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WO2008117982A1 - Dérivés d'acide carboxylique hétérocyclique et composition pharmaceutique les contenant pour inhiber l'accumulation des lipides - Google Patents

Dérivés d'acide carboxylique hétérocyclique et composition pharmaceutique les contenant pour inhiber l'accumulation des lipides Download PDF

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Publication number
WO2008117982A1
WO2008117982A1 PCT/KR2008/001682 KR2008001682W WO2008117982A1 WO 2008117982 A1 WO2008117982 A1 WO 2008117982A1 KR 2008001682 W KR2008001682 W KR 2008001682W WO 2008117982 A1 WO2008117982 A1 WO 2008117982A1
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Prior art keywords
methyl
carboxylic acid
benzyl
oxazol
ethoxy
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PCT/KR2008/001682
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English (en)
Inventor
Joong Myung Cho
Seonggu Ro
Dongkyu Shin
Young-Lan Hyun
Jun Hee Lee
Gyu Hwan Yon
Eun Bok Choi
Hyeon Kyu Lee
Chwang Siek Pak
Hyae Gyeong Cheon
Sang Dal Rhee
Won Hoon Jung
Heui Cheol Yang
So Hee Jo
Eunsil Lee
Jung Hee Im
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Korea Research Institute of Chemical Technology KRICT
CrystalGenomics Inc
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Korea Research Institute of Chemical Technology KRICT
CrystalGenomics Inc
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Publication of WO2008117982A1 publication Critical patent/WO2008117982A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a novel heterocyclic carboxylic acid derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient for inhibiting the lipid accumulation in the body.
  • PPARs peroxisome proliferating-activated receptors
  • PPARs which belong to the family of nuclear receptors are hormones that control the lipid level in the cell.
  • PPARs consist of 2nd zinc finger binding domain and a hydrophobic ligand binding pocket, and are divided into three subtypes, "PPAR ⁇ ,” “PPAR ⁇ ” and “PPAR ⁇ .”
  • PPAR ⁇ which is expressed in the muscle, heart, kidney, and particularly in the liver at a high level, controls the degradation of fatty acids.
  • PPAR ⁇ null mice Studies using PPAR ⁇ null mice have revealed that PPAR ⁇ is involved in the beta oxidation of long chain fatty acids such as palmitic acid present in mitochondria. Also, OEA(oleylethanolamide) which is effective in reducing the weight of normal mice, does not affect the weight of PPAR ⁇ null mice, suggesting that PPAR ⁇ is a target of OEA which controls the appetite and body weight.
  • the activation of PPAR ⁇ lowers the expression of apolipoprotein C-III which is known to inhibit the hydrolysis of TGs(triglycerides) by LDL(low density lipoprotein), leading to the degradation of VLDL(very low density lipoprotein) and lowering of the lipid content in the body.
  • the activation of PPAR ⁇ prevents arteriosclerosis by inhibiting the expression of VCAM(vascular cell adhesion molecule)- 1 to prevent arteriosclerosis, IL-linterleukin-l(interleukin-l)-induced secretion of IL-6(interleukin-6), or the production of prostaglandin in vascular smooth muscles.
  • PPAR ⁇ Compounds which have been previously found to promote the activity of PPAR ⁇ include Wy-14643, clofibrate, fenofibrate, bezafibrate, GW2331, SW9578 and BM17.0744(Willson et al, J. Med. Chem., 43, 527-550, 2000). These agonists of PP ARa bring about increased insulin sensitivity in mouse models by way of reducing the blood levels of TGs as well as suppressing the adiposity and steatosis of the liver or muscle(Chou et al, JBC, 277, 24484-24489, 2002; Kim et al, Diabetes, 52, 1770-1778, 2003; Peters et al, MoI. Cell.
  • ring A is a 4 to 6-membered heterocycle comprising 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
  • R 1 is a heterocyclic moiety selected from , ? an( j
  • R 2 and R 3 are each independently H, C r C 4 alkyl, or phenyl substituted with halogen, Ci-C 4 alkyl, or Ci-C 3 alkoxy;
  • X is H or Ci-C 4 alkyl;
  • m is 0, 1 or 2; and
  • n is 1 or 2.
  • a pharmaceutical composition for inhibiting the accumulation of lipids in the body comprising the heterocyclic carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the heterocyclic carboxylic acid derivative of the present invention may also be used in the form of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt may be a salt formed with an inorganic or organic base.
  • said inorganic base include alkali metal and alkaline earth metal hydroxides
  • examples of the organic base include ammonium hydroxide, organic amines such as methylamine, ethylamine and pyridine, guanidine, and arginine.
  • Preferred examples of the compounds of formula (1) according to the present invention are the compounds wherein ring A has a thiazolidine, azetidine, pyrrolidine, piperidine, morpholine or thiomorpholine structure.
  • heterocyclic carboxylic acid derivative of formula (1) of the present invention wherein m is 0; ring A is thiazolidine; and X is H(com ⁇ ound of formula Ia) may be prepared by the procedure shown in Reaction Scheme (I):
  • L is a leaving group such as Cl, Br, I 5 mesyl, or tosyl, or hydroxyl; and R 1 and n have the same meanings as defined in formula (1).
  • an alkyl or alcohol compound of formula 2 is allowed to react with a hydroxybenzaldehyde of formula 3 to obtain an alkoxy benzaldehyde of formula 4.
  • the compound of formula 2, in which L is a leaving group such as Cl, Br, I 5 mesyl, or tosyl, is subjected to an alkylation reaction in the presence of a base in a solvent.
  • the base include an inorganic base such as sodium hydride, potassium t-butoxide, butyl lithium, potassium carbonate, or sodium carbonate, and an organic base such as triethylamine, diisopropylethylamine, N-alkylmorpholine, or N-alkylpyrrolidine.
  • the solvent include dimethylformamide(DMF), tetrahydrofuran(THF), dioxane, or an alcohol such as methanol, ethanol, isopropanol or r-butanol, or a mixture thereof with water.
  • the reaction may be carried out at a temperature ranging from -20 to 100 0 C, and a quaternary amine halogen salt such as (Bu) 4 NI may be added thereto in a catalytic amount to enhance the reaction rate.
  • the compound of formula 4 is allowed to react with cysteine in an alcohol to obtain the inventive heterocyclic carboxylic acid derivative(compound of formula Ia).
  • cycteine is of the form of a hydrochloride salt
  • the reaction may be carried out in the presence of an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate, or an organic base such as triethylamine, using a solvent such as methanol, ethanol or tetrahydrofuran.
  • heterocyclic carboxylic acid derivative of formula (1) of the present invention wherein m is 1; ring A is a heterocyclic moiety; and X is H or C 1 -C 4 alkyl(the compound of formula Ic or Ib, respectively) may be respectively prepared by the procedures shown in Reaction Schemes (Ha) to (lie):
  • R 1 , R 2 , R 3 , n, and L have the same meanings as defined above.
  • the compounds of formulae Ib and Ic may be prepared by a process comprising the following steps: An aromatic aldehyde compound of formula 4 is subjected to reductive amination with a heterocyclic carboxylate of formula 5 in the presence of a reducing agent to obtain a carboxylic acid derivative of formula Ib.
  • the reducing agent used in this step may be sodium triacetoxyborohydride or sodium borohydride.
  • the compound of formula 5 is an acid addition salt
  • the above reaction may be conducted in the presence of an organic base such as triethylamine. Also, the reaction may be carried out at a temperature ranging from 0 to 40 "C , using a solvent such as dichloromethane, chloroform or dichloroethane.
  • the compound of formula Ib is then subjected to hydrolysis in the presence of a base to obtain the inventive heterocyclic carboxylic acid derivative of formula Ic.
  • the hydrolysis reaction may be conducted in the presence of an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate, or an organic base such as diisopropylethylamine, using a solvent such as water, an alcohol, e.g., methanol and ethanol, an ether, e.g., tetrahydrofuran, and a mixture thereof with water.
  • the compounds of formulae Ib and Ic may be prepared by a process comprising the following steps: An aromatic aldehyde compound of formula 4 is subjected to reductive reaction in the presence of a reducing agent to obtain a benzyl alcohol compound of formula 7.
  • the reducing agent which may be used in this reaction includes metal hydride such as sodium borohydride, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium or potassium alkoxyborohydride, DIBAL-H(diisobutylaluminum hydride), diborane, a metal salt thereof, or a mixture thereof.
  • the above reaction may be carried out at a temperature ranging from -20 to 100 ° C, using a solvent such as water, an alcohol, e.g., methanol and ethanol, an ether such as tetrahydrofuran, and a mixture thereof with water.
  • a solvent such as water, an alcohol, e.g., methanol and ethanol, an ether such as tetrahydrofuran, and a mixture thereof with water.
  • the compound of formula 7 thus obtained is then subjected to a reaction to convert the hydroxyl group to a leaving group such as Cl, Br, I, mesyl, or tosyl in a suitable solvent to obtain a substituted aromatic compound of formula 8.
  • the compound of formula 8 in which M is mesyl or tosyl may be prepared by treating the compound of formula 7 with methanesulfonyl chloride or 4-toluenesulfonyl chloride, in the presence of an inorganic base such as potassium carbonate or an organic base such as triethylamine, in benzene or dichloromethane. Subsequently, the compound of formula 8 is allowed to react with a heterocyclic carboxylate of formula 5 in the presence of a base to obtain the inventive heterocyclic carboxylic acid derivative of formula Ib.
  • an inorganic base such as potassium carbonate or an organic base such as triethylamine
  • the base may be an inorganic base such as sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, butyl lithium, potassium carbonate, and sodium carbonate, or an organic base such as triethyl amine, diisopropyl ethylamine, N-alkyl morpholine, and N-alkyl pyrrolidine.
  • the reaction may be carried out at a temperature ranging from -20 to 100 ° C, in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, an alcohol such as methanol, ethanol, isopropanol, and t-butanol, or a mixure thereof with water.
  • a quaternary amine halide such as (Bu) 4 NI may be added thereto in a catalytic amount to enhance the reaction rate.
  • the compound of formula Ib is hydrolyzed as described in the second step of Reaction Scheme (Ha) to obtain the inventive heterocyclic carboxylic acid derivative of formula Ic.
  • the compounds of formulae Ib and Ic may be prepared by a process comprising the following steps:
  • the hydroxybenzaldehyde of formula 3 is subjected to reductive amination by the procedure described in the first step of Reaction Scheme (Ha) to obtain a heterocyclic carboxylate of formula 9.
  • the procedure in the first step of Reaction Scheme (I) is repeated except for using the compound of formula 9 to obtain a heterocyclic carboxylic acid derivative of formula Ib, which was converted to the inventive heterocyclic carboxylic acid derivative of formula Ic by the procedure described in the second step of Reaction Scheme (Ha).
  • the inventive heterocyclic carboxylic acid derivative of formula (1) wherein m is 1; ring A is thiazolidine; X is H(compound of formula Id) may be preprared by the procedure shown in Reaction Scheme (III):
  • L is Cl, Br, I, mesyl, or tosyl
  • the compound of formula Id may be prepared by a process comprising the following steps: In case L of the compound of formula 2a is a leaving group, the procedure of the first step of Reaction Scheme (I) was repeated except for using hydroxyphenethylalcohol of formula 10 to obtain a phenethyl alcohol compound of formula 11, which is then treated with IBX(I -hydroxy- 1,2-benziodoxo 1-3 (lH)-one l-oxide(2-iodoxybenzoic acid)) in a solvent such as ethyl acetate at the boiling temperature of the solvent in accordance with a conventional method ⁇ ee Marco Frigerio et al, Journal of Organic Chemistry, 64(12), 4537-538(1999)) to obtain an aromatic aldehyde compound of formula 12. Subsequently, the compound of formula 12 is allowed to react with cycteine as in the second step of Reaction Scheme (I) to obtain the inventive heterocyclic carboxylic acid derivative
  • the inventive heterocyclic carboxylic acid derivative of formula (1) wherein m is 2; ring A is a heterocycle; and X is ⁇ or C 1 -C 4 alkyl(compound of formula If or Ie, respectively) may be prepared by repeating the procedure of Reaction Scheme (Ua) except for using an aromatic acetaldehyde compound of formula 12 as a starting material as shown in Reaction Scheme (IV): Reaction Scheme (IV)
  • X is C 1 -C 4 alkyl
  • R 1 , R 2 , R 3 , and n have the same meaning as defined in formula (1).
  • the formulation for administration may be prepared by mixing or diluting the inventive heterocyclic carboxylic acid derivative with a carrier, or sealing in a carrier in the form of a vessel. If the carrier is used as a diluent, it may be a vehicle, adjuvant or medium for active ingredient in the form of a solid, semi-solid, or liquid.
  • the formulation for administration may take various forms such as a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterilized injection, sterilized powder, or the like, and additionally include conventional additives such as a filler, anti-flocculation agent, lubricant, wetting agent, flavor, emulsifier, preservative, or the like.
  • the pharmaceutical composition of the present invention may also be formulated for fast, continuous or delayed release of an active ingredient after administration using conventional methods.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally as an active ingredient in an effective amount ranging from about 0.1 to 1000 mg/kg body weight per day, preferably from about 1 to 100 mg/kg body weight per day in a single dose or in divided doses in case of mammals including human.
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl ⁇ thiazolidine-4-carboxylic acid
  • Methanesulfonic acid-2-(benzoxazol-2-yl-methylamino)-ethyl ester(246 mg, 0.91 mmol) was dissolved in dimethylformamide(15 ml), and potassium carbonate(190 mg, 1.37 mmol) and 4-hydroxybenzaldehyde(110 mg, 0.91 mmol) were added thereto.
  • the resulting mixture was stirred at a temperature ranging from 90 to 100 ° C for 15 hrs, and then, 30 ml of ethyl acetate and a saturated aqueous NaHCO 3 were added thereto. Then, the resulting mixture was extracted with ethyl acetate(3 x 30 ml).
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(benzoxazol-2-yl-methylamino)-ethoxy]- phenyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 2(0.1 g, 0.34 mmol) and L-cysteine(0.042 g, 0.34 mmol) to obtain the title compound(0.082 g, yield: 61%).
  • Step 1 Preparation of 4-[2-(methylpyridin-2-yl-methylamino)-ethoxy]- benzaldehyde
  • Step 1 of Example 2 The procedure of Step 1 of Example 2 was repeated except for using methanesulfonic acid-2-(methyl-pyridin-2-yl-methylamino)-ethyl ester(209 mg, 0.91 mmol) and 4-hydroxybenzaldehyde(110 mg, 0.91 mmol) to obtain the title compo ⁇ md(185 mg, yield: 79%).
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(methyl-pyridin-2-yl-methylamino)-ethoxy]- phenyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 3(0.087 g, 0.34 mmol) and L-cysteine(0.042 g, 0.34 mmol) to obtain the title compound(0.089 g, yield: 73%).
  • Step 1 Preparation of 4-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 2-(5-methyl-2-(4-trifluoromethyl ⁇ henyl)-phenyloxazol-4-yl)ethanol(0.48 g, 1.76 mmol), 4-hydroxybenzaldehyde(0.215 g, 1.76 mmol), triphenylphosphine(0.46 g,
  • Step 2 Prepration of (R)-2- ⁇ 4-[2-(5-methyl-2-(4-trifluoromethyl ⁇ henyl)-oxazol-
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 4(0.1 g, 0.26 mmol) and L-cysteine(0.032 g, 0.26 mmol) to obtain the title compound(0.08 g, yield: 63%).
  • Step 1 Preparation of 4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] benzaldehyde
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] phenyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 5(0.1 g, 0.324 mmol) and L-cysteine(0.04 g, 0.324 mmol) to obtain the title compound(0.077 g, yield: 57%).
  • Step 1 Preparation of 3-[2-(5-methyl-2-/?-tolyloxazol-4-yl)ethoxy]benzaldehyde The procedure of Step 1 of Example 1 was repeated except for using
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 6(0.032 g, 0.09 mmol) and L-cysteine(0.012 g 5 0.09 mmol) to obtain the title com ⁇ ound(0.009 g, yield: 21%).
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 7(0.09 g, 0.287 mmol) and
  • Step 1 Preparation of 3-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl) ethoxy]benzaldehyde
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 8(0.06 g, 0.162 mmol) and L-cysteine(0.02 g, 0.162 mmol) to obtain the title com ⁇ ound(0.025 g, yield: 32%).
  • Step 1 Preparation of 3-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] benzaldehyde
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] phenyl ⁇ thiazolidine-4-carboxylic acid
  • the procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 9(0.06 g, 0.19 mmol) and L-cysteine(0.023 g, 0.19 mmol) to obtain the title compound(0.063 g, yield: 77%).
  • Step 2 Preparation of Preparation of (R)-2- ⁇ 3-[2-(5-methyl-2-/?-tolyl-oxazol-4-yl)- ethoxy] -phenyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 10(0.06 g, 0.19 mmol) and L-cysteine(0.023 g, 0.19 mmol) to obtain the title compound(8.9 mg, yield: 21%).
  • Step 1 Preparation of 3- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzaldehyde
  • Step 2 Preparation of (R)-3-(3- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-yl]-ethoxy ⁇ -benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • step 2 of Example 11 The compound obtained in step 2 of Example 11 was dissolved in methanol(7 ml), and lithium hydroxide(l 1 mg, 0.44 mmol) was added thereto. The resulting mixture was heated to reflux for 18 hrs. To the reaction product, water and ethyl acetate were sequentially added. To the resulting mixture, 1 N HCl was added until the reaction solution would become transparent. Then, the organic layer was separated, dried over magnesium sulfate, and distilled under reduced pressure to obtain the title compound(47 mg, yield: 44%).
  • Step 1 Preparation of 4- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzaldehyde
  • Step 1 of Example 11 The procedure of Step 1 of Example 11 was repeated except for using 4-hydroxybenzaldehyde(730 mg, 6 mmol) and methanesulfonic 2-[5-methyl-2-(4- trifluoromethylphenyl)-oxazol-4-yl]-ethyl ester(1.4 g, 4 mmol) to obtain the title compound(500 mg, yield: 33%).
  • Step 2 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(60 mg, yield: 17%).
  • Step 3 Preparation of 3-(4- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-4-carboxylic acid
  • Step 1 Preparation of 3-(4- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-2-carboxylic acid methyl ester
  • Example 11 was repeated except for using the resulting mixture to obtain the title compound(25 mg, yield: 7%).
  • Step 2 Preparation of 3-(4- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-2-carboxylic acid
  • the compound obtained in Step 1 of Example 13(25 mg, 0.05 mmol) was dissolved in methanol(5 ml).
  • the procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(10 mg, yield: 42%).
  • Step 1 Preparation of (R)-3-(3-hydroxy-benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid methyl ester
  • Step 1 Preparation of (R)-3-[3-(5-methyl-2-jo-tolyl-oxazol-4-ylmethoxy)-benzylj- thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[3-(5-methyl-2-/>-tolyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid 3-[3-(5-Methyl-2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid methyl ester(30 mg, 0.07 mmol) and lithium hydroxide(3.4 mg, 0.14 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg, yield: 100%).
  • Step 1 Preparation of (R)-3-[3-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[3-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid
  • the compound obtained in Step 1 of Example 16(30 mg, 0.06 mmol) and lithium hydroxide(2.9 mg, 0.12 mmol) were dissolved in methanol(7 ml).
  • the procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg, yield: 100%).
  • Step 1 Preparation of (R)-3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 1 Preparation of (R)-3-[3-(5-methyl-2-(-trifluoromethylphenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3- ⁇ 3-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-ylmethoxy]-benzyl ⁇ -thiazolidine-4-carboxy lie acid
  • Step 2 Preparation of (R)-3- ⁇ 3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 1 Preparation of 3-(4-hydroxy-benzyl)-thiazolidine-2-carboxylic acid methyl ester Thiazolidine-2-carboxylic acid methyl ester hydrochloride(1.22 g, 0.01 mol),
  • Step 2 Preparation of 3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 3 Preparation of 3-[4-(5-methyl-2- ⁇ henyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-[4-(5-methyl-2-j ⁇ -tolyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[4-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
  • Example 11 was repeated except for using the resulting mixture to obtain the title com ⁇ ound(29 mg 5 100%).
  • Step 1 Preparation of 3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 1 Preparation of 3-[4-(5-methyl-2-(-trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-2-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3- ⁇ 4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid methyl ester
  • the procedure of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol), 2-(2-biphenyl-4-yl-methyl-oxazol-4-yl)-ethanol(110 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(88 mg, yield: 43%).
  • Step 2 Preparation of 3- ⁇ 4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3- ⁇ 4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol),
  • Step 2 Preparation of 3- ⁇ 4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-(3-hydroxy-benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 3 Preparation of 3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy) ⁇ benzyl]-thiazolidine-2-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
  • Step 1 Preparation of 3- ⁇ 3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl ⁇ - thiazolidine-2-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
  • Step 2 Preparation of 3- ⁇ 3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl ⁇ - thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3- ⁇ 3-[2-(2-bi ⁇ henyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
  • Step 2 Preparation of 3- ⁇ 3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-(3- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-2-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
  • Step 2 Preparation of 3-(3- ⁇ 2-[5-methyl-2-(4-trifluoromethyl ⁇ henyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-2-carboxylic acid
  • Step 1 Preparation of (R)-3-(4-hydroxy-benzyl)-thiazolidine-4-carboxylic acid methyl ester (R)-thiazolidine-4-carboxylic acid methyl ester hydrochloride(1.47 g, 8 mmol), 4-hydroxybenzaldehyde(0.97 g, 8 mmol), sodium triacetoxyborohydride(2.54 g, 0.12 mol) and triethylamine(2.02 g, 0.012 mol) were dissolved in l,2-dichloromethane(50 ml). The procedure of Step 2 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(1.15 g, yield: 57%).
  • Step 2 Preparation of (R)-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)- benzyl] -thiazolidine-4-carboxylic acid methyl ester
  • Step 3 Preparation of (R)-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid
  • the procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(14 mg, yield: 100%).
  • Step 1 Preparation of (R)-3-[4-(5-methyl-2-p-toryl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[4-(5-methyl-2-/>-tolyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazoli dine-4-carboxylic acid
  • the compound obtained in Step 1 of Example 35(30 mg, 0.06 mmol) and lithium hydroxide(2.9 mg, 0.12 mmol) were dissolved in methanol(10 ml).
  • the procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(22 mg, yield: 76%).
  • Step 1 Preparation of (R)-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[4-(5-methyl-2-thio-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3-[4-(5-methyl-2-(trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[4-(5-methyl-2-(trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3- ⁇ 4-[2-(5-methyl-2- ⁇ henyl-4-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3- ⁇ 4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)- ethoxy] -benzyl ⁇ -thiazolidine-4-carboxy lie acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol), 2-(2-biphenyl-4-yl-methyl-oxazol-4-yl)-ethanol(112 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(20 mg, yield: 8%).
  • Step 2 Preparation of (R)-3- ⁇ 4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)- ethoxy]-benzyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3- ⁇ 4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol), 2-(5-methyl-thiophen-2-yl-oxazol-4-yl)-ethanol(84 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(17 mg, yield: 9%).
  • Step 2 Preparation of (R)-3- ⁇ 4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 2 Preparation of (S)-3-[3-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
  • Step 2 of Example 41 The procedure of Step 2 of Example 41 was repeated except for using the compound obtained in Step 1 of Example 41(64.7 mg, 0.48 mmol), 4-(5-methyl-2-p-toryloxazol-4-ylmethoxy)benzaldehyde(150 mg, 0.48 mmol), triethylamine(122 mg, 1.21 mmol) and sodium triacetoxyborohydride(154 mg, 0.72 mmol) to obtain the title compound(20.2 mg, yield: 9.7%).
  • Step 1 Preparation of (R)-3-[4-(3-j9-tolylisoxazol-5-ylmethoxy)benzyl]thiazolidine- 4-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.14 g, 0.56 mmol),(3-;?-torylisoxazol-5-yi)methanol(0.15 g, 0.62 mmol), triphenylphosphine(0.18 g, 0.71 mmol) and diisopropylazodicarboxylate(0.143g,
  • Step 1 Preparation of (R)-3-[4-(3-phenylisoxazol-5-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.097 g, 0.385 mmol),(3-phenylisoxazol-5-yl)methanol(0.075 g, 0.427 mmol), triphenylphosphine(0.128 g, 0.49 mmol) and diisopropylazodicarboxylate(0.099 g,
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 44(0.093 g, 0.227 mmol) and lithium hydroxide monohydrate(0.0143 g, 0.341 mmol) to obtain the title compound(0.08 g, yield: 88%).
  • Step 1 Preparation of (R)-3- ⁇ 4-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.163 g, 0.644 mmol),
  • Step 2 Preparation of (R)-3- ⁇ 4-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 45(0.1 g, 0.225 mmol) and lithium hydroxide monohydrate(0.014 g, 0.337 mmol) to obtain the title com ⁇ ound(0.098 g, yield: 98%).
  • Step 1 Preparation of (R)-3- ⁇ 4-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.14 g, 0.555 mmol), [3-(4-trifluoromethylphenyl)isoxazol-5-yl]methanol(0.15 g, 0.617 mmol), triphenylphosphine(0.186 g, 0.71 mmol) and diisopropylazodicarboxylate(0.143 g, 0.71 mmol) to obtain the title compound(0.09 g, yield: 35%).
  • Step 2 Preparation of (R)-3- ⁇ 4-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 46(0.081 g, 0.169 mmol) and lithium hydroxide monohydrate(0.011 g, 0.254 mmol) to obtain the title compound(0.046 g, yield: 60%).
  • Step 1 Preparation of (R)-3-[3-(3-j3-tolylisoxazol-5-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol), 3-(/?-tolylisoxazol-5-yl)methanol(0.15 g, 0.789 mmol), triphenylphosphine(0.258 g, 0.936 mmol) and diisopropylazodicarboxylate(0.2 g, 0.986 mmol) to obtain the title compound(0.12 g, yield: 36%).
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 47(0.077 g, 0.18 mmol) and lithium hydroxide monohydrate(0.0115 g, 0.275 mmol) to obtain the title compound(0.04 g 5 yield: 54%).
  • Step 1 Preparation of (R)-3-[3-(3-phenylisoxazol-5-ylmethoxy)benzyl]thiazolidine- 4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol),(3-phenylisoxazol-5-yl)methanol(0.14 g, 0.789 mmol), triphenylphosphine(0.258 g, 0.986 mmol) and diisopropylazodicarboxylate(0.2 g, 0.986 mmol) to obtain the title compound(0.15 g, yield: 47%).
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 48(0.06 g, 0.146 mmol) and lithium hydroxide monohydrate(0.092 g 5 0.219 mmol) to obtain the title compound(0.023 g 5 yield: 40%).
  • Step 1 Preparation of (R)-3- ⁇ 3-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl ⁇ - thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol),
  • Step 2 Preparation of (R)-3- ⁇ 3-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl ⁇ - thiazolidine-4-carboxylic acid
  • the procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 49(0.042 g, 0.094 mmol) and lithium hydroxide monohydrate(0.006 g, 0.142 mmol) to obtain the title compound(0.0158 g, yield: 39%).
  • Step 1 Preparation of (R)-3- ⁇ 3-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol), [3-(4-trifluoromethylphenyl)isoxazol-5-yl]methanol(0.19 g, 0.789 mmol), triphenylphosphine(0.258 g, 0.986 mmol) and diisopropylazodicarboxylate(0.2 g, 0.986 mmol) to obtain the title com ⁇ ound(0.2 g, yield: 53%).
  • Step 2 Preparation of (R)-3- ⁇ 3-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 50(0.2 g, 0.418 mmol) and lithium hydroxide monohydrate(0.026 g, 0.627 mmol) to obtain the title compound(0.14 g, yield: 71%).
  • Step 1 Preparation of (R)-2-isopropylthiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 51 The procedure of Step 1 of Example 51 was repeated except for using D-cysteine methyl ester hydrochloride(1.0 g, 5.82 mmol), potassium acetate(0.63 g,
  • Step 2 Preparation of (R)-2-isopropyl-3-[3-(5-methyl-2-p-tolyloxazol-4- ylmethoxy)-benzyl]thiazolidine-4-carboxylic acid
  • the procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 52(0.284 g, 1.5 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-/>-tolyloxazole(0.3 g, 0.92 mmol) and potassium carbonate(0.126 g, 0.915 mmol) to obtain the title compound(0.045 g, yield: 11%).
  • Step 1 of Example 51 The procedure of Step 1 of Example 51 was repeated except for using D-cysteine hydrochloride monohydrate(1.5 g, 8.54 mmol), potassium acetate(0.92 g,
  • Step 2 Preparation of (R)-3-[3-(5-methyl-2- j p-tolyloxazol-4-ylmethoxy)-benzyl]- 2-/>-tolyl-thiazolidine-4-carboxylic acid
  • Step 2 of Example 51 The procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 53(0.3 g, 0.92 mmol) and potassium carbonate(0.126 g, 0.915 mmol) to obtain the title compound(0.071 g, yield: 11%).
  • Step 1 Preparation of (R)-2-(4-chlorophenyl)thiazolidine-4-carboxylic acid
  • Step 1 of Example 51 The procedure of Step 1 of Example 51 was repeated except for using D-cysteine hydrochloride monohydrate(2 g, 10.77 mmol), potassium acetate(1.057 g> 10.77 mmol) and 4-chlorobenzaldehyde(1.514 g, 10.77 mmol) to obtain the title compound(1.8 g, yield: 65%).
  • Step 2 Preparation of (R)-2-(4-chlorophenyl)-3-[3-(5-methyl-2-p-tolyloxazol-4- ylmethoxy)-benzyl] -thiazolidine-4-carboxylic acid
  • Step 2 of Example 51 The procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 54(0.387 g, 1.5 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2- J p-tolyloxazole(0.3 g, 0.92 mmol) and potassium carbonate(0.126g, 0.915mmol) to obtain the title compound(0.11 g, yield: 23%).
  • Step 1 Preparation of (R)-2-(4-methoxyphenyl)thiazolidine-4-carboxylic acid
  • the procedure of Step 1 of Example 51 was repeated except for using D-cysteine hydrochloride monohydrate(1.4 g, 7.94 mmol), potassium acetate(0.857 g, 8.73 mmol) and 4-methoxybenzaldehyde(1.42 g, 10.45 mmol) to obtain the title compound(1.45 g, yield: 76%).
  • Step 2 Preparation of (R)-2-(4-methoxyphenyl)-3-[3-(5-methyl-2-jo-tolyloxazol-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
  • the procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 55(0.36 g, 1.5 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-/>-tolyloxazole(0.3 g, 0.92 mmol) and potassium carbonate(0.126 g, 0.915 mmol) to obtain the title compound(0.07 g, yield: 15%).
  • Step 1 Preparation of 2-[4-(5-methyl-2-j3-tolyloxazol-4-ylmethoxy)phenyl]ethanol 4-Chloromethyl-5-methyl-2-phenyloxazole(3.8 g, 17 mmol) and 4-hydroxyphenethyl alcohol(2 g, 14.5 mmol) were dissolved in acetone(50 ml), and potassium carbonate(3 g, 21.7 mmol) was added thereto. The resulting mixture was heated to reflux for 18 hrs. The reaction product was filtered and the filtrate was distilled under reduced pressure.
  • Step 2 Preparation of [4-(5-methyl-2-jc-tolyloxazol-4-ylmethoxy)phenyl] acetaldehyde
  • the compound obtained in Step 1 of Example 56(0.8 g, 2.4 mmol) was dissolved in ethyl acetate(20 ml), and IBX(o-Iodoxybenzoic acid; 2 g, 7.4 mmol) was added thereto. The resulting mixture was stirred at 80 °C for 4 hrs. After the completion of the reaction, the reactionproduct was filtered. The filtrate was distilled under reduced pressure to obtain the title compound(0.5 g, yield: 63%)
  • Step 3 Preparation of (R)-2-[4-methyl-2-p-tolyloxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
  • Step 1 Preparation of 2-[4-(5-methyl-2-(4-trifluoromethylphenyl)oxazol-4- y lmethoxy)pheny 1] ethanol
  • Step 2 Preparation of [4-(5-methyl-2-(4-trifluoromethylphenyl)oxazol-4- ylmethoxy)phenyl] acetaldehyde
  • Step 2 of Example 56 The procedure of Step 2 of Example 56 was repeated except for using the compound obtained in Step 1 of Example 57(2 g, 5.29 mmol) and IBX(4.45 g, 15.8 mmol) to obtain the title compound(1.56 g, yield: 70%).
  • Step 3 Preparation of (R)-2- ⁇ 4-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4- ylmethoxy]benzyl ⁇ thiazolidine-4-carboxylic acid
  • Step 3 of Example 56 The procedure of Step 3 of Example 56 was repeated except for using the compound obtained in Step 2 of Example 57(0.285 g, 0.75 mmol) and L-cysteine(0.092 g, 0.75 mmol) to obtain the title compound(0.273 g, yield: 75%).
  • Step 1 Preparation of 2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl]ethanol The procedure of Step 1 of Example 56 was repeated except for using
  • Step 2 Preparation of [4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl] acetaldehyde
  • the procedure of Step 2 of Example 56 was repeated except for using the compound obtained in Step 1 of Example 58(0.71 g, 2.3 mmol) and IBX(1.9 g, 6.87 mmol) to obtain the title compound(0.456 g 5 yield: 65%).
  • Step 3 Preparation of (R)-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
  • Step 3 of Example 56 The procedure of Step 3 of Example 56 was repeated except for using the compound obtained in Step 2 of Example 58(0.328 g, 1 mmol) and L-cysteine(0.13 g, 1 mmol) to obtain the title compound(0.25 g, yield: 57%).
  • Step 1 Preparation of 2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)phenyl] ethanol The procedure of Step 1 of Example 56 was repeated except for using
  • Step 2 Preparation of [4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)phenyl] acetaldehyde
  • the procedure of Step 2 of Example 56 was repeated except for using the compound obtained in Step 1 of Example 59(0.6 g, 1.8 mmol) and IBX(15 g, 5.637 mmol) to obtain the title compound(0.26 g, yield: 44%).
  • Step 3 Preparation of (R)-2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy) benzyl]thiazolidine-4-carboxylic acid
  • Step 3 of Example 56 The procedure of Step 3 of Example 56 was repeated except for using the compound obtained in Step 2 of Example 59(0.297 g, 0.94 mmol) and L-cysteine(0.115 g, 0.94 mmol) to obtain the title compound(0.18 g, yield: 45%).
  • Step 1 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-/»-tolyloxazol-4-ylmethoxy)phenyl] ethyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • the procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 56(0.15 g, 0.46 nimol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.085 g, 0.46 mmol), triethylamine(0.117 g, 1.16 mmol) and sodium triacetoxyborohydride(0.15 g, 0.7 mmol) to obtain the title compound(0.16 g, yield: 76%).
  • Step 2 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2- ⁇ -tolyloxazol-4-ylmethoxy) ⁇ henyl] ethyl ⁇ thiazolidine-4-carboxylic acid
  • Step 3 of Example 11 The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 60(0.17 g, 0.37 mmol) and lithium hydroxide monohydrate(0.186 g, 0.44 mmol) to obtain the title compound(0.118 g, yield: 72%).
  • Step 1 Preparation of (R)-3-(2- ⁇ 4-[5-methyl-2-(4-trifluoromethyl ⁇ henyl)oxazol- 4-ylmethoxy]phenyl ⁇ ethyl)thiazolidine-4-carboxylic acid methyl ester
  • the procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 58(0.284 g, 0.75 mmol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.06 g, 0.32 mmol), triethylamine(0.4 g, 1.89 mmol) and sodium triacetoxyborohydride(0.301 g, 1.13 mmol) to obtain the title compound(0.231 g, yield: 60%).
  • Step 2 Preparation of (R)-3-(2- ⁇ 4-[5-methyl-2-(4-trifluoromethyl ⁇ henyl)oxazol-4- ylmethoxy]phenyl ⁇ ethyl)thiazolidine-4-carboxylic acid
  • Step 3 of Example 11 The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 61(0.117 g, 0.23 mmol) and lithium hydroxide monohydrate(0.01 g, 0.277 mmol) to obtain the title compound(0.08 g, yield: 70%).
  • Step 1 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl] ethyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • Step 2 of Example 11 The procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 57(0.1 g, 0.32 mmol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.06 g, 0.32 mmol), triethylamine(0.082 g, 0.81 mmol) and sodium triacetoxyborohydride(0.103 g, 0.488 mmol) to obtain the title compound(0.097 g, yield: 68%).
  • Step 2 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl] ethyl ⁇ thiazolidine-4-carboxylic acid
  • Step 3 of Example 11 The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 62(0.096 g, 0.22 mmol) and lithium hydroxide monohydrate(0.01 g, 0.264 mmol) to obtain the title compound(0.032 g, yield: 34%).
  • Step 1 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy) phenyl]ethyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • the procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 59(0.261 g, 0.83 mmol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.06 g, 0.32 mmol), triethylamine(0.21 g, 2.08 mmol) and sodium triacetoxyborohydride(0.265 g, 1.25 mmol) to obtain the title compound(0.254 g, yield: 68%).
  • Step 2 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy) phenyl]ethyl ⁇ thiazolidine-4-carboxylic acid
  • Step 3 of Example 11 The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 63(0.255 g, 0.575 mmol) and lithium hydroxide monohydrate(0.03 g, 0.7 mmol) to obtain the title compound(0.18 g, yield: 73%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid
  • the procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 65(40.8 mg, 0.10 mmol) to obtain the title compound(35 mg, yield: 89%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3 -carboxylic acid
  • Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 66(42 mg, 0.10 mmol) to obtain the title compound(24.6 mg, 60%).
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxylic acid methyl ester
  • Step 1 of Example 64 The procedure of Step 1 of Example 64 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(4-methylphenyl)-oxazole(34.5 mg, 0.10 mmol) and (3S)-morpholine carboxylic acid methyl ester(15.3 mg, 0.10 mmol) to obtain the title compound(31.3 mg, yield: 70%).
  • Step 2 Preparation of (3S)-4-[3-(5-methyl-2-(4-methyl ⁇ henyl)-oxazol-4-yl- methoxy)benzyl] -morpholine-3 -carboxylic acid
  • Step 2 of Example 64 The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 67(31.3 mg, 0.07 mmol) to obtain the title compound(20 mg, yield: 69%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl] -morpholine-3 -carboxylic acid methyl ester
  • the procedure of Step 1 of Example 64 was repeated except for using
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-yl-methoxy)benzyl]-morpholine-3-carboxylic acid
  • the procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 68(50 mg, 0.10 mmol) to obtain the title compound(35 mg, yield: 74%).
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxylic acid methyl ester
  • Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 69(32.2 mg, 0.07 mmol) to obtain the title compound(25.3 mg, yield: 82%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzylj-morpholine-S-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid
  • Step 2 of Example 64 The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 70(50 mg, 0.12 mmol) to obtain the title compound(28 mg, yield: 62%).
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 64 was repeated except for using
  • Step 2 Preparation of (3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid
  • Step 2 of Example 64 The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 71(22 mg, 0.05 mmol) to obtain the title compound(13 mg, yield: 62%).
  • Step 1 Preparation of 4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- 3-thiomorpholinecarboxylic acid ethyl ester
  • Step 2 Preparation of 4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- 3-thiomorpholinecarboxylic acid
  • Step 1 Preparation of 4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-3- thiomorpholinecarboxylic acid ethyl ester
  • Step 1 of Example 72 The procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyl-oxazole(50 mg, 0.16 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(27.9 mg, 0.16 mmol) to obtain the title compound(43 mg, yield: 60%).
  • Step 2 Preparation of 4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-3- thiomorpholinecarboxylic acid
  • the procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 73(40 mg, 0.09 mmol) to obtain the title compound(34 mg, yield: 89%).
  • Step 1 Preparation of 4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxylic acid ethyl ester
  • Step 1 of Example 72 The procedure of Step 1 of Example 72 was repeated except for using 4-(4-chloromethylphenoxymethyl)-5-methyl-2-(4-methylphenyl)-oxazole(83.4 mg, 0.25 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(44.6 mg, 0.25 mmol) to obtain the title compound(82 mg, yield: 71%).
  • Step 2 Preparation of 4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl]-3-thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 74(42 mg, 0.09 mmol) to obtain the title compound(9 mg, yield: 23%).
  • Step 1 Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl]-3-thiomorpholinecarboxylic acid ethyl ester
  • Step 2 Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 75(64.5 mg, 0.14 mmol) to obtain the title compound(10 mg, yield: 17%).
  • 1 H NMR(200MHz, CDCl 3 ): ⁇ (ppm) 7.89(d, 2H 5 J 8.2Hz) 3 7.32-7.19(m, 3H), 7.03(s, IH), 7.03-6.88(m, 2H), 4.97(s, 2H), 3.97-3.71(m, IH), 3.60-3.58(m, 2H), 3.32(m, IH), 2.97-2.67(m, 3H), 2.58-2.53(m, 2H), 2.44(s, 3H), 2.39(s, 3H).
  • Step 1 Preparation of 4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiomorpholinecarboxylic acid ethyl ester
  • the procedure of Step 1 of Example 72 was repeated except for using
  • Step 2 Preparation of 4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl -methoxy)benzyl]-3-thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 76(27 mg, 0.05 mmol) to obtain the title compound(18.3 mg, yield: 74%).
  • Step 1 Preparation of 4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiomorpholinecarboxylic acid ethyl ester
  • the procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(7 6.3 mg, 0.20 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(35 mg, 0.20 mmol) to obtain the title compound(31 mg, yield: 30%).
  • Step 2 Preparation of 4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiornorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 77(31 mg, 0.059 mmol) to obtain the title compound(17 mg, yield: 58%).
  • Step 1 Preparation of 4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxylic acid ethyl ester
  • the procedure of Step 1 of Example 72 was repeated except for using
  • Step 2 Preparation of 4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]- 3 -thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 78(40 mg, 0.09 mmol) to obtain the title compound(22.6 mg, yield: 60%).
  • Step 1 Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxy lie acid ethyl ester
  • Step 1 of Example 72 The procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(2-thiophene)-oxazole(l 11 mg, 0.35 mmol)and 3-thiomorpholine carboxylic acid ethyl ester(61 mg, 0.35 mmol) to obtain the title compound(86 mg, yield: 54%).
  • Step 2 Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-3-thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 79(80 mg, 0.17 mmol) to obtain the title compound(61.2 mg, yield: 82%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3 -carboxylic acid
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid methyl ester
  • Step 1 of Example 64 The procedure of Step 1 of Example 64 was repeated except for using 4-(3-chloromethylphenoxyethyl)-5-methyl-2-phenyl-oxazole(35 mg, 0.11 mmol) and (3S)-morpholine carboxylic acid methyl ester(15.5 mg, 0.11 mmol) to obtain the title compound(43 mg, yield: 89%).
  • Step 2 Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid
  • Step 2 of Example 64 The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 81(40 mg, 0.09 mmol) to obtain the title compound(34.7 mg, yield: 89%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 64 was repeated except for using

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Abstract

La présente invention porte sur un nouveau dérivé d'acide carboxylique hétérocyclique ou sur un sel pharmaceutiquement acceptable de celui-ci, et sur une composition pharmaceutique comprenant celui-ci comme ingrédient actif pour inhiber l'accumulation de lipides dans le corps.
PCT/KR2008/001682 2007-03-28 2008-03-26 Dérivés d'acide carboxylique hétérocyclique et composition pharmaceutique les contenant pour inhiber l'accumulation des lipides Ceased WO2008117982A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010042925A3 (fr) * 2008-10-10 2010-07-29 Vm Discovery Inc. Compositions et méthodes pour traiter les troubles liés à la consommation d'alcool, la douleur et d'autres maladies
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2018167631A1 (fr) 2017-03-13 2018-09-20 Richter Gedeon Nyrt. Procédé de séparation d'isomères optiques d'esters éthyliques de l'acide 3-alkylpipéridine-carboxylique racémique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994001420A1 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Composes heterocycliques comme produits pharmaceutiques
WO1997031907A1 (fr) * 1996-02-28 1997-09-04 Glaxo Group Limited Derives d'acide 4-hydroxy-phenylalcanoique substitue possedant une activite agoniste envers ppar-gamma
WO2006018855A1 (fr) * 2004-08-20 2006-02-23 Cadila Healthcare Limited Nouveaux composes antidiabetiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994001420A1 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Composes heterocycliques comme produits pharmaceutiques
WO1997031907A1 (fr) * 1996-02-28 1997-09-04 Glaxo Group Limited Derives d'acide 4-hydroxy-phenylalcanoique substitue possedant une activite agoniste envers ppar-gamma
WO2006018855A1 (fr) * 2004-08-20 2006-02-23 Cadila Healthcare Limited Nouveaux composes antidiabetiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAIGH D. ET AL.: "Non-thiazolidinedione antihyperglycaemic agents. Part 3: the effect of stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids", BIOORG. MED. CHEM., vol. 7, 1998, pages 821 - 830 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010042925A3 (fr) * 2008-10-10 2010-07-29 Vm Discovery Inc. Compositions et méthodes pour traiter les troubles liés à la consommation d'alcool, la douleur et d'autres maladies
US8729081B2 (en) 2008-10-10 2014-05-20 Vm Discovery Inc. Compositions and methods for treating alcohol use disorders, pain and other diseases
EP2356109A4 (fr) * 2008-10-10 2012-05-30 Vm Discovery Inc Compositions et méthodes pour traiter les troubles liés à la consommation d'alcool, la douleur et d autres maladies
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2018167631A1 (fr) 2017-03-13 2018-09-20 Richter Gedeon Nyrt. Procédé de séparation d'isomères optiques d'esters éthyliques de l'acide 3-alkylpipéridine-carboxylique racémique
US11091436B2 (en) 2017-03-13 2021-08-17 Richter Gedeon Nyrt. Process for the separation of optical isomers of racemic 3-alkylpiperidine-carboxylic acid ethyl esters

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