated with energy metabolism, in a fatty acid degradation process
  • UCPs ⁇ -oxidation and uncoupling proteins
  • PPAR ⁇ makes it possible to increase HDL levels and improve type II diabetes without changing bodyweight and (Proc. Natl. Acad. Sci. USA 2001, 98, p5306-5311., 2003, 200, pl5924-
  • the regulation of fat metabolism by PPAR ⁇ provides an important solution required to treat obesity, diabetes, hyperlipidemia and arteriosclerosis.
  • PPAR ⁇ LBD As a result of examining the crystal structure of PPAR ⁇ LBD in further detail, it consists of 13 ⁇ -helixes and 4 small ⁇ - strands, and its ligand-binding pocket is Y-shaped and has a size of about 1300 A 3 . It can be seen that the entrance of the ligand-binding pocket is about 100 A 2 in size, and its periphery consists of polar amino acids.
  • the binding assay of natural eicosapentaenoic acid (EPA) and synthetic ligand GW2433 showed that the Y473 amino acid at the AF-2 site of crystal structure of PPAR ⁇ makes a hydrogen bond with the carboxylic acid of the ligand (Proc. Natl. Acad. Sci.
  • a selective ligand developed in the first stage is L-631033 reported by the research team of Merk Co. (J. Steroid Biochem. MoI. Biol. 1997, 63, pl-8), in which the L-631033 ligand was made by introducing a functional group capable of fixing a side chain, based on the structure of natural fatty acids. Also, the same research team reported more effective ligand L-165041 (J. Med. Chem. 1996, 39, p2629-2654), which is a compound already known as a leukotriene agonist which acts also as an activator on human PPAR ⁇ .
  • This ligand was reported to be spatially well bound to the ligand-binding pocket, since it has a Y-shaped structure containing a benzene structure, unlike ligands developed so far. However, this ligand is a double-activating ligand showing activity also for hPPAR ⁇ and showed reduced selectivity for PPAR ⁇ .
  • PPAR ⁇ -selective ligand GW501516 [2- methyl-4-[ [ [4-methyl-2- [ 4- (trifluoromethyl) phenyl] -1, 3- thiazol-5-yl]methyl] sulfanyl] phenoxy] acetic acid) recently developed by Glaxo-Smith-Kline Co.
  • the ligand GW501516 had a very good affinity (1-10 nM) for PPAR ⁇ and showed a 1000-fold higher selectivity for PPAR ⁇ and
  • the present invention relates to novel thiazole derivatives represented by Formula I, as peroxisome proliferator-activated Receptor ⁇ (PPAR ⁇ ) -activating ligands, which can be used for the treatment of obesity, hyperlipidemia, arteriosclerosis and diabetes, as well as their intermediates and preparation methods thereof:
  • PPAR ⁇ peroxisome proliferator-activated Receptor ⁇
  • A is hydrogen, R 2 or ;
  • Ri is a hydrogen atom, a Ci- 4 alkyl group, a Ci_ 4 alkyloxy group, a Ci-4 alkylthioxy group, a Ci_ 4 alkylamine group, a fluorine atom or a chlorine atom;
  • M is an integer from 0 to 4;
  • R 2 is a phenol-protecting group selected from among C 1 - 4 lower alkyl groups, allyl groups, alkylsilyl groups, alkylarylsilyl groups and a tetrahydropyranyl group;
  • R 3 groups are different from each other and denote a hydrogen atom, a halogen atom, or a C 1 - 4 alkyl or alkoxy group substituted or unsubstituted with halogen;
  • N is an integer from 0 to 5;
  • R 5 is a hydrogen atom, a hydroxyl group or a Ci_ 4 alkyl group
  • Re is a carboxylic acid protecting group having C 1 -4 alkyl, an allyl group, a hydrogen atom or an alkali metal
  • Rn is an arylaminoalkyl group or an alkylaminoalkyl group
  • R 12 is a halogen atom, a cyano group, or a C 1 -4 alkyl or alkoxy group substituted or unsubstituted with halogen;
  • Ri 3 is a hydrogen atom, a halogen atom, a cyano group, a C x - 4 alkyl or alkoxy group substituted or unsubstituted with halogen;
  • o, p and q are each independently an integer from 1 to 5; and r is an integer from 1 to 9.
  • the thiazole derivative compounds according to the present invention include racemates or optical isomers represented by Formulas VI, VII and IX, and compounds of
  • Ri, R 3 to R 5 , m and n have the same meanings as described in Formula I above, and R ⁇ & is a carboxylic acid protecting group having a Ci_ 4 alkyl group, or an allyl group; [Formula X]
  • Ri, R 3 to R 5 , m and n have the same meanings as described in Formula I above, and R ⁇ b is a hydrogen atom or an alkali metal.
  • the thiazole derivative compounds of Formula X according to the present invention are characterized by having activity for a peroxisome proliferator-activated receptor ⁇ (PPAR ⁇ ) .
  • PPAR ⁇ peroxisome proliferator-activated receptor ⁇
  • the novel compounds according to the present invention can be prepared through the following reaction pathways.
  • the phenol group of a 4-halogen phenol compound of Formula II as a starting material is protected with an alkylsilyl group to obtain a compound of Formula III, which is substituted with lithium and allowed to react with sulfur and a compound of Formula IV to obtain a compound of Formula V.
  • the formula V compound is allowed to react various electrophilic compounds in the presence of a strong base to synthesize compounds of Formula VI, followed by removal of the silyl protecting group from the phenol group, thus obtaining compounds of Formula VII.
  • the phenol group of the formula II compound is protected with a Grignard reagent, and the halogen of the compound is substituted with lithium, and the resulting compound is allowed to react with sulfur and a compound of Formula IV to form thioether.
  • the formula VII compounds thus obtained are allowed to react with alkyl halogen acetate of Formula VIII in the presence of inorganic salt to synthesize compounds of Formula IX, followed by ester hydrolysis, so as to obtain compounds of Formula X.
  • the present invention has been completed.
  • Ri is a hydrogen atom, a C 1 -4 alkyl group, a C1-4 alkyloxy group, a Ci_ 4 alkylthioxy group, a C 1 -4 alkylamine group, a fluorine atom or a chlorine atom;
  • m is an integer from 0 to 4;
  • R. 2 is a phenol-protecting group selected from among C 1 - 4 lower alkyl groups, allyl groups, alkylsilyl groups, alkylarylsilyl groups and a tetrahydropyranyl group;
  • R 3 groups are different from each other and denote a hydrogen atom, a halogen atom, or a Ci- 4 alkyl or alkoxy group substituted or unsubstituted with halogen;
  • n is an integer from 0 to 5;
  • R 5 is a hydrogen atom, a hydroxyl group, or a Ci- 4 alkyl group
  • R 6 is a carboxylic acid protecting group having Ci_ 4 alkyl, allyl group, a hydrogen atom or an alkali metal;
  • Rn is an arylaminoalkyl group or an alkylaminoalkyl group;
  • Ri 2 is a halogen atom, a cyano group, or a Ci- 4 alkyl or alkoxy group substituted or unsubstituted with halogen
  • Ri 3 is a hydrogen atom, a halogen atom, a cyano group, or a Ci- 4 alkyl or alkoxy group substituted or unsubstituted with halogen
  • o, p and q are each independently an integer from 1 to 5
  • r is an integer from 1 to 9.
  • an object of the present invention is to provide novel PPAR ⁇ -activating ligands represented by Formula X, which can be used as agents for treating obesity, hyperlipidemia, arteriosclerosis and diabetes.
  • Another object of the present invention is to provide a method for preparing compounds of Formula VI, which comprises reacting a compound of Formula II with a phenol-protecting group to obtain a compound of Formula III, subjecting the formula III compound to halogen-lithium substitution, reacting the resulting compound with sulfur (S) and a compound of Formula IV without separation and purification so as to prepare a compound of Formula V, reacting the formula V compound with a strong base and then with various electrophilic compounds.
  • Still another object of the present invention is to provide a method for preparing compounds of Formula VII by removing the phenol-protecting group from the compounds of Formula VI .
  • Still another object of the present invention is to provide a method for preparing compounds of Formula VII through a single process in a convenient manner, the method comprising protecting the phenol group of a phenolic compound of Formula II with a Grignard reagent without conducting a special reaction for introducing a protecting group, subjecting the protected compound to halogen-to-lithium substitution, reacting the resulting compound with sulfur (S) and then with a compound of Formula IV to prepare a thioether compound, and reacting the thioether compound with a strong base and electrophilic compounds.
  • Still another object of the present invention is to provide a method for preparing compounds of Formula IX, comprising reacting the compounds of Formula VII with alkyl halogen acetate and inorganic salt.
  • Still another object of the present invention is to provide a method for preparing compounds of Formula X by hydrolyzing the ester compounds of Formula IX.
  • Ri denotes a hydrogen atom, a Ci- 4 alkyl group, a Ci- 4 alkyloxy group, a Ci_ 4 alkylthioxy group, a C 1 - 4 alkylamine group, a fluorine atom or a chlorine atom.
  • Each of Ri groups is at an ortho or meta position with respect to the phenol group, and the number (m) of R 1 groups is 0-4.
  • R 2 is a phenol-protecting group, such as C 1 - 4 lower alkyl, allyl, alkylsilyl or alkylarylsilyl such as trimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or tert-butyldimethylsilyl, or tetrahydropyranyl.
  • R 2 is a phenol-protecting group, such as C 1 - 4 lower alkyl, allyl, alkylsilyl or alkylarylsilyl such as trimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or tert-butyldimethylsilyl, or tetrahydropyranyl.
  • these protecting groups preferred is tert-butyl, tetrahydropyranyl, or a silylated protecting group.
  • R 3 groups are different from each other and denote a hydrogen atom, a halogen atom or a C 1 - 4 alkyl or alkoxy group substituted or unsubstituted with halogen, and the number (n) of R 3 groups is 0-5.
  • R 4 denotes , O' R " , O r
  • R 5 denotes a hydrogen atom, a hydroxyl group or a C ⁇ - 4 alkyl group.
  • R 6 is a carboxylic acid protecting group having a C 1 - 4 alkyl group (e.g., methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl or tert-butyl), an allyl, a hydrogen atom or an alkali metal (Li + , Na + , K + ) .
  • Rn is an arylaminoalkyl group, such as methyl pridinyl amino ethyl, methyl phenyl amino ethyl, or t-butyl phenyl amino ethyl, or an alkylaminoalkyl group, such as methyl amino ethyl, t-butyl amino ethyl or ethyl amino propyl.
  • Ri 2 is a halogen atom, a cyano group or a C 1 -4 alkyl or alkoxy group substituted or unsubstituted with halogen.
  • Ri 3 is a hydrogen atom, a halogen atom, a cyano group or a Ci- 4 alkyl or alkoxy group substituted or unsubstituted with halogen.
  • o, p and q are each independently an integer from 1 to 5.
  • r is an integer from 1 to 9.
  • Xi is a halogen atom, such as a bromine atom (Br) and a iodine atom (I) .
  • X 2 denotes a leaving group in nucleophilic reaction.
  • the leaving group conventional leaving groups can be used, for example, halogen atoms, such as chlorine, bromine or iodine, methanesulfonyloxy (MsO ' ) and p-toluenesulfonyloxy (TsO " ) .
  • halogen atoms such as chlorine, bromine or iodine
  • MsO ' methanesulfonyloxy
  • TsO " p-toluenesulfonyloxy
  • X 3 denotes a leaving group.
  • the leaving group conventional leaving groups, for example, halogens, methanesulfonyloxy (MsO " ) and p-toluenesulfonyloxy (TsO ⁇ ) , can be used.
  • the halogens include fluorine, chlorine, bromine and iodine. Among these leaving groups, preferred are halogens, and more preferred are chlorine, bromine and iodine .
  • X 4 denotes a halogen atom, such as chlorine (Cl) , bromine (Br) or iodine (I) .
  • the compounds of Formulas (I) and (II) and the electrophilic compounds, used as raw materials or intermediates in the preparation method according to the present invention, are known compounds which can be commercially easily available or easily prepared according to the literature.
  • a compound represented by Formula II is preferably allowed to react with a compound conventionally used as a phenol protecting group, in the presence of a base.
  • Non-protonic polar solvents which can be used in this step may include N 1 N-dimethylformamide, N, W-dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform and dichloromethane .
  • Ether solvents which can be used in this step may include tetrahydrofuran, dioxane, dimethoxyethane, diethyleneglycoldimethylether and triethyleneglycoldimethylether .
  • Aromatic hydrocarbons may include benzene, toluene and xylene. Among these solvents, preferred are non-protonic polar solvents, and more preferred are N,N-dimethylformamide, chloroform and dichloromethane .
  • Bases which can be used in this step include amine bases, such as pyridine, triethylamine, imidazole and N,N- dimethylaminopyridine, and if alkyl or allylether is used as the protecting group, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate will be used as the base.
  • amine bases such as pyridine, triethylamine, imidazole and N,N- dimethylaminopyridine
  • alkyl or allylether alkyl or allylether is used as the protecting group
  • sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate will be used as the base.
  • preferred bases are imidazole and potassium carbonate.
  • the tetrahydropyranyl-protecting group is obtained by reacting 3, 4-dihydro-2H-pyran with alkyl or allyltriphenylphosphonium bromide in the presence of a catalyst.
  • the reaction temperature may vary depending on the kind of solvent used, but is generally -10 to 80 0 C, and preferably 0 to room temperature (25 °C) .
  • the reaction time may vary depending on the reaction temperature and the kind of solvent used, but is generally 1 hour to 1 day, and preferably 4 hours or shorter.
  • a compound represented by Formula V is obtained in a single process by subjecting the compound of Formula III to halogen-to-lithium substitution, sulfur introduction and then reaction with a compound of Formula IV.
  • Anhydrous solvents which can be used in this step include diethylether, tetrahydrofuran, hexane, heptane and a mixture of two or more thereof.
  • the most preferred solvents are diethylether, tetrahydrofuran and a mixed solvent of diethylether and tetrahydrofuran.
  • Metal reagents which can be used in the halogen-to- metal substitution reaction include metals, such as lithium metal and magnesium metal, and organic metal reagents, such as n-butyllithium, sec-butyllithiuna and tert-butyllithium. Among these reagents, preferred are the organic metal reagents, and more preferred are n-butyllithium and tert- butyllithium.
  • the reaction temperature may vary depending on the kind of solvent used, but is generally -100 to 25 °C, and preferably -75 0 C to room temperature for the halogen-to- lithium substitution and the sulfur introduction reaction, and room temperature (25 0 C) for the reaction with the compound of Formula III.
  • the reaction time may vary depending on the reaction temperature and the kind of solvent used, but is generally 30 minutes to 4 hours, and preferably 1 hour or shorter.
  • a compound represented by Formula VI is obtained by treating the ⁇ -proton of thioether of the compound of Formula V with a strong base to prepare a nucleophile which is then allowed to react with various electrophilic compounds.
  • Anhydrous solvents which can be used in this step include diethylether, tetrahydrofuran, hexane, heptane, and a mixture of two or more thereof. Among these solvents, preferred solvents are diethylether, tetrahydrofuran and a mixed solvent of diethylether and tetrahydrofuran.
  • Strong base reagents which can be used in the alpha- hydrogen extraction reaction include potassium tert-butoxide (t-BuOK) , lithium diisopropylamide (LDA) , n-butyllithium, sec-butyllithium and tert-butyllithium. Among these reagents, the most preferred is tert-butyllithium.
  • the electrophilic compounds that react with the nucleophilic thioether compound are known compounds which can be commercially easily available or easily prepared according to the literature and contain halogen, aldehyde or ketone. These compounds are added for reaction after dissolution in anhydrous solvent or without dissolution.
  • the reaction temperature may vary depending on the kind of solvent used, but is generally -78 to 25 0 C.
  • the alpha-hydrogen extraction with the strong base is conducted at -75 0 C, and the electrophilic compounds are added at -75 0 C and reacted while elevating the temperature slowly to room temperature (25 °C) .
  • the reaction time may vary depending on the reaction step, but is 10-30 minutes for the alpha-hydrogen extraction with the strong base and 30-90 minutes for the reaction with the electroophilic compounds.
  • a compound of Formula VII is obtained by removing the phenol-protecting group from the compound of Formula VI.
  • Polar solvents which can be used in this step include N f iV-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethylacetate, carbon tetrachloride, chloroform and dichloromethane .
  • Ether solvents may include tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethylether .
  • Alcohol solvents may include methanol and ethanol.
  • Aromatic hydrocarbons may include benzene, toluene and xylene. Among these solvents, preferred are the polar solvents, and the most preferred is tetrahydrofuran.
  • Lewis acids such as trimethylsilyl iodide, sodium ethane thioalcohol, lithium iodide, aluminum halide, boron halide and trifluoroacetic acid are used to remove protecting groups, such as methyl, ethyl, tert-butyl, benzyl and allylether.
  • fluorides such as tetrabutylammonium fluoride (Bu 4 N + F-) , halogenic acids (fluoric acid, hydrochloric acid, bromic acid and iodic acid) , potassium fluoride are used to remove silylated protecting groups, such as trimethylsilyl, tert- butyldiphenylsilyl, triisopropylsilyl and tert- butyldimethylsilyl .
  • silylated protecting groups such as trimethylsilyl, tert- butyldiphenylsilyl, triisopropylsilyl and tert- butyldimethylsilyl .
  • the reaction temperature may vary depending on the kinds of deprotecting group and solvent used, but is generally 0-120 0 C and preferably 10-25 0 C.
  • the reaction time may vary depending on the reaction time, but is generally 30 minutes to 1 day, and preferably 2 hours or shorter.
  • Anhydrous solvents which can be used in this step include diethylether, tetrahydrofuran, hexane, heptane and a mixed solvent of two or more thereof.
  • diethylether, tetrahydrofuran or a mixed solvent of diethylether and tetrahydrofuran are preferred.
  • a Grignard reagent used is methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl magnesium chloride (R 2 MgCl) or alkyl magnesium bromide (R 2 MgBr) .
  • R 2 MgCl sec-butyl magnesium chloride
  • R 2 MgBr alkyl magnesium bromide
  • the most preferred is iso-propyl magnesium chloride (CH 3 JaCHMgCl).
  • the reaction temperature may vary depending on the kind of solvent used, but is generally -20 to 40 0 C, and preferably 0 0 C to room temperature (25 0 C) .
  • the reaction time may vary depending on the reaction temperature and the kind of solvent used, but is generally 10-60 minutes, and preferably 10-30 minutes.
  • Organic metal reagents which can be used in halogen-to- lithium substitution reaction include n-butyllithium, sec- butyllithium and tert-butyllithium. Among these metal reagents, preferred is tert-butyllithium.
  • S is preferably in the form of fine particle powder and is added for reaction after dissolution in an anhydrous tetrahydrofuran solvent or without dissolution.
  • the reaction temperature may vary depending on the kind of solvent used, but is generally -78 to 25 °C, and preferably -75 0 C for the halogen-to-metal substitution reaction, and room temperature (25 °C) starting from -75 °C for the sulfur introduction reaction.
  • the reaction temperature is 10-30 minutes for the halogen-to-metal substitution reaction and 30-90 minutes for the sulfur introduction reaction.
  • halogen in the formula IV compound include chlorine, bromine and iodine. Among these halogens, preferred is chlorine.
  • the reaction temperature may vary depending on the kind of solvent used, but is generally -78 °C to 25 0 C, and preferably 0 0 C to 10 0 C.
  • the reaction time is generally 10- 120 minutes, and preferably 10-60 minutes.
  • Strong bases which can be used to treat the ⁇ -proton of thioether to prepare nucleophilic compounds include potassium tert-butoxide (t-BuO ⁇ K + ) , lithium diisopropyl amide (LDA) , n- butyllithium, sec-butyllithium and tert-butyllithium.
  • t-BuO ⁇ K + potassium tert-butoxide
  • LDA lithium diisopropyl amide
  • n- butyllithium n- butyllithium
  • sec-butyllithium sec-butyllithium
  • tert-butyllithium is most preferable.
  • the electrophilic compound that reacts with nucleophilic thioether compounds is a known compound which is commercially easily available or easily prepared according to the literature and contains highly reactive halogen, aldehyde or ketone. This compound is added for reaction after dissolution in anhydrous solvent or without dissolution.
  • the reaction temperature may vary depending on the kind of solvent used, but is generally -78 to 25 0 C.
  • the alpha-hydrogen extraction with the strong base is carried out at -75 0 C, and the electrophilic compounds are added at - 75 °C and allowed to react while elevating the temperature to room temperature (25 0 C) .
  • the reaction time varies depending on the reaction step, but is 10-30 minutes for the alpha- hydrogen extraction with the strong base, and 30-90 minutes for the reaction with the electrophilic compounds.
  • Step F Preparation of compound represented by Formula IX
  • a compound represented by Formula VII is preferably allowed to react with halogen acetic acid alkyl ester in the presence of a base.
  • the halogen acetic acid alkyl ester is a known compound which is commercially easily available and in which the halogen is chlorine, bromine or iodine.
  • the most preferred example of the halogen acetic acid alkyl ester is bromoacetic acid methyl ester or bromoacetic acid ethyl ester.
  • Solvents which can be used in this step include water- soluble solvents, such as N, N-dimethylformamide, N, N- dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethanol and methanol, or a mixture of any one thereof with 1- 10% water.
  • water- soluble solvents such as N, N-dimethylformamide, N, N- dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethanol and methanol, or a mixture of any one thereof with 1- 10% water.
  • solvents the most preferred is a mixture of acetone or dimethylsulfoxide with 1-5% water.
  • the base used is not specifically limited regardless of a strong base or weak base as long as it does not adversely affects the reaction, and examples thereof include alkali metal hydrides, such as sodium hydride and lithium hydride, alkaline earth metal hydride such as potassium hydride, alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates, such as lithium carbonate, potassium carbonate, potassium hydrogen carbonate and cesium carbonate.
  • alkali metal hydrides such as sodium hydride and lithium hydride
  • alkaline earth metal hydride such as potassium hydride
  • alkali metal hydroxides such as sodium hydroxide and potassium hydroxide
  • alkali metal carbonates such as lithium carbonate, potassium carbonate, potassium hydrogen carbonate and cesium carbonate.
  • alkali metal carbonate preferred is alkali metal carbonate, and more preferred is potassium carbonate .
  • the reaction temperature is not specifically limited as long as it is below the boiling point of a solvent used, but a reaction at a relatively high temperature is preferably avoided in order to suppress side reactions.
  • the reaction temperature is generally 0-60 0 C.
  • the reaction temperature may vary depending on the reaction temperature, but is generally 30 minutes to 1 day, and preferably 30-90 minutes.
  • a compound represented by Formula X is prepared by hydrolyzing the carboxylic ester of the compound of Formula IX with a water-soluble inorganic salt in alcohol solvent.
  • Solvents which can be used in this step include water- soluble alcohol solvents, such as methanol and ethanol.
  • Bases which can be used in this step include about 0.1-3 N aqueous solutions prepared using alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide, according to the form of carboxylic acid alkali salts.
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • acetic acid or 0.1-3 ⁇ J hydrochloric acid aqueous solution is preferably used.
  • the reaction is preferably carried out at a relatively low temperature in order to inhibit side reactions, and is generally at 0 °C to room temperature.
  • the reaction time may vary depending on the reaction temperature, but is generally 10 minutes to 3 hours, and preferably 30 minutes to 1 hour.
  • Sep G-2 Preparation of compound represented by Formula X_
  • a compound represented by Formula X is prepared by substituting the allyl ester of the compound of Formula IX with a metal salt of 2-ethylhexanoate in an organic solvent in the presence of a metal catalyst.
  • the solvent used in this step is an anhydrous organic solvents, such as chloroform, dichloromethane or ethyl acetate. ⁇
  • palladium tetrakistriphenylphosphin is preferably used in an amount of 0.01-0.1 equivalent.
  • the reaction is preferably carried out at a relatively low temperature in order to inhibit side reactions, and is generally conducted at 0 °C to room temperature.
  • the reaction time may vary depending on the reaction temperature, but is generally 10 minutes to 3 hours, and preferably 30 minutes to 1 hour.
  • This salt compound is separated with high purity by centrifugation.
  • the obtained metal salt-type compound of Formula X is easier to separate than the salt-type compound prepared using the step G-I (hydrolysis step) .
  • the Y-shaped thiazole compounds of Formula X thus obtained are important substances as ligands for PPAR ⁇ . Also, these compounds have chiral carbon, and so stereoisomers thereof exist. Among the compounds of Formula X, R-form or S-form isomers are confirmed to be effective compared to racemates, and the scope of the present invention encompasses the compounds of Formula X, and their stereoisomers, solvates and salts.
  • the novel thiazole derivative compounds according to the present invention have the characteristics of PPAR ⁇ -activating ligands and show a high possibility to be used as agents for treating cardiovascular disease, lowering cholesterol levels and treating diabetes and obesity. Also, the inventive preparation method is useful for the preparation of the thiazole derivative compounds .
  • Example 4 Preparation of 5- [1- [3-methyl-4- ( tert- butyldimethylsilyloxy) phenylthio] -3-phenylpropyl] -2- [4- (trifluoromethyl) phenyl] -4-methylthiazole (VI) [Step C] In a nitrogen atmosphere, 510 mg (1.0 mmol) of 5- [4- ( tert-butyldimethylsilanyloxy) -3-methyl- phenylsulfanylmethyl] -4-methyl-2- [ (4-trifluoromethyl) phenyl] - thiazole prepared in Example 3 was dissolved in 20 ml of anhydrous tetrahydrofuran.
  • reaction solution was sufficiently cooled to -78 0 C, to which 1.2 ml (2.0 equivalents) of tert-butyllithium (1.7 M-heptane solution) was then slowly added. While the reaction solution maintained a deep blue color, 137 ⁇ l (1.0 mmol) of (2- bromoethyl) benzene was added thereto, and the reaction temperature was slowly elevated to room temperature. After reduction for an additional time of about 30 minutes, the reaction was terminated with aqueous ammonium chloride solution, and the reaction product was extracted wit ethyl acetate and aqueous salt solution, and the organic layer was dried over magnesium sulfate.
  • reaction product was extracted with aqueous ammonium chloride solution and ethyl acetate, and the organic layer was dried over magnesium sulfate. After filtration, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography, thus obtaining 306 mg (94 % yield) of the title compound.
  • Example 39 Preparation of 4- [2- (2-chloro-6- fluorophenyl) -1- [2- [4- (trifluoror ⁇ ethyl) phenyl] -A- methylthiazol-5-yl] ethylthio] -2-methylphenol (VII) from compound of Formula II [Step E]
  • 585 mg (2.5 mmol) of 4-iodo- 2-methylphenol was dissolved in 35 ml of anhydrous tetrahydrofuran and maintained at a temperature of 0 0 C.
  • 1.3 ml (1.0 equivalent) of isopropyl magnesium chloride (2 M-ether solution) was slowly added and the mixture was allowed to react for 10 minutes.
  • Test Example 1 Activity and cytotoxicity tests The compounds prepared in Examples were tested for PPAR ⁇ activity by a transfection assay. In addition, the compounds were tested for selectivity for PPAR ⁇ and PPAR ⁇ , the subtypes of PPARs, and also tested for toxicity by a MTT assay.
  • Transfection assay A transfection assay was performed using CV-I cells. The culture of the cells was performed using a DMEM medium (10% FBS, DBS (delipidated) and 1% penicillin/streptomycin) on a 96-well plate in a 5% carbon dioxide-containing incubator at 37 °C. The test was performed in four steps consisting of cell inoculation, transfection, treatment of the compounds, and analysis of results. Specifically, CV-I cells were inoculated onto a 96-well plate at a concentration of 5,000 cells/well, and after 24 hours, the cells were transfected.
  • DMEM medium % FBS, DBS (delipidated) and 1% penicillin/streptomycin
  • PPARs plasmid DNA full-length PPARs plasmid DNA, reporter DNA that has luciferase activity and thus allows the identification of PPARs, and ⁇ -galactosidase DNA that provides the information of transfection efficiency.
  • DMSO dimethylsulfoxide
  • the cells were cultured in an incubator for 24 and then lysed with lysis buffer. The lysed cells were measured for luciferase and ⁇ -galactosidase activities using a luminometer and a microplate reader. The measured luciferase values were normalized with the ⁇ - galactosidase values and graphed. From the graph, EC 50 values were determined.
  • MTT assay The compounds of Examples 47-97 according to the present invention were tested for cytotoxicity using a MTT assay.
  • MTT is a water-soluble yellow substance, but if it is introduced into living cells, it will be degenerated into a water-insoluble purple crystal due to dehydrogenase contained in mitochondria. If this substance is dissolved in dimethylsulfoxide and then measured for absorbance at 550 nm, cytotoxicity can be assayed.
  • the test method is as follows.
  • CV-I cells were first inoculated onto a 96-well plate at a concentration of 5,000 cells/well.
  • the inoculated cells were cultured in a 5% carbon dioxide-containing humidified incubator at 37 0 C for 24 hours, and then treated with the inventive compounds at various concentrations.
  • a MTT reagent was added to the cultured cells.
  • the resulting purple crystal was dissolved in dimethylsulfoxide and then measured for absorbance using a microplate reader. From the measured absorbance, cytotoxicity was assayed.
  • test results showed that most of the inventive compounds had no cytotoxicity even at a concentration of 90 ⁇ M.
  • the present invention provides novel thiazole derivatives as peroxisome proliferator-activated receptor ⁇
  • PPAR ⁇ PPAR ⁇ -activating ligands, which can be used for treatment of obesity, hyperlipidemia, arteriosclerosis and diabetes, as well as their intermediates and preparation methods thereof.
  • the present invention is useful to provide novel thiazole derivative compounds as PPAR ⁇ -activating ligands.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés dérivés de thiazole qui possèdent une activité pour le récepteur d (PPARd) activé par le proliférateur de peroxisome, ainsi que leurs intermédiaires et des techniques de synthèse de ceux-ci..
PCT/KR2006/000663 2005-02-25 2006-02-24 Derives de thiazole utilises comme ligands ppar delta et processus de fabrication de ceux-ci WO2006091047A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA2599281A CA2599281C (fr) 2005-02-25 2006-02-24 Derives de thiazole utilises comme ligands ppar delta et processus de fabrication de ceux-ci
CN2006800090529A CN101146784B (zh) 2005-02-25 2006-02-24 作为PPARδ配体的噻唑衍生物及其制造方法
BRPI0606232-6A BRPI0606232A2 (pt) 2005-02-25 2006-02-24 derivados de tiazole como os ligantes delta ppar e seus processos de produção
US11/816,925 US20090054493A1 (en) 2005-02-25 2006-02-24 Thiazole derivatives as ppar delta ligands and their manufacturing process
JP2007556978A JP5191744B2 (ja) 2005-02-25 2006-02-24 ペルオキシソーム増殖子活性化受容体デルタリガンドのチアゾール誘導体及びその製造方法
EP06716113A EP1856072A4 (fr) 2005-02-25 2006-02-24 Derives de thiazole utilises comme ligands ppar delta et processus de fabrication de ceux-ci

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KR10-2005-0015663 2005-02-25
KR20050015663 2005-02-25
KR1020060018360A KR100797798B1 (ko) 2005-02-25 2006-02-24 퍼록시솜 증식자 활성화 수용체 델타 리간드 티아졸 유도체및 그의 제조방법
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JP2010511604A (ja) * 2006-12-02 2010-04-15 ソウル ナショナル ユニバーシティー インダストリー ファンデーション ペルオキシソーム増殖因子活性化受容体リガンドアリール化合物及びこれらの化合物の用途
WO2012030165A2 (fr) 2010-08-31 2012-03-08 서울대학교산학협력단 Utilisation de la reprogrammation fœtale d'un agoniste des ppar δ
US20120197024A1 (en) * 2007-01-08 2012-08-02 Seoul National University Industry Foundation Thiazole Compound (as PPAR delta) Ligand and Pharmaceutical, Cosmetic and Health Food Comprised Thereof
EP2540711A1 (fr) * 2010-02-25 2013-01-02 SNU R & DB Foundation Dérivé de sélénazole ayant un ligand qui active le récepteur activé de la prolifération des peroxysomes (ppar), son procédé de préparation et utilisation des composés chimiques

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WO2000063153A1 (fr) * 1999-04-20 2000-10-26 Novo Nordisk A/S Nouveaux composes, preparation et utilisation de ces derniers
EP1092711A1 (fr) * 1998-07-01 2001-04-18 Takeda Chemical Industries, Ltd. Regulateurs du recepteur associe aux retinoides
WO2002062774A1 (fr) 2000-12-20 2002-08-15 Glaxo Group Limited Derives thiazole destines au traitement de troubles associes a des recepteurs ppar
WO2003072100A1 (fr) 2002-02-25 2003-09-04 Eli Lilly And Company Modulateurs du recepteur active du proliferateur des peroxysomes
KR20030086373A (ko) * 2002-05-04 2003-11-10 강헌중 티아졸 유도체의 제조방법 및 이를 제조하기 위한 중간체

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EP1092711A1 (fr) * 1998-07-01 2001-04-18 Takeda Chemical Industries, Ltd. Regulateurs du recepteur associe aux retinoides
WO2000063153A1 (fr) * 1999-04-20 2000-10-26 Novo Nordisk A/S Nouveaux composes, preparation et utilisation de ces derniers
WO2002062774A1 (fr) 2000-12-20 2002-08-15 Glaxo Group Limited Derives thiazole destines au traitement de troubles associes a des recepteurs ppar
WO2003072100A1 (fr) 2002-02-25 2003-09-04 Eli Lilly And Company Modulateurs du recepteur active du proliferateur des peroxysomes
KR20030086373A (ko) * 2002-05-04 2003-11-10 강헌중 티아졸 유도체의 제조방법 및 이를 제조하기 위한 중간체
WO2003106442A1 (fr) 2002-05-04 2003-12-24 Heonjoong Kang Procede pour l'elaboration de derive thiazole et composes intermediaires a cet effet

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010511604A (ja) * 2006-12-02 2010-04-15 ソウル ナショナル ユニバーシティー インダストリー ファンデーション ペルオキシソーム増殖因子活性化受容体リガンドアリール化合物及びこれらの化合物の用途
US8519145B2 (en) 2006-12-02 2013-08-27 Seoul National University Industry Foundation Aryl compounds as PPAR ligands and their use
US20120197024A1 (en) * 2007-01-08 2012-08-02 Seoul National University Industry Foundation Thiazole Compound (as PPAR delta) Ligand and Pharmaceutical, Cosmetic and Health Food Comprised Thereof
US8236831B2 (en) * 2007-01-08 2012-08-07 Seoul National University Industry Foundation Thiazole compound (as PPARδ) ligand and pharmaceutical, cosmetic and health food comprised thereof
US8431715B2 (en) 2007-01-08 2013-04-30 Seoul National University Industry Foundation Thiazole compound (as PPARδ) ligand and pharmaceutical, cosmetic and health food comprised thereof
EP2540711A1 (fr) * 2010-02-25 2013-01-02 SNU R & DB Foundation Dérivé de sélénazole ayant un ligand qui active le récepteur activé de la prolifération des peroxysomes (ppar), son procédé de préparation et utilisation des composés chimiques
EP2540711A4 (fr) * 2010-02-25 2014-01-22 Snu R&Db Foundation Dérivé de sélénazole ayant un ligand qui active le récepteur activé de la prolifération des peroxysomes (ppar), son procédé de préparation et utilisation des composés chimiques
WO2012030165A2 (fr) 2010-08-31 2012-03-08 서울대학교산학협력단 Utilisation de la reprogrammation fœtale d'un agoniste des ppar δ

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