WO2005040127A1 - Nouveaux composes agonistes de ppar$g(g) et ppar$g(a), leur methode de preparation et composition pharmaceutique les contenant - Google Patents

Nouveaux composes agonistes de ppar$g(g) et ppar$g(a), leur methode de preparation et composition pharmaceutique les contenant Download PDF

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WO2005040127A1
WO2005040127A1 PCT/KR2004/002729 KR2004002729W WO2005040127A1 WO 2005040127 A1 WO2005040127 A1 WO 2005040127A1 KR 2004002729 W KR2004002729 W KR 2004002729W WO 2005040127 A1 WO2005040127 A1 WO 2005040127A1
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benzyl
butyric acid
phenyl
methyl
mmol
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PCT/KR2004/002729
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English (en)
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Geun Tae Kim
Jong Sung Koh
Hee Oon Han
Seung Hae Kim
Kyoung-Hee Kim
Hee-Kyung Chung
Yeon Chul Kim
Misun Kim
Ki Dong Koo
Hyeon Joo Yim
Gwong-Cheung Hur
Sun Hwa Lee
Chang-Seok Lee
Sung Ho Woo
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Lg Life Sciences Ltd.
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/67—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • 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
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring

Definitions

  • the present invention relates to a novel compound as an agonist for peroxisome proliferator-activated receptor gamma (PPAR ⁇ ) and alpha (PPAR ⁇ ), processes of preparing the same, and pharmaceutical compositions containing the same as an active agent.
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ alpha
  • Diabetes mellitus has serious effects on people's health and accompanies various complications.
  • Type II diabetes mellitus accounts for 90% or more of total patients with diabetes mellitus.
  • Representative examples of complications accompanying diabetes include hyperlipidemia, obesity, hypertension, retinopathy and renal insufficiency (Paul Zimmer, et al., Nature, 2001, 414, 782).
  • Sulfonylureas (stimulating insulin secretion in pancreatic cells), biguanides (inhibiting glucose production in the liver), ⁇ -glucosidase inhibitors (inhibiting glucose absorption in the intestines), etc. have been used as agents to treat diabetes.
  • PPARy peroxisome proliferator-activated receptor gamma
  • Thiazolidinediones increasing insulin sensitivity
  • these drugs have side effects such as hypoglycemia, weight gain and the like (David E. Moller, Nature, 2001, 414, 821).
  • these agents raise concerns of inducing hypoglycemia. Accordingly, there is a strong need to develop diabetes therapeutic agents which can treat hyperglycemia and reduce complications of diabetes mellitus with decreased side effects, without inducing hypoglycemia and weight gain.
  • A is optionally substituted alkyl or cycloalkyl, optionally substituted aromatic or heteroaromatic, optionally substituted amine or amido, optionally substituted alkoxy, optionally substituted sulfonyl, or optionally substituted sulfanyl group;
  • B, D and X are each independently hydrogen, or optionally substituted lower alkyl group;
  • E is hydrogen, or optionally substituted lower alkyl or aromatic group.
  • the compound(s) of Formula 1 as an active agent for treatment of diseases is intended to include a pharmaceutically acceptable non-toxic salt, physiologically hydrolyzable ester, hydrate, solvate, isomer, or prodrug thereof.
  • pharmaceutically acceptable non-toxic salt means alkali metal salts, alkaline earth metal salts, salts of inorganic acids, salts of organic acids, salts with amino acids, etc.
  • the concrete examples of the pharmaceutical salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; and salts of organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid; or methanesulfonic acid or p-toluenesulfonic acid, and the like.
  • These acid addition salts can be prepared by known methods on the basis of the said Formula 1.
  • the compound of Formula 1 can also be treated with a base to form non-toxic salts, in which the base includes, for example, inorganic bases such as alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide), alkali metal hydrogencarbonates (for example, sodium bicarbonate, potassium bicarbonate), alkali metal carbonates (for example, sodium carbonate, potassium carbonate, calcium carbonate), etc. and amino acids.
  • inorganic bases such as alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide), alkali metal hydrogencarbonates (for example, sodium bicarbonate, potassium bicarbonate), alkali metal carbonates (for example, sodium carbonate, potassium carbonate, calcium carbonate), etc. and amino acids.
  • esters means a compound species of formula -(R) n - COOR' where R and R' are each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded via carbon of ring) and heteroalicyclic (bonded via a ring carbon), and n is 0 or 1.
  • hydrate means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound thereto by non-covalent intermolecular forces.
  • solvate means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound thereto by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans.
  • the term “isomer” means a compound of the present invention or a salt thereof, that has the same chemical formula or molecular formula but is optically or stereochemically different therefrom.
  • prodrug means an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug.
  • prodrug may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transport across a cell membrane, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell.
  • a further example of a prodrug might be a short peptide (polyamino acid) bonded to an active group, where the peptide is metabolized to release the active moiety.
  • substituent group(s) may be covalently bonded to the primary molecule or not.
  • the substituent group(s) is (are) one or more group(s) individually and independently selected from alkyl, cycloalkyl (including dicycloalky and tricycloakyl), perhaloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, alkoxyalkoxy, arylalkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-car
  • the substituent group(s) is(are) not limited thereto but is(are) intended to include a variety of substituents. In any case, the substituent group(s) could also be optionally substituted.
  • aromatic means an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • heterocyclic i.e., rings which share adjacent pairs of carbon atoms
  • alkyl means an aliphatic hydrocarbon group.
  • the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
  • the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
  • An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety may be branched, straight chain, or cyclic.
  • the term "lower alkyl” in the present disclosure means an alkyl having 1 to 20 carbon atoms, preferably 1 to 10 atoms, more preferably 1 to 6 atoms, which may also be optionally substituted.
  • the substituent "R”, as a designation used in the present disclosure, appearing by itself and without a number designation refers to a substituent selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl (bonded through a ring carbon), and optionally substituted heteroalicyclic (bonded through a ring carbon).
  • a “cyano” group refers to a -CN group.
  • An “isocyanato” group refers to a -NCO group.
  • a “thiocyanato” group refers to a -CNS group.
  • An “isothiocyanato” group refers to a -NCS group.
  • perhaloalkyl refers to an alkyl group in which all of the hydrogen atoms are replaced by halogen atoms.
  • Other terms used herein can be interpreted as having their usual meanings in the art to which the present invention pertains.
  • a in Formula 1 above is preferably selected from the below substitutents:
  • n is an integer of 1 to 3;
  • R 0 is a substituent having the below structure;
  • R 0 ', R 0 " and Ro'" are each independently hydrogen, halogen, or optionally substituted lower alkyl group; Ri and R 2 are each independently hydrogen, hydroxy group, optionally substituted lower alkyl group, or optionally substituted alkoxy group; wherein, n is an integer of 1 to 3; R 3 is a substituent having the below structure; Ra "
  • n is an integer of 0 to 2;
  • R ', R 3 " and R 3 '" are each independently hydrogen, halogen, or optionally substituted lower alkyl group;
  • n is an integer of 1 to 3;
  • R 4 is a hydrogen, optionally substituted aromatic or heteroaromatic group, and preferably, is selected from the below substitutents:
  • R 4 ', R ' and R '" are each independently hydrogen, halogen, or optionally substituted linear or branched lower alkyl group;
  • R 5 is hydrogen or optionally substituted lower alkyl group;
  • Z is O or S;
  • n is an integer of 1 to 3;
  • R 6 , R 7 , R 9 and R 10 are each independently hydrogen or lower alkyl group;
  • R 8 is hydrogen, or -OSO R, wherein R is hydrogen or optionally substituted lower alkyl or aromatic group;
  • n is an integer of 1 to 3 R ⁇ , R 12 and R 1 are each independently hydrogen, or optionally substituted lower alkyl; R 13 is hydrogen, optionally substituted lower alkyl, optionally substituted carboxylic group, or optionally substituted aromatic group;
  • n is an integer of 0 to 2, preferably 0;
  • R 15 is hydrogen, or optionally substituted lower alkyl or aromatic group;
  • R 16 is hydrogen or lower alkyl group
  • R 17 and R 18 are each independently hydrogen, halogen, or optionally substituted lower alkyl group
  • n is an integer of 1 to 3
  • R 19 is optionally substituted lower alkyl or aromatic group, preferably aromatic group
  • n is an integer of 1 to 3
  • R 2 o and R 1 is each independently hydrogen, halogen, or optionally substituted lower alkyl group
  • R 22 is hydrogen or lower alkyl
  • R 23 and R 24 are each independently hydrogen, optionally substituted lower alkyl group, optionally substituted carboxylic group, or optionally substituted aromatic group.
  • B, D and X are preferably each independently hydrogen or methyl.
  • the compounds of Formula 1 according to the present invention have an asymmetric center (asymmetric carbon atom), they can be present in the form of optical isomers such as enantiomer and partial stereoisomer. Furthermore, since the oxime structure in Formula 1 can be present in (E) or (Z)-form, the compounds of Formula 1 can have geometric isomers, of which the (E)-form isomer is more preferable. These optical isomers and geometric isomers are of course included in the range of the present invention.
  • the compounds of Formula 1 are compounds as defined below:
  • the compounds of Formula I above according to the present invention have different structure from known PPAR ⁇ and PPAR ⁇ accelarators and exhibit excellent accelerating effect to human PPAR ⁇ and PPAR ⁇ relating to the prevention and treatment of diabetes mellitus, diabetes mellitus-related diseases such as hyperlipidemia, arteriorsclerosis and the like, and inflammation, as will be seen in experimental examples later.
  • the present invention also relates to processes for preparation of the compounds of Formula 1.
  • a person skilled in the art could easily manufacture the compound of Formula 1 on the basis of the chemical structure thereof by various processes.
  • the compound of Formula 1 can be prepared by reacting the compound of Formula 2 with the compound of Formula 3 in the presence of base, as shwon in Reaction Scheme 1 below.
  • Reaction Scheme 1 Reaction Scheme 1
  • A, B, D, E, X and n are the same as defined in Formula 1, and LG is a leaving group.
  • the example of the leaving group means CI, -OSO 2 CH 3 , etc.
  • the reaction can be conducted in the presence of organic solvent, such as dimethylformamide, dimethylacetamide and acetonitrile and the like, and in some cases, two or more kinds of them can be used.
  • the typical examples of the base includes sodium hydroxide, potassium t-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium bis (trimethylsilyl) amide and the like, and in some cases, two or more kinds of them can be used.
  • the compound of Formula 2 in which Ro is not hydrogen is prepared by reacting hydrazine with enamine to obtain pyrrazole ester, and then reacting it with LAH to give alcohol, followed by halogenation thereof, as shown in Reaction Scheme 3 or 4.
  • R 0 and R t are the same as in Formula 1, Me means methyl, LAH means Lithium Aluminum Hydride, THF means Tetrahydrofuran, MsCl means Mefhanesulfonyl Chloride, and TEA means Triethylamine.
  • the compound in which A in Formula 2 is the substituent (ii) can be prepared by Reaction Scheme 5 below. Reaction Scheme 5
  • R 3 is the same as defined in Formula 1, Tr means Triphenylmethyl, and MsCl means Methanesulfonyl Chloride.
  • Tr means Triphenylmethyl
  • MsCl Methanesulfonyl Chloride.
  • An aromatic nifrile compound is reacted in the presence of hydroxylamine hydrochloride, sodium hydrogen carbonate, and ethanol or methanol to prepare an aromatic aldoxim.
  • the synthesized aldoxim is subjected to cyclization reaction with glycolic acid protected with frityl in the presence of carbodiimide to produce oxadiazole, then subjected to deprotection to synthesize oxadiazolyl methanol.
  • the synthesized alcohol compound is reacted with MsCl in the presence of base to produce a desired compound.
  • the compound in which A in Formula 1 is the substituent (iii) and Z is O can be prepared by Reaction Scheme 6 below as the known method (Koji Ando and Masanobu Suzuki WO99/50267).
  • Reaction Scheme 6 Fourthly, the compound in which A in Formula 1 is the substituent (iii) and Z is S can be prepared by Reaction Scheme 7 below as the known method (Chao, Esther, Yu-Hsuan et al. WO01/00603).
  • R 5 is the same as defined in Formula 1, Me means methyl, and Et means ethyl group.
  • the compound in which B is hydrogen, D is methyl and X is ethyl in Formula 3 can be prepared by Reaction Scheme 8 below as the known method (Roberto Antonioletti, Paolo Bovicelli and Savina Malacona, Tetrahedron, 2002, 58, 589). Reaction Scheme 8
  • the present invention provides a pharmaceutical composition for accelerating PPAR ⁇ and PPAR ⁇ comprising (a) a therapeutically effective amount of the compound of Formula 1, and (b) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof .
  • pharmaceutical composition as used herein means a mixture of a compound of the invention with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism.
  • compositions can also be obtained by reacting compounds with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • therapeutically effective amount means that amount of the compound being administered which will alleviate to some extent one or more of the symptoms of the disease being treated.
  • a therapeutically effective amount refers to that amount which has the effect of (1) reversing the rate of progress of a disease; (2) inhibiting to some extent or preferably, completely ceasing further progress of the disease; and/or, (3) alleviating to some extent (or, preferably, eliminating) one or more symptoms associated with the disease.
  • carrier means a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • Salts dissolved in buffered solutions are utilized as diluents in the art.
  • One commonly used buffered solution is phosphate buffered saline because it mimics the ionic strength conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • the compounds of Formula 1 can be administered in various pharmaceutical dosage forms in accordance with intended use.
  • an active agent more specifically the compound of Formula 1 may be mixed with one or more physiologically acceptable carriers which can be selected depending on the dosage form to be prepared.
  • the pharmaceutical composition according to the present invention can be formulated into dosage forms suitable for injection or oral administration.
  • the compound of Formula 1 may be formulated in a conventional manner using known physiologically acceptable carriers and excipients and presented in unit dosage form or in multi-dose containers.
  • the formulations may take such forms as solutions, suspensions or emulsions in oily or aqueous vehicles, and may contain conventional dispersing, suspending or stabilizing agents.
  • the active ingredient may be in powder form for reconstitution with sterile pyrogen-free water, before use.
  • the compound of Formula 1 may also be formulated into suppositories containing conventional suppository bases such as cocoa butter or other glycerides.
  • Solid dosage forms for oral administration include capsule, tablet, pill, powder and granule. Preferable dosage forms are capsule and tablet. It is preferable that tablets and pills be coated.
  • the solid dosage forms for oral administration may be obtained by mixing the compound of Formula 1 as an active agent with inactive diluents such as sucrose, lactose, starch and the like and carriers such as lubricant, for example magnesium stearate, including disintegrator, binder and the like. If necessary, the compound of Formula 1 and composition comprising the same according to the present invention may be administrated in combination with other pharmaceutical agents, for example, other diabetes treating agents.
  • the term "therapeutically effective amount” means an amount of active ingredients effective to alleviate, ameliorate or prevent symptoms of disease or decrease or delay the onset of clinical markers or symptoms of disease.
  • the therapeutically effective amount may be determined by experiments on the efficacy of compound as an active agent via in vivo and in vitro known model systems for diseases to be treated.
  • the compound of Formula 1 as an active agent can be preferably contained in an amount of about 0.1 ⁇ 1,000 mg unit dosage.
  • the dosage amount of the compound of Formula 1 will be dependent on the subject's weight and age, the nature and severity of the affliction and the judgment of the prescribing physician.
  • the dosage amount required will be in the range of about 1 to 1000 mg a day depending on the frequency and strength of the dosage.
  • a total dosage amount of about 1 ⁇ 500 mg a day will be sufficient. In some patients, the dosage amount in a day will be higher than that.
  • the present invention also provides a method for treating or preventing diseases involving human PPAR ⁇ and PPAR ⁇ by the use of effective amounts of the compound of Formula 1.
  • Diseases involving PPAR ⁇ and PPAR ⁇ mean the diseases which can be treated and prevented by activating human PPAR ⁇ and PPAR ⁇ , and include, for example, but are in no way limited to diabetes mellitus, complications associated with diabetes mellitus, inflammation, etc. Representative examples of the complications associated with diabetes mellitus are hyperlipidemia, arteriorasclerosis, obesity, hypertension, retinopathy, kidney inefficiency, etc.
  • the term “treating” means ceasing or delaying progress of diseases when the compound of Formula 1 or composition comprising the same is administered to subjects exhibiting symptoms of diseases.
  • the term “preventing” means ceasing or delaying symptoms of diseases when the compound of Formula 1 or composition comprising the same is administered to subjects exhibiting no symptoms of diseases, but having high risk of developing symptoms of diseases.
  • Preparation Example 12 ( ⁇ ) 3-isopropyloxyimino-2 ⁇ (4-hydroxy-benzy ⁇ )-butyric acid methyl ester. 133 mg (0.6 mmol) of the compound obtained in Preparation Example 10 (2), 110 mg (0.9 mmol) of isopropoxyamine hydrochloride, and 0.17 ml (1.2 mmol) of triethylamine were added to 5 ml of ethanol, then the resulting solution was reacted for 24 hours at 45°C. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto. The resulting solution was washed twice with 10 ml of water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent.
  • Preparation Example 14 ( ⁇ ) 3-[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)]- butyric acid methyl ester 222 mg (1.0 mmol) of the compound obtained in Preparation Example 10 (2) and 152 mg (1.1 mmol) of 4-fluorobenzyloxyamine were added to 10 ml of ethanol, then the resulting solution was reacted for 48 hours at room temperature. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto. The resulting solution was washed twice with 10 ml of water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent.
  • Preparation Example 15 ( ⁇ ) 3-[3-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)]- butyric acid methyl ester 160 mg (0.7 mmol) of the compound obtained in Preparation Example 10 (2) and 100 mg (0.7 mmol) of 3-fluorobenzyloxyamine were added to 5 ml of ethanol, then the resulting solution was reacted for 12 hours under reflux. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto. The resulting solution was washed twice with 10 ml of water and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent.
  • Preparation Example 17 ( ⁇ ) 3-[4-chlorobenzyloxyimino-2-(4-hydroxy-benzyl)]- butyric acid methyl ester 200 mg (0.9 mmol) of the compound obtained in Preparation Example 10 (2), 140 mg (0.9 mmol) of 4-chlorobenzyloxyamine, and 147 mg (1.8 mmol) of sodium acetate were added to 10 ml of methanol, then the resulting solution was reacted for 24 hours at room temperature. After the reaction, solvent was removed and 20 ml of ethylacetate was added thereto. The resulting solution was washed twice with 10 ml of water, and an organic layer was separated, followed by drying over magnesium sulfate and filtering to remove solvent.
  • Example 1 ( ⁇ ) 3-benzyloxyimino-2- ⁇ 4-[l-(phenyl)-5-methyl-lH-pyrrazole-4- ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 500 mg (2.6 mmol) of the compound obtained in Preparation Example 1 and 1.5 ml of (10.6 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, then the resulting solution was cooled to 0°C and 610 mg (5.3 mmol) of methane sulfonylchloride was added thereto. After 3 hours, an organic layer was separated by adding 10 ml of saturated sodium bicarbonate and then dried over sodium sulfate to remove solvent.
  • Example 2 ( ⁇ ) 3-benzyloxyimino-2- ⁇ 4-[l-(phenyl)-5-methyl-lH-pyrrazole-4- ylmethoxy]-benzyl ⁇ -butyric acid 5 mg (0.01 mmol) of the compound obtained in Example 1 was added to a mixture of 0.5 ml of tetrahydrofuran, 0.5 ml of methanol and 0.5 ml of 2N lithium hydroxide, and the resulting solution was reacted for 2 hours at room temperature. After the reaction, 0.5 ml of saturated ammonium chloride and 5 ml of ethylacetate were added thereto. An organic layer was separated and then dried over sodium sulfate, followed by filtering. Solvent was removed to obtain 4.2 mg (93 micromol) of the title compound in a yield of 93% yield. Mass(EI) 484(M + +1)
  • Example 4 ( ⁇ ) 3-benzyloxyimino-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH ⁇ pyrrazole-4 ⁇ ylmethoxy]-benzyl ⁇ -butyric acid 70 mg (0.13 mmol) of the compound obtained in Example 3 was added to a mixture of 2.5 ml of tetrahydrofuran, 2.5 ml of methanol and 2.5 ml of 2N lithium hydroxide, and the resulting solution was reacted for 2 hours at room temperature. After the reaction, 2.5 ml of saturated ammonium chloride and 20 ml of ethylacetate were added thereto. An organic layer was separated and dried over sodium sulfate, followed by filtering. Solvent was removed and the residue was purified by column chromatography to obtain 60 mg (113 micromol) of the title compound in a yield of 87%.
  • Example 5 ( ⁇ ) 3-methyloxyimino-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 5 ml of acetonitrile was added to 20 mg (0.08 mmol) of the compound obtained in Example 3 (1), then 33 mg (1.0 mmol) of cesium carbonate and 20 mg (0.08 mmol) of the compound obtained in Preparation Example 11 were further added thereto.
  • Example 5 in the same manner as in Example 4.
  • Example 7 ( ⁇ ) 3-isopropyloxyimino-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 5 ml of acetonitrile was added to 20 mg (0.08 mmol) of the compound obtained in Example 3 (1), then 33 mg (1.0 mmol) of cesium carbonate and 25 mg (0.086 mmol) of the compound obtained in Preparation Example 12 were further added thereto.
  • Example 8 ( ⁇ ) 3-isopropyloxyimino-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH-pyrazole-4- ylmethoxy] ⁇ benzyl ⁇ -butyric acid
  • the title compound was synthesized using 8 mg of the compound obtained in
  • Example 7 in the same manner as in Example 4.
  • Example 9 ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2- ⁇ 4-[l-(4 ⁇ isoburyl-phenyl)-lH- pyrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 5 ml of acetonitrile was added to 20 mg (0.08 mmol) of the compound obtained in Example 3 (1), then 33 mg (1.0 mmol) of cesium carbonate and 30 mg (0.09 mmol) of the compound obtained in Preparation Example 14 were further added thereto.
  • Example 10 ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH- pyrazzole-4-ylmethoxy]-benzyl ⁇ -butyric acid
  • the title compound was synthesized using 10 mg of the compound obtained in
  • Example 11 (+) 3-(3-fluorobenzyloxyimino)-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 5 ml of acetonitrile was added to 20 mg (0.08 mmol) of the compound obtained in Example 3 (1), then 33 mg (1.0 mmol) of cesium carbonate and 30 mg (0.09 mmol) of the compound obtained in Preparation Example 15 were further added thereto.
  • Example 12 ( ⁇ ) 3-(3-fluorobenzyloxyimino)-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH- pyrrazole-4-ylmethoxy] -benzy ⁇ -butyric acid
  • the title compound was synthesized using 10 mg of the compound obtained in
  • Example 11 in the same manner as in Example 4.
  • Example 13 ( ⁇ ) 3-(4-chIorobenzyloxyimino)-2- ⁇ 4-[l-(4-isobutyl-phenyl) ⁇ lH- pyrrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 5 ml of acetonitrile was added to 60 mg (0.26 mmol) of the compound obtained in Example 3 (1), then 140 mg (0.42 mmol) of cesium carbonate and 80 mg (0.21 mmol) of the compound obtained in Preparation Example 17 were further added thereto.
  • Example 14 ( ⁇ ) 3-(4-chlorobenzyloxyimino)-2 ⁇ 4 ⁇ [l-(4-isobutyI-phenyl)-lH- pyrrazole-4-ylmethoxy] -benzyl ⁇ -butyric acid
  • the title compound was synthesized using 10 mg of the compound obtained in
  • Example 13 in the same manner as in Example 4.
  • Example 15 (+) 3-(4-methylbenzyloxyimino)-2- ⁇ 4-[l-(4-methyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 5 ml of acetonitrile was added to 60 mg (0.26 mmol) of the compound obtained in Example 3 (1), then 140 mg (0.42 mmol) of cesium carbonate and 80 mg (0.21 mmol) of the compound obtained in Preparation Example 18 were further added thereto.
  • Example 16 ( ⁇ ) 3-(4-methylbenzyloxyimino)-2- ⁇ 4-[l-(4-methyl-phenyl)-lH- pyrrazole-4-ylmethoxy] -benzyl ⁇ -butyric acid
  • the title compound was synthesized using 10 mg of the compound obtained in
  • Example 15 in the same manner as in Example 4
  • Example 17 ( ⁇ ) 3-(2,4-difluorobenzyloxyimino)-2- ⁇ 4-[l-(4-isobutyl ⁇ phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 5 ml of acetonitrile was added to 120 mg (0.52 mmol) of the compound obtained in Example 3 (1), then 280 mg (0.84 mmol) of cesium carbonate and 170 mg (0.47 mmol) of the compound obtained in Preparation Example 16 were further added thereto.
  • Example 18 (+) 3-(2,4-difluorobenzyloxyimino)-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid
  • the title compound was synthesized using 110 mg of the compound obtained in Example 17 in the same manner as in Example 4.
  • Example 19 ( ⁇ ) 3-benzyloxyimino-2- ⁇ 4-[l-(4-chloro-phenyl)-lH-pyrrazole-4- ylmethoxy] -benzylj-butyric acid methyl ester 200 mg (0.96 mmol) of the compound obtained in Preparation Example 6 (3) and 0.27 ml (1.9 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.11 ml (1.4 mmol) of methane sulfonylchloride was added thereto.
  • Example 20 ( ⁇ ) 3-benzyloxyimino-2- ⁇ 4-[l-(4-chIoro-phenyl)-lH-pyrrazoIe ⁇ 4 ⁇ ylmethoxy]-benzyl ⁇ -butyric acid
  • the title compound was synthesized using 110 mg of the compound obtained in Example 19 in the same manner as in Example 4.
  • Example 21 ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2- ⁇ 4-[l-(4-chloro-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 200 mg (0.96 mmol) of the compound obtained in Preparation Example 6 (3) and 0.27 ml (1.9 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.11 ml (1.4 mmol) of methane sulfonylchloride was added thereto.
  • Example 22 ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2- ⁇ 4-[l-(4-chloro-phenyl)-lH- pyrrazole-4-ylmethoxy] -benzylj-butyric acid
  • the title compound was synthesized using 110 mg of the compound obtained in Example 21 in the same manner as in Example 4.
  • Example 24 ( ⁇ ) 3-benzyloxyimino ⁇ 2- ⁇ 4 ⁇ [l-(4-methyl-pheny ⁇ )-lH-pyrrazole-4- ylmethoxy]-benzyl ⁇ -butyric acid
  • the title compound was synthesized using 110 mg of the compound obtained in Example 23 in the same manner as in Example 4.
  • Example 25 ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2- ⁇ 4-[l-(4-methyl-phenyl)-lH- pyrrazole-4-ylmethoxy] -benzyl ⁇ -butyric acid
  • 150 mg (0.8 mmol) of the compound obtained in Preparation Example 7 and 0.33 ml (2.4 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.09 ml (1.2 mmol) of methane sulfonylchloride was further added thereto.
  • Example 27 ( ⁇ ) 3-benzyloxyimino-2- ⁇ 4-[l-(3,5-ditrifluoromethyl-phenyl)-lH- pyrrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 100 mg (0.32 mmol) of the compound obtained in Preparation Example 8 and 0.09 ml (0.64 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.04 ml (0.48 mmol) of methane sulfonylchloride was added thereto.
  • Example 28 ( ⁇ ) 3-fluorobenzyloxyimino-2- ⁇ 4-[l-(3,5-ditrifluoromethy-phenyl)- lH-pyrrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid
  • the title compound was synthesized using 20 mg of the compound obtained in
  • Example 27 in the same manner as in Example 4.
  • Example 29 ( ⁇ ) 3-(4-fluoro-benzyloxyimino-2- ⁇ 4-[l-(phenyl) ⁇ 5-methyl-lH- pyrrazole-3-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 146 mg (0.65 mmol) of the compound obtained in Preparation Example 2 (2) and 0.18 ml (1.3 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.08 ml (0.97 mmol) of methane sulfonylchloride was added thereto.
  • Example 30 ( ⁇ ) 3-(4-fluoro-benzyloxyimino)-2- ⁇ 4-[l-(phenyl)-5-methyl-lH- pyrrazole-3-ylmethoxy]-benzy ⁇ -butyric acid
  • the title compound was synthesized using 50 mg of the compound obtained in Example 29 in the same manner as in Example 4.
  • Example 31 ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2- ⁇ 4-[l-(4-isobutyl-phenyl)-5-ethyl- lH-pyrrazole-3-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 30 mg (0.12 mmol) of the compound obtained in Preparation Example 3 (3) and 0.05 ml (0.35 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.014 ml (0.18 mmol) of methane sulfonylchloride was added thereto.
  • Example 32 ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2- ⁇ 4-[l-(4-isobutyl-phenyl)-5-ethyl- lH-pyrrazole-3-ylmethoxy]-benzyl ⁇ -butyric acid
  • the title compound was synthesized using 20 mg of the compound obtained in Example 31 in the same manner as in Example 4.
  • Example 33 (+) 3-(4-fluoro-benzyloxyimino)-2- ⁇ 4-[l-(4-isobutyl-phenyl)-5-propyl- lH-pyrrazole-3-ylmethoxy]-benzyl ⁇ -butyric acid methyl ester 33 mg (0.13 mmol) of the compound obtained in Preparation Example 4 (3) and 0.05 ml (0.35 mmol) of triethylamine were dissolved in 5 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 0.014 ml (0.18 mmol) of methane sulfonylchloride was added thereto.
  • Example 35 ( ⁇ ) 3-benzyloxyimino-2- ⁇ 4-[l-(phenyl)-5-methyl-lH-pyrrazole-4- ylmethoxy] -benzyl ⁇ -butyric acid methyl ester 110 mg (0.54 mmol) of the compound obtained in Preparation Example 9 (3) and 0.15 ml (1.1 mmol) of triethylamine were dissolved in 10 ml of methylene dichloride, then the resulting solution was cooled to 0°C, and 50 ⁇ l (0.65 mmol) of methane sulfonylchloride was added thereto.
  • Example 36 ( ⁇ ) 3-benzyloxyimino-2- ⁇ 4-[l-(phenyl)-5-methyl-lH-pyrrazole-4- ylethoxy]-benzyl ⁇ -butyric acid 5 mg (0.01 mmol) of the compound obtained in Example 35 was added to a mixture of 0.5 ml of tetrahydrofuran, 0.5 ml of methanol and 0.5 ml of 2N lithium hydroxide, and the resulting solution was reacted for 2 hours at room temperature. After the reaction, 0.5 ml of saturated ammonium chloride and 5 ml of ethylacetate were added thereto. An organic layer was separated and then dried over sodium sulfate, followed by filtering. Solvent was removed to give 4.0 mg (84 micromol) of the title compound in a yield of 84%. Mass(EI) 498(M + +1)
  • Example 37 (+) 3-benzyloxyimino-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH-pyrrazole-4- ylmethoxy]-benzyl ⁇ -2-methyl-butyric acid methyl ester 24 mg (0.10 mmol) of the compound obtained in Preparation Example 5 (3) was dissolved in 5 ml of acetonitrile, and 40 mg (0.12 mmol) of cesium carbonate and 34 mg (0.10 mmol) of the compound obtained in Preparation Example 19 (2) were added the resulting solution.
  • Example 38 ( ⁇ ) 3-benzyloxyimino-2- ⁇ 4-[l-(4-isobutyl-phenyl)-lH-pyrrazole-4- yhnethoxy] ⁇ benzyl ⁇ -2-methyl ⁇ butyric acid
  • the title compound was synthesized using 10 mg of the compound obtained in Example 37 in the same manner as in Example 4.
  • Example 40 ( ⁇ ) 2-(benzyloxyimino-methyI)-3-(4- ⁇ 2-[l-(4-isopropyl-phenyl)-lH- pyrrazole-4-yl]-ethoxy ⁇ -phenyl)-propionic acid 2.5 mg of the title compound was obtained from 3 mg of compound of Example
  • Preparation Example 25 ( ⁇ ) 3-propyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 24 (2) and 176 mg (2.5 mmol) of propyloxyamine hydrochloride were added to 5 ml of methanol, and the resulting solution was reacted at room temperature for 24 hours. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water. An organic layer was separated and then dried over magnesium sulfate to obtain 591 mg (2.1 mmol) of the title compound at 96% yield.
  • Preparation Example 27 ( ⁇ ) 3-[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyI)]- butyric acid methyl ester 222 mg (1.0 mmol) of the compound obtained in Preparation Example 25 (2) and 152 mg (1.1 mmol) of 4-fluorobenzyloxyamine were added to 10 ml of ethanol, and the resulting solution was reacted at room temperature for 24 hours. After the reaction, solvent was removed and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water.
  • Example 41 ( ⁇ ) 3-ethoxyimino-2-[4-(3-tolyl-[l,2,4]oxadiazole-5-ylmethoxy)- benzyl]-butyric acid (1) Preparation of 3-ethoxyimino-2 ⁇ [4-(3 ⁇ toIyl-[l,2,4]oxadiazole-5-yImethoxy)- benzylj-butyric acid methyl ester 20 mg (0.10 mmol) of the compound obtained in Preparation Example 20 (3) was dissolved in 1 ml of dichloromethane, and 44 ⁇ l (0.31 mmol) of triethyl was added thereto.
  • Example 42 ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2-[4-(3-tolyl-[l,2,4]oxadiazole -5- ylmethoxy)-benzyl]-butyric acid (1) Preparation of ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2-[4-(3-tolyI-
  • Example 46 ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2-[4-(3-4-trifluoromethylphenyl)- [l,2,4]oxadiazole-5-ylmethoxy]-benzyl]-butyric acid 23 mg (0.04 mmol, yield: 36%) of ( ⁇ ) 3-(4-fluorobenzyloxyimino)-2-[4-(3-(4- trifluoromethylphenyl)-[l ,2,4]oxadiazole-5-ylmethoxy)-benzyl]-butyric acid methyl ester was synthesized using [3-(4-trifluoromethyl-phenyl)-[l,2,4]oxadiazole-5-yl]- methanol (30 mg, 0.122 mmol) obtained in Preparation Example 23 (3) and ( ⁇ ) 3-[4- fluorobenzyloxyimino-2-(4-hydroxy-benzyl)]-butylic acid methyl ester (
  • Example 47 ( ⁇ ) 3-ethoxyimino-2-[4-(3-tolyl-[l,2,4]oxadiazole-5-ylmethoxy)- benzyl]-pentanoic acid 15 mg (yield: 45%) of ( ⁇ ) 3-ethoxyimino-2-[4-(3-tolyl-[l,2,4]oxadiazole-5- ylmethoxy)-benzyl]-pentanoic acid methyl ester was synthesized using ( ⁇ ) 2-(4- hydroxy-benzyl)-3-methoxyimino-pentanoic acid methyl ester (20 mg, 0.096 mmol) obtained in Preparation Example 29 and (3-p-tolyl-[l,2,4]oxadiazole-5-yl)-methanol (20 mg, 0.077 mmol) obtained in Preparation Example 20 (3) in the same manner as in Example 44 (1).
  • Preparation Example 32 2- [2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl] -ethanol (1)
  • 2-(4-fluoro-benzoylamino)-succinic acid 4-methyl ester 7.8 g (yield: 100%) of the title compound was synthesized using 5 g (27.2 mmol) of 2-amino-succinic acid 4-methyl ester hydrochloride and 4.53 g (28.5 mmol) of 4-fluorobenzoic chloride in the same manner as in Preparation Example 31 (1).
  • Preparation Example 34 2-(5-methyl-2-thiopen-2-yl-oxazole-4-y ⁇ )-ethanol 207 mg (yield of three steps: 18%) of the title compound was obtained using 1 g (5.44 mmol) of 2-amino-succinic acid 4-methyl ester hydrochloride according to the method of Preparation Examples 31 (1), 32 (2), 33 (3) and 34 (4).
  • Preparation Example 39 ( ⁇ ) 3-propyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 276 mg (2.5 mmol) of n-propoxy amine hydrochloride, and 406 mg (4.9 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed, and 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water.
  • Preparation Example 40 ( ⁇ ) 3-butyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 311 mg (2.5 mmol) of n-butoxyamine hydrochloride and 406 mg (4.9 mmol) of sodium acetate were added to 10 ml of methanol and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed and 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water.
  • Preparation Example 41 ( ⁇ ) 3-(2-fluoro-ethyloxyimino)-2-(4-hydroxy-benzy ⁇ )- butyric acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 286 mg (2.5 mmol) of 2-fluoroethoxyamine hydrochloride, and 406 mg (4.9 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed and 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water.
  • Preparation Example 43 ( ⁇ ) 3-isopropoxyimino-2-(4 ⁇ hydroxy-benzyl)-butylic acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 276 mg (2.5 mmol) of isopropoxyamme hydrochloride, and 406 mg (4.9 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed, and 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water.
  • Preparation Example 44 ( ⁇ ) 3-cyclopropylmethoxyimino-2-(4-hydroxy-benzyl)- butyric acid methyl ester 500 mg (2.2 mmol) of the compound obtained in Preparation Example 36 (2), 417 mg (3.4 mmol) of cyclopropylmethoxyamine hydrochloride, and 406 mg (4.9 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed and, 10 ml of ethylacetate was added thereto, followed by washing twice with 10 ml of water.
  • Preparation Example 46 ( ⁇ ) 3-[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)] ⁇ butyric acid methyl ester 222 mg (1.0 mmol) of the compound obtained in Preparation Example 36 (2) and 152 mg (1.1 mmol) of 4-fluorobenzyloxyamine were added to 10 ml of ethanol, and the resulting solution was reacted for 48 hours at room temperature. After the reaction, the solvent was removed, and 10 ml of dichloromethane was added thereto, followed by washing twice with 10 ml of water.
  • Preparation Example 52 ( ⁇ ) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-pentanoic acid methyl ester 300 mg (1.3 mmol) of the compound obtained in Preparation Example 51 (2), 140 mg (1.4 mmol) of ethoxyamine hydrochloride, and 230 mg (2.8 mmol) of sodium acetate were added to 10 ml of methanol, and the resulting solution was reacted for 5 hours at room temperature. After the reaction, solvent was removed, and 10 ml of ethylacetate was added, followed by washing twice with 10 ml of water.
  • Example 49 3-methoxyimino-2- ⁇ 4-[2-(5-methyI-2-phenyl-oxazole-4-yl)-ethoxy]- benzylj-butyric acid methyl ester 150 mg (0.73 mmol) of the compound of 2-(5-methyl-2-phenyl-oxazole-4-yl)- ethanol obtained in Preparation Example 31 and 0.20 ml (1.46 mmol) of triethylamine were dissolved in 5 ml of methylene chloride, and the resulting solution was cooled to 0°C, then 0.084 ml (1.09 mmol) of mesylchloride was further added thereto.
  • Example 50 3-methoxyimino ⁇ 2- ⁇ 4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]- benzyl ⁇ -butylic acid 120 mg (0.27 mmol) of 3-methoxyimino-2- ⁇ 4-[2-(5-methyl-2-phenyl-oxazole- 4-yl)-ethoxy]-benzyl ⁇ -butyric acid methyl ester obtained in Example 49 was added to a mixture of 2.5 ml of tetrahydrofuran, 2.5 ml of methanol and 2.5 ml of 2N lithium hydroxide, and the resulting solution was reacted for 2 hours at room temperature.
  • Example 51 3-ethoxyimino-2- ⁇ 4-[2-(5-methyl-2-phenyl-oxazole ⁇ 4-yl)-ethoxy]- benzylj-butyric acid 140 mg (yield: 57%) of the title compound was obtained using 114 mg (0.56 mmol) of 2-(5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 118 mg (0.44 mmol) of ( ⁇ ) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 38 in the same manner as in Examples 49 and 50.
  • Example 53 3-butyloxy imino-2- ⁇ 4- [2-(5-methy l-2-phenyl-oxazole-4-yl)-ethoxy] - benzyl ⁇ -butyric acid 4 mg (yield of two steps: 9%) of the title compound was obtained using 20 mg (0.098 mmol) of 2-(5-mefhyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 27 mg (0.096 mmol) of ( ⁇ ) 3-butyloxyimino-2-(4-hydroxy-benzyl)- butyric acid methyl ester obtained in Preparation Example 40 in the same manner as in Examples 49 and 50.
  • Example 54 3-(2-methyI ⁇ propyloxyimino)-2- ⁇ 4-[2-(5-methyl-2-phenyl-oxazole-4- yl)-ethoxy]-benzyl ⁇ -butyric acid 35 mg (yield of two steps: 18%) of the title compound was obtained using 2-(5- methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 (100 mg, 0.49 mmol) and ( ⁇ ) 3-(2-methyl-propyl)oxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 42 (120 mg, 0.40 mmol) in the same manner as in Examples 49 and 50.
  • Example 55 3-cyclopropyImethoxyimino-2- ⁇ 4-[2-(5-methyl-2-phenyl-oxazole-4-yl)- ethoxy]-benzyl ⁇ -butyric acid 82 mg (yield of two steps: 13%) of the title compound was obtained using 350 mg (1.72 mmol) of 2-(5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 380 mg (1.30 mmol) of ( ⁇ ) 3-cyclopropylmethoxyimino-2-(4- hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 44 in the same manner as in Examples 49 and 50.
  • Example 56 3-isopropyloxyimino-2- ⁇ 4-[2-(5-methyl-2-phenyl-oxazole-4-yl)- ethoxy] -benzylj-butyric acid 10 mg (yield of two steps: 22%) of the title compound was obtained using 20 mg (0.098 mmol) of 2-(5-mefhyl-2-phenyl-oxazole-4-yl)-ethanol obtained in
  • Example 58 3-(4-fluorobenzyloxyimino-2- ⁇ 4-[2-(5-methyl-2-phenyl-oxazole-4-yl)- ethoxy]-benzyl ⁇ -butyric acid 6 mg (yield of two steps: 9%) of the title compound was obtained using 30 mg
  • Example 60 3-ethoxy imino-2- ⁇ 4- [2-(2-phenyl)-5-methyl-oxazole4-y 1] -methoxy ⁇ - benzyl-pentanoic acid 4 mg (yield of two steps: 20%>) of the title compound was obtained using 25 mg (0.12 mmol) of 2-(5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 24 mg (0.086 mmol) of ( ⁇ ) 3-ethyloxyimino-2-(4-hydroxy-benzyl)- pentanoic acid methyl ester obtained in Preparation Example 52 in the same manner as in Examples 49 and 50.
  • Example 61 2-(4- ⁇ 2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy ⁇ -benzyl)-3- methoxymino-butylic acid 7 mg (yield of two steps: 29%) of the title compound was obtained using 15 mg (0.066 mmol) of 2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 32 and 13 mg (0.053 mmol) of ( ⁇ ) 3-methyloxyimino-2-(4- hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 7 in the same manner as in Examples 49 and 50.
  • Example 62 3-ethoxyimino-2-(4- ⁇ 2- [2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl] - ethoxy ⁇ -benzyl)-butyric acid 8 mg (yield of two steps: 33%) of the title compound was obtained using 15 mg (0.066 mmol) of 2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in
  • Example 63 2-(4- ⁇ 2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy ⁇ -benzyl)-3- propyloxyimino-butyric acid 7 mg (yield of two steps: 28%) of the title compound was obtained using 15 mg (0.066 mmol) of 2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 32 and 15 mg (0.053 mmol) of ( ⁇ ) 3-propyloxyimino-2-(4- hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 39 in the same manner as in Examples 49 and 50.
  • Example 64 3-fluoroethoxyimino-2-(4- ⁇ 2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4- yl]-ethoxy ⁇ -benzyl)-butyric acid 7 mg (yield of two steps: 31%) of the title compound was obtained using 15 mg
  • Example 65 2-(4- ⁇ 2-[2-(3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethoxy ⁇ -benzyl)-3- methoxyimino-butylic acid 8 mg (yield of two steps: 34%) of the title compound was obtained using 15 mg (0.066 mmol) of 2-[2-(3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in
  • Example 66 3-ethoxyimino-2-(4- ⁇ 2- [2-(3-fluoro-pheny l)-5-methyl-oxazole-4-yl] - ethoxy ⁇ -benzyl)butyric acid 9 mg (yield of two steps: 37%) of the title compound was obtained using 15 mg (0.066 mmol) of 2-[2-(3-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol obtained in Preparation Example 33 and 14 mg (0.053 mmol) of ( ⁇ ) 3-ethyloxyimino-2-(4- hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 38 in the same manner as in Examples 49 and 50.
  • Example 68 3-cyclomethoxyimino-2-(4- ⁇ 2-[2-(3-fluoro-phenyl)-5-methyl-oxazole- 4-yl]-ethoxy ⁇ -benzyl)-butyric acid 9 mg (yield of two steps: 28%) of the title compound was obtained using 15 mg (0.066 mmol) of 2-[2-(4-fluoro-phenyl)-5-mefhyl-oxazole-4-yl]-ethanol obtained in Preparation Example 32 and 19 mg (0.066 mmol) of ( ⁇ ) 3-cyclopropylmethoxyimino- 2-(4-hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 44 in the same manner as in Examples 49 and 50.
  • Example 69 3-methoxyimino-2- ⁇ 4-[2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)- ethoxy]-benzyl ⁇ -butyric acid 12 mg (yield of two steps: 29%) of the title compound was obtained using 20 mg (0.095 mmol) of 2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-efhanol obtained in Preparation Example 34 and 47 mg (0.10 mmol) of ( ⁇ ) 3-methyloxyimino-2-(4- hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 37 in the same manner as in Examples 49 and 50.
  • Example 70 3-ethoxyimino-2- ⁇ 4- [2-(5-methy l-2-thiopen-2-yl-oxazole-4-yl)-ethoxy] - benzylj-butyric acid 7.1 mg (yield of two steps: 17%) of the title compound was obtained using 20 mg (0.095 mmol) of 2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol obtained in Preparation Example 34 and 28 mg (0.10 mmol) of ( ⁇ ) 3-ethyloxyimino-2-(4-hydroxy- benzyl)-butyric acid methyl ester obtained in Preparation Example 38 in the same manner as in Examples 49 and 50.
  • Example 71 2- ⁇ 4-[2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethoxy]-benzyl ⁇ -3- propyloxymino-butylic acid 27 mg (yield of two steps: 21%) of the title compound was obtained using 120 mg (0.57 mmol) of 2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol obtained in Preparation Example 34 and 80 mg (0.28 mmol) of ( ⁇ ) 3-propyloxyimino-2-(4- hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 39 in the same manner as in Examples 49 and 50.
  • Example 72 3-fluoroethyloxyimino-2- ⁇ 4-[2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)- ethoxy]-benzyl ⁇ -butyric acid 12 mg (yield of two steps: 27%) of the title compound was obtained using 20 mg (0.095 mmol) of 2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol obtained in Preparation Example 34 and 30 mg (0.10 mmol) of ( ⁇ ) 3-(2-fluoro-ethyloxyimino)-2- (4-hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 41 in the same manner as in Examples 49 and 50.
  • Example 74 3-ethoxyimino-2- ⁇ 4- [2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]- benzyl ⁇ -2-methyl-butylic acid 8 mg (yield: 55%) of the title compound was obtained using 8 mg (0.034 mmol) of 2-(5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and
  • Example 75 2- ⁇ 4- [2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy] -benzyl ⁇ -2-methyl-3- propyloxyimino-butylic acid 8 mg (yield: 52%) of the title compound was obtained using 9 mg (0.044 mmol) of 2-(5-methyl-2-phenyl-oxazole-4-yl)-ethanol obtained in Preparation Example 31 and 9 mg (0.033 mmol) of ( ⁇ ) 3-propoxyimino-2-(4-hydroxy-benzyl)-2-methyl-butylic acid methyl ester obtained in Preparation Example 50 in the same manner as in Examples 49 and 50.
  • Example 76 3-methoxyimino-2- ⁇ 4-[2-(5-methyl-2-thiopen-2 ⁇ yI-oxazoIe-4-y ⁇ )- ethoxy]-benzyl ⁇ -2-methyl-buty lie acid 13 mg (yield: 29%)) of the title compound was obtained using 30 mg (0.12 mmol) of 2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-etl ⁇ anol obtained in Preparation Example 34 and 26 mg (0.098 mmol) of (+) 3-methoxyimino-2-(4-hydroxy-benzyi)-2- methyl-butylic acid methyl ester obtained in Preparation Example 48 in the same manner as in Examples 49 and 50.
  • Example 77 3-(4-fluoro-benzyloxyimino)-2- ⁇ 4-[5-methyl-2-(4-trifluoromethyl- phenyl)-thiazole-4-ylmethoxy]-benzyl ⁇ -butyric acid 20 mg (yield of two steps: 30%) of the title compound was obtained using 30 mg (0.13 mmol) of [5 -methyl-2-(4-trifluoromethyl-phenyl)-thiazole-4-yl] -methanol obtained in Preparation Example 35 and 39 mg (0.11 mmol) of ( ⁇ ) 3-[4- fluorobenzyloxyimino-2-(4-hydroxy-benzyl)] -butyric acid methyl ester obtained in Preparation Example 46 in the same manner as in Examples 49 and 50.
  • Example 78 2- ⁇ 4-[2-(5-methyl-2-p-oxazole-4-ylmethoxy)-benzyl]-3- propyloxyimino-butylic acid 14 mg (yield of two steps: 32%) of the title compound was obtained using 20 mg (0.098 mmol) of (5-methyl-2-p-tolyl-oxazole-4-yl)-methanol obtained in Preparation Example 53 and 26 mg (0.097 mmol) of ( ⁇ ) 3-propyloxyimino-2-(4- hydroxy-benzyl)-butyric acid methyl ester obtained in Preparation Example 39 in the same manner as in Examples 49 and 50.
  • Example 79 l-[2-(4- ⁇ 3-benzyloxyimino ⁇ -2-carboxy-butyl)-phenoxy]-ethyl-4- phenyl-lH-pyrrole-3-carboxylic acid ethyl ester 15 mg (0.07 mmol) of 4-phenyl-l H-pyrrole-3 -carboxylic acid ethyl ester was dissolved in 0.5 ml of dimethylformamide, and 3.4 mg (0.084 mmol) of sodium hydride was added thereto, then the resulting solution was stirred for about 30 minutes, and 30 mg (0.07 mmol) of 3-(benzyloximino)-2-[4-(2-bromo-ethoxy)-benzyl]-butyric acid methyl ester was added thereto.
  • Example 80 3-[4-fluoro-benzyloxyimino]-2- ⁇ 4-[2-(4-methansulfonyloxy-phenyl)- ethoxy]-benzyl ⁇ -butyric acid 50 mg (0.144 mmol) of ( ⁇ ) 3-[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)]- butyric acid methyl ester, 63 mg (0.216 mmol) of methansulfonic acid 2-(4- methansulfonyloxy-phenyl)-ethyl ester and 93 mg (0.288 mmol) of cesium carbonate were stirred in acetonitrile at 80°C.
  • Example 81 3-[4-fluoro-benzyloxyimino]-2- ⁇ 4-[l ⁇ (4-isopropyl-phenyl)-5-methoxy- lH ⁇ pyrrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid 11 mg (0.045 mmol) of [l-(4-isopropyl-phenyl)-5-methoxy-lH-pyrazole-3-yl]- methanol and 0.019 ml (0.14 mmol) of triethylamine were dissolved in 1 ml of dichloromethane, then 0.006 ml (0.067 mmol) of methanesulfonyl chloride was added to the resulting solution at 0°C.
  • Example 82 2- ⁇ 4-[l-(4-ethyl-phenyl)-lH-pyrrazole-4-ylmethoxy]-benzyl ⁇ -3-[4- fluoro-benzyloxyimino] -butyric acid 176 mg (yield: 67%) of 2- ⁇ 4-[l-(4-ethyl-phenyl)-lH- ⁇ yrazole-4-ylmethoxy]- benzyl ⁇ -3 -[4-fluoro-benzyloxyimino] -butyric acid methyl ester was obtained from 100 mg (0.49 mmol) of [l-(4-ethyl-phenyl)-lH-pyrazole-4-yl] -methanol and 153 mg (0.442 mmol) of ( ⁇ ) 3 -[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)] -butyric acid methyl ester in the same manner as in Example 49
  • Example 83 3-[benzyloxyimino]-2-4-[l-4-ethoxy-phenyl]-lH-pyrrazole-4- ylmethoxy]-benzyl ⁇ -butyric acid 161 mg (yield: 63%) of 2- ⁇ 4-[l-(4-ethyl-phenyl)-lH-pyrrazole-4-ylmethoxy]- benzyl ⁇ -3-[benzyloxyimono]-butyric acid methyl ester was obtained from 100 mg (0.49 mmol) of [l-(4-ethyl-phenyl)-lH-pyrazole-4-yl]-methanol and 146 mg (0.445 mmol) of ( ⁇ ) 3- [benzyloxyimino] -2-(4-hydroxy-benzyl)] -butyric acid methyl ester in the same manner as in Example 49.
  • Example 84 3- [4-fluoro-benzyloxyimino] -2-4- [l-4-methyl-phenyl]-5-methoxy -1H- pyrrazole-4-ylmethoxy] -benzylj-butyric acid 25 mg (yield: 36%) of 3 -[4-fluoro-benzyloxyimino] -2-4- [1 -4-methyl-phenyl] -5- methoxy-lH-pyrazole-4-ylmethoxy]-benzyl ⁇ -butyric acid was obtained from 30 mg (0.13 mmol) of [l-(4-methyl-phenyl)-5-methoxy-lH-pyrazole-4-yl]-methanol and 45 mg (0.13 mmol) of ( ⁇ ) 3 -[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)] -butyric acid methyl ester in the same manner as in Example 81.
  • Example 85 3- [4-fluoro-benzyloxyimino] -2-4- [2-(l-phenyl-lH-pyrrazole-4 ⁇ yl)- ethoxy] -benzyl] -butyric acid 87 mg (yield: 72%) of the title compound was obtained from 100 mg (0.53 mmol) of 2-(l-phenyl-lH-pyrrazole-3-yl)-ethanol and 83 mg (0.24 mmol) of ( ⁇ ) 3-[4- fluorobenzyloxyimino-2-(4-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.
  • Example 86 3-[4-fluoro-benzyloxyimino]-2- ⁇ 3-[l-(4-isopropyl-phenyl)-lH- py rrazole-4-ylmethoxy] -benzy l ⁇ -buty ric acid 10 mg (yield: 27%) of the title compound was obtained from 15 mg (0.07 mmol) of [l-(4-isopropyl-phenyl)-5-methyl-lH-pyrrazole-4-yl]-methanol and 22 mg (0.07 mg) of ( ⁇ ) 3 -[4-fluorobenzyloxyimino-2-(3-hydroxy-benzyl)] -butyric acid methyl ester in the same manner as in Example 81.
  • Example 87 3-[4-fluoro-benzyloxyimino]-2- ⁇ 3-[2-(5-methyl-2-phenyl-oxazole-4-yl)- ethoxy]-benzyl ⁇ -butyric acid 15 mg (yield: 19%) of the title compound was obtained from 30 mg (0.15 mmol) of 2-(5-methyl-2-phenyl-oxazole-4-yl)-ethanol and 34 mg (0.1 mg) of ( ⁇ ) 3-[4- fluorobenzyloxyimino-2-(3-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.
  • Example 88 3- [4-fluoro-benzyloxyimino] -2- ⁇ 3- [2-(5-methyl-2-thiopen-2-yl-oxazole -4-yl)-ethoxy]-benzyl ⁇ -butyric acid 5 mg (yield: 10%) of the title compound was obtained from 20 mg (0.095 mmol) of 2-(5-methyl-2-thiopen-2-yl-oxazole-4-yl)-ethanol and 35 mg (0.1 mmol) of ( ⁇ ) 3 -[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)] -butyric acid methyl ester in the same manner as in Example 81.
  • Example 89 3-[4-fluoro-benzyloxyimino]-2- ⁇ 4-methanesulfonyloxy-benzyl ⁇ - butyric acid 5 mg (yield: 55%) of 3-[4-fluoro-benzyloxyimino]-2- ⁇ 4-methanesulfonyloxy- benzyl ⁇ -butyric acid was obtained from 20 mg (0.06 mmol) of ( ⁇ ) 3-[4- fluorobenzyloxyimino-2-(4-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Preparation Example 55 and Example 50.
  • Example 90 2- ⁇ 4-benzenesulfonyloxy-benzyl ⁇ -3-[4-fluoro-benzyloxyimino]- butyric acid 10 mg (yield: 34%) of 2- ⁇ 4-benzenesulfonyloxy-benzyl ⁇ -3-[4-fluoro- benzyloxyimino] -butyric acid was obtained from 20 mg (0.06 mmol) of ( ⁇ ) 3-[4- fluorobenzyloxyimino-2-(4-hydroxy-benzyl)] -butyric acid methyl ester and 0.012 ml (0.09 mmol) of benzenesulfonyl chloride in the same manner as in Preparation Example
  • Example 91 3-[4-fluoro-benzyloxyimino]-2- ⁇ 4-phenylmethanesulfonyloxy-benzyl ⁇ - butyric acid 9.7 mg (yield: 32%) of the title compound was obtained from 20 mg (0.06 mmol) of ( ⁇ ) 3 -[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)] -butyric acid methyl ester and 18 mg (0.09 mmol) of benzenesulfonyl chloride in the same manner as in Preparation Example 55 and Example 50.
  • Example 92 3-[4-fluoro-benzyloxyimino]-2- ⁇ 4-[l-phenyl-lH-pyrrazole ⁇ 4- ylmethoxy]-benzyl ⁇ -butyric acid 20 mg (yield: 17%) of 3-[4-fluoro-benzyloxyimino]-2- ⁇ 4-[l-phenyl-lH- pyrrazole-4-ylmethoxy] -benzyl ⁇ -butyric acid was obtained from 63 mg (0.18 mmol) of (+) 3 -[4-fluorobenzyloxyimino-2-(4-hydroxy-benzyl)] -butyric acid methyl ester and 40 mg (0.23 mmol) of 1 -phenyl- lH-pyrrazole-4-yl-methanol in the same manner as in Example 81.
  • Example 93 3-[ethoxyimino]-2- ⁇ 4-[2-(5-methyl-l-phenyl-lH-pyrrazole-3-yl)- ethoxy]-benzyl ⁇ -butyric acid 14 mg (yield: 26%) of the title compound was obtained from 25 mg (0.12 mmol) of 2-(5-methyl-l -phenyl- 1 H-pyrrazole-3 -yl)-ethanol and 23 mg (0.086 mmol) of ( ⁇ ) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Example 81.
  • Preparation Example 63 2-(5-methyl-l-phenyl-lH-pyrrazole-3-yl)-ethanol 150 mg (yield: 27%) of 2-(5 -methyl- 1 -phenyl- 1 H-pyrrazole-3 -yl)-ethanol was obtained from 500 mg (2.65 mmol) of 2-(5-methyl-l -phenyl- 1 H-pyrrazole-3 -yl)- methanol in the same manner as in Preparation Example 60.
  • Example 95 3- [ethoxyimino] -2- ⁇ 4- [2-(4-methanesulf onyloxy-phenyl)-ethoxy ] - benzyl ⁇ -butyric acid 5.7 mg (yield: 8.6%>) of the title compound was obtained from 71 mg (0.21 mmol) of methanesulfonic acid 2-(4-methanesulfonyloxy-phenyl)-ethyl ester and 39 mg (0.147 mmol) of ( ⁇ ) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Example 81.
  • Example 96 3-[2-fluoro-ethoxyimino]-2- ⁇ 4-[2-(4-methanesulfonyloxy-phenyl)- ethoxy]-benzyl ⁇ -butyric acid 6.7 mg (yield: 9.9%) of the title compound was obtained from 71 mg (0.21 mmol) of methanesulfonic acid 2-(4-methanesulfonyloxy-phenyl)-ethyl ester and 41 mg (0.144 mmol) of ( ⁇ ) 3-(2-fluoro-ethyloxyimino)-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Example 81.
  • Example 98 3- [benzyloxyimino] -2- (4- [2-(4-fluoro-phenyl)-5-methy l-oxazole-4-y 1] - ethoxy ⁇ -benzyl ⁇ -2-methyl-butylic acid 7 mg (yield: 54%) of the title compound was obtained from 10 mg (0.03 mmol) of ( ⁇ ) 3-benzyloxyimino-2-(4-hydroxy-benzyl)-2-methyl-butyric acid methyl ester and 5.4 mg (0.024 mmol) of 2-[2-(4-fluoro-phenyl)-5-methyl-oxazole-4-yl]-ethanol in the same manner as in Example 81.
  • Example 99 3-[propoxyimino]-2- ⁇ 4-[l-(p-tolyl-lH-pyrrazole-4-yl)-methoxy]- benzyl ⁇ -butyric acid 12 mg (yield: 27%) of the title compound was obtained from 25 mg (0.13 mmol) of [l-(4-methyl-phenyl)-5-methyl-lH-pyrrazole-4-yl]-methanol and 29 mg (0.10 mg) of ( ⁇ ) 3 -propyloxyimino-2-(3-hydroxy-benzyl)] -butyric acid methyl ester in the same manner as in Example 81.
  • Example 100 3-[4-fluoro-benzyloxyimino]-2- ⁇ 4-[2-(4-methyl-thiazole-5-yl)- ethoxy]-benzyl ⁇ -butyric acid 17 mg (yield: 34%) of the title compound was obtained from 20 mg (0.139 mmol) of 2-(4-methyl-thiazole-5-yl)-ethanol and 37 mg (0.107 mmol) of 3-[4-fluoro- benzyloxyimino] -2- ⁇ 4- [ 1 -phenyl- 1 H-pyrrazole-4-y Imethoxy] -benzyl ⁇ -butyric acid in the same manner as in Example 81.
  • Example 101 2- ⁇ 4-[2-(4-methyl-thiazole-5-yl)-ethoxy]-benzyl ⁇ -3-[propoxyimino]- butyric acid 9 mg (yield: 32%) of the title compound was obtained from 20 mg (0.139 mmol) of 2-(4-methyl-thiazole-5-yl)-ethanol and 37 mg (0.071 mg) of ( ⁇ ) 3- propyloxyimino-2-(3-hydroxy-benzyl)] -butyric acid methyl ester in the same manner as in Example 81.
  • Example 102 2- ⁇ 4- [2-(5-ethyl-py ridine-2-y l)-ethoxy] -benzyl ⁇ -3- [propoxyimino] - butyric acid 9 mg (yield: 64%) of the title compound was obtained from 10 mg (0.66 mmol) of 2-(5-ethyl-pyridine-2-yl)-ethanol and 10 mg (0.035 mmol) of ( ⁇ ) 3-propyloxyimino- 2-(3-hydroxy-benzyl)] -butyric acid methyl ester in the same manner as in Example 81.
  • Example 103 2- ⁇ 4-[2-(5-ethyl-pyridine-2-yl)-ethoxy]-benzyl ⁇ -3-[methoxyimino]-2- methyl-butyric acid 8 mg (yield: 53%>) of the title compound was obtained from 10 mg (0.66 mmol) of 2-(5-ethyl-pyridine-2-yl)-ethanol and 10 mg (0.039 mmol) of ( ⁇ ) 3-methoxyimino-2- (4-hydroxy-benzyl)-2-methyl-butyric acid methyl ester in the same manner as in Example 81.
  • Example 104 2- ⁇ 4-[2-(benzoxazole ⁇ 2-yl-methyl-amino)-ethoxy ⁇ -benzyl ⁇ -3- [methoxyimino] -butyric acid 6 mg (yield: 37%) of the title compound was obtained from 13 mg (0.048 mmol) of 2-(benzoxazole-2-yl-methyl-amino)-ethanol and 10 mg (0.039 mmol) of ( ⁇ ) 3-methyloxyimino-2-(3-hydroxy-benzyl)]-butyric acid methyl ester in the same manner as in Example 81.
  • Example 105 ( ⁇ ) 2- ⁇ 3-[2-(benzoxazoIe-2-yl-methyIamino)-ethoxy]-benzyl ⁇ -3- [methoxyimino] -butylic acid methyl ester 100 mg (0.52 mmol) of 2-(benzoxazole-2-yl-methylamino)-ethanol was dissolved in 1 ml of dichloromethane and then 150 ⁇ l (1.0 mmol) of triethylamine was added to the resulting solution. To the reaction solution, 60 ⁇ l (0.78 mmol) of mesylchloride was added and the resulting solution was reacted for 1 hour.
  • Example 106 ( ⁇ ) 2- ⁇ 3-[2-(benzoxazole-2-yl-methylamino)-ethoxy]-benzyl ⁇ -3 ⁇ [methoxyimino] -butyric acid 6 mg (0.014 mmol) of the compound obtained in Example 105 was dissolved in 2 ml of a mixed solution of tetrahydrofuran/water/methanol (1/1/1, v/v/v), and 15 mg (0.63 mmol) of lithium hydroxide was added to the resulting solution which was then reacted for 3 hours. After the reaction, 1 ml of saturated ammonium chloride and 5 ml of ethyl acetate were added to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate and filtered off. Then, solvent was removed to obtain 5 mg (0.012 mmol) of the title compound in a yield of 86%.
  • Example 108 ( ⁇ ) 3-[ethoxyimino]-2-[4-(5-methyl-2-phenyloxazoIe-4-ylmethoxy)- benzyl] -butyric acid 5 mg (0.012 mmol, yield: 51%) of the title compound was obtained from 10 mg (0.023 mmol) of ( ⁇ ) 3-[ethoxyimino]-2-[4-(5-mefhyl-2-phenyloxazole-4-ylmethoxy)- benzyl] -butyric acid methyl ester in the same manner as in Example 106.
  • Example 110 ( ⁇ ) 2- ⁇ 4-[2-(4-fluorophenyl-5-methyloxazole-4-ylmethoxy)-benzyl]-3- [methoxyimino]-2-methyl butyric acid 10 mg (yield: 34%) of the title compound was obtained from 20 mg (0.097 mmol) of [2-(4-fluorophenyl)-5-methyloxazole-4-yl]-methanol and 19 mg (0.067 mmol) of ( ⁇ ) 3-methoxyimino-2-(4-hydroxy-benzyl)-2-methyl-butyric acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 111 ( ⁇ ) 2- ⁇ 4-[2-(4-fluorophenyl-5-methyloxazole-4-ylmethoxy)-benzyl]-3- [methoxyimino] -2-methyl propionic acid 3 mg (yield: 26%) of the title compound was obtained from 6 mg (0.029 mmol) of [2-(4-fluorophenyl)-5-methyloxazole-4-yl]-methanol and 7 mg (0.026 mmol) of ( ⁇ ) 3-methoxyimino-2-(4-hydroxy-benzyl)-2-methyl-propionic acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 112 ( ⁇ ) 3-[ethoxyimino]-2-[4-(2-isopropyl-5-methyloxazole-4-ylmethoxy)- benzyl] -butyric acid 6 mg (0.015 mmol, yield: 26%) of the title compound was obtained from 15 mg (0.1 mmol) of (2-isopropyl-5-methyl-oxazole-4-yl)-methanol and 10 mg (0.038 mmol) of ( ⁇ ) 3-ethoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl in the same manner as in Examples 105 and 106.
  • Example 113 ( ⁇ ) 2-[4-(2-isopropyl-5-methyloxazole ⁇ 4-ylmethoxy)-benzyl]-3- [propoxyimino] -butyric acid 5 mg (0.012 mmol, yield: 42%) of the title compound was obtained from 15 mg (0.1 mmol) of (2-isopropyl-5-methyl-oxazole-4-yl)-methanol and 10 mg (0.030 mmol) of ( ⁇ ) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 114 ( ⁇ ) 3-[2-fluoro-ethoxyimino]-2-[4-(5-methyl-2-paratolyloxazole-4- ylmethoxy)-benzyl]-butyric acid 42 mg (0.092 mmol, yield: 32%) of the title compound was obtained from 50 mg (0.24 mmol) of the compound obtained in Preparation Example 53 and 70 mg (0.24 mmol) of ( ⁇ ) 3-(2-fluoro-ethyloxyimino)-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106. Mass(EI) 455(M + +1)
  • Example 115 ( ⁇ ) 3-[2-fluoro-ethoxyimino]-2- ⁇ 4-5-methyl-2-(4-fluorophenyl)-5- methyloxazole-4-ylmethoxy] -benzyl ⁇ -butyric acid 50 mg (0.11 mmol, yield: 40%) of the title compound was obtained from 60 mg (0.29 mmol) of [2-(4-fluorophenyl)-5-methyloxazole-4-yl]-mefhanol and 78 mg (0.27 mmol) of ( ⁇ ) 3-(2-fluoro-ethyloxyimino)-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 117 ( ⁇ ) 2-[4-(3-benzyl-[l,2,4]oxadiazole-5-ylmethoxy)-benzyl]-3- [ethoxyimino] -butyric acid 10 mg (0.024 mmol, yield: 34%) of the title compound was obtained from 25 mg (0.26 mmol) of (3-benzyl-[l,2,4]oxadiazole-5-yl)-methanol and 20 mg (0.075 mmol) ( ⁇ ) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 118 ( ⁇ ) 3-[ethoxyimino]-2- ⁇ 4-[2-(4-ethylphenyl)-5-methyloxazoIe-4- ylmethoxy]-benzyl ⁇ -butyric acid 0.24 g (5.3 mmol, yield: 72%) of the title compound was obtained from 0.20 g (0.92 mmol) of [2-(4-ethyl- ⁇ henyl)-5-methyl-oxazole-4-yl]-methanol and 0.20 g (0.74 mmol) of 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 119 ( ⁇ ) 2- ⁇ 4-[2-(4-ethylphenyl)-5-methyloxazole -4-ylmethoxy]-benzyl ⁇ -3- [propoxyimino] -butyric acid 8 mg (0.017 mmol, yield: 37%) of the title compound was obtained from 20 mg (0.092 mmol) of [2-(4-ethyl-phenyl)-5-methyl-oxazole-4-yl] -methanol and 13 mg (0.047 mmol) of ( ⁇ ) 3-ethyloxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 120 ( ⁇ ) 2-[4-(4-methanesulfonyIoxy-benzyloxy)-benzyl]-3-[ethoxyimino]- butyric acid 0.13 mg (0.030 mmol, yield: 40%) of the title compound was obtained from 20 mg (0.091 mmol) of methanesulfonic acid 4-chloromethyl-phenyl ester and 20 mg (0.074 mmol) of ( ⁇ ) 3-ethoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 121 ( ⁇ ) 3-[methoxyimino]-2- ⁇ 4-[5-methyl-2-(4-methanesulfanyl-pheny ⁇ )- oxazole-4-ylmethoxy]-benzyl ⁇ -butyric acid 15 mg (0.033 mmol, yield: 55%) of the title compound was obtained from 30 mg (0.12 mmol) of [5-methyl-2-(4-methylsulfanyl-phenyl)-oxazole-4-yl]-methanol and 15 mg (0.060 mmol) of ( ⁇ ) 3-methoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 122 ( ⁇ ) 3-[ethoxyimino]-2- ⁇ 4-[5-methyl-2-(4-methanesulfanyl-phenyl)- oxazole-4-ylmethoxy]-benzyl ⁇ -butyric acid 0.10 mg (0.021 mmol, yield: 38%) of the title compound was obtained from 30 mg (0.12 mmol) of [5-methyl-2-(4-methylsulfanyl-phenyl)-oxazole-4-yl]-methanol and 15 mg (0.056 mmol) of ( ⁇ ) 3-ethoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in Examples 105 and 106.
  • Example 123 ( ⁇ ) 3-[ethoxyimino]-2- ⁇ 4-[2-(4-methanesulfonyl-phenyl)-5-methyl- oxazole-4-ylm ethoxy] -benzyl ⁇ -butyric acid 0.13 mg (0.026 mmol, yield: 30%) of the title compound was obtained from 30 mg (0.11 mmol) of [5 -methyl-2-(4-methylsulfonyl-phenyl)-oxazole-4-yl] -methanol and 23 mg (0.087 mmol) of ( ⁇ ) 3-efhoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as Examples 105 and 106.
  • Example 124 ( ⁇ ) 3-[ethoxyimino]-2-[4-(2-phenylsulfanyl-ethoxy)-benzyl]-butyric acid 0.8 mg (0.021 mmol, yield: 28%) of the title compound was obtained from 16 mg (0.075 mmol) of (2-bromo-ethylsulfanyl)-benzene and 20 mg (0.074 mmol) of ( ⁇ ) 3-ethoxyimino-2-(4-hydroxy-benzyl)-butyric acid methyl ester in the same manner as in
  • Example 126 ( ⁇ ) 3-[ethoxyimino]-2-[4-(2-phenylsulfonyl-ethoxy)-benzyl]-butyric acid 6 mg (yield 80%) of the title compound was obtained from 8 mg (0.018 mmol) of ( ⁇ ) 3-[ethoxyimino]-2-[4-(2-phenylsulfonyl-ethoxy)-benzyl]-butyric acid methyl ester in the same manner as in Example 106.
  • Example 127 ( ⁇ ) 3-[ethoxyimino]-2- ⁇ 4-[2-(3-oxo-2,3-dihydro-benzo[l,4]oxazine-4- yl-ethoxy)-benzyl]-butyric acid methyl ester 30 mg (0.08 mmol) of ( ⁇ ) 2-[4-(2-(bromo-ethoxy)-benzyl)-3-[ethoxyimino]- butyric acid methyl ester, 12 mg (0.08 mmol) of 4H-benzo[l,4]oxazine-3-one and 40 mg (0.12 mmol) of cesium carbonate were added to 10 ml of acetonitrile and the resulting solution was reacted for 3 hours under reflux.
  • Example 128 ( ⁇ ) 3- [ethoxyimino] -2- ⁇ 4- [2-(3-oxo-2,3-dihydro-benzo [1,4] oxazine-4- yl-ethoxy)-benzyl] -butyric acid 17 mg (0.040 mmol, yield: 89%) of the title compound was obtained from 20 mg (0.045 mmol) of ( ⁇ ) 3-[ethoxyimino]-2- ⁇ 4-[2-(3-oxo-2,3-dihydro- benzo[l, 4] oxazine-4-yl-ethoxy)-benzyl] -butyric acid methyl ester in the same manner as in EXAMPLE 106.
  • Experimental Example 1 Construction of reporter vector containing luciferase structural gene in GAL4 transcription gene sequence
  • CCGGAGGACAGTACTCCG TA
  • CCGGAGGACAGTACTCCG TA
  • CTCGGAGGACAGTACTCCG TA
  • Experimental Example 2 Construction of vector expressing fusion protein of GAL4 and ligand-binding domain of PPAR protein
  • a vector expressing a protein in which the DNA-binding domain of GAL4 is fused with the ligand-binding domain of PPAR under control of SV40 promoter, was constructed using pZeoSN (Invitrogen, Cat. No. V85001) being a mammalian cell expression vector as a basic vector.
  • primer GAL4-HIII (5'-GC AAGCTT GAAGCAAGCCTCCTGAAAG ATG AAG CTA CTG TCT TCT ATC GAA C-3') contains the sequence encoding amino acids 1 to 8 of the N-terminal of the GAL4 DNA-binding domain, and also the restriction enzyme Hindlll recognition domain.
  • Another primer GAL4-KI (5'-AA GGTACC GGT AAA TTC CGG CGA TAG AGT CAA CTG TCT TTG A-3') contains the sequence encoding amino acids 141 to 147 of the C-terminal of the DNA-binding domain of GAL4, and also the restriction enzyme Kpnl recognition domain. 2 ⁇ g of the primer GAL4-HIII and 2 ⁇ g of the primer GAL4-KI were added into a reaction tube, then 10 ng of plasmid pGBT9 (Clonetech, Cat. No.
  • K1605-A as a template, and 10 ⁇ l of 10 x polymerization buffer (50 mM KC1, 100 mM Tris-HCI, pH 9.0, 1% Triton X-100, 2.5 mM MgCl 2 ), 10 ⁇ l of 2 mM dNTP (2 mM dGTP, 2 mM dATP, 2 mM dCTP and 2 mM dTTP), 2.5 units of Taq polymerase, and distilled water were further added to a total volume of 100 ⁇ l, and PCR was carried out for 25 cycles with denaturation at 95°C for 40 seconds, annealing at 55°C for 30 seconds, and polymerization at 72°C for 1 minute.
  • 10 x polymerization buffer 50 mM KC1, 100 mM Tris-HCI, pH 9.0, 1% Triton X-100, 2.5 mM MgCl 2
  • 10 ⁇ l of 2 mM dNTP 2 mM
  • 'fragment GAL4-H/K' The DNA fragment thus seperated and purified (hereinafter, referred to as 'fragment GAL4-H/K') was fully restricted with Hindlll and Kpnl in NEB buffer 2 (50 mM NaCl, 10 mM Tris-HCI, 10 mM MgC12, 1 mM dithiothreitol (pH 7.9)), and extracted with phenol/chloroform, then eluted with 20 ⁇ l of TE (10 mM Tris-HCI, 1 mM EDTA, pH 8.0) solution.
  • NEB buffer 2 50 mM NaCl, 10 mM Tris-HCI, 10 mM MgC12, 1 mM dithiothreitol (pH 7.9)
  • fragment pZeoSN-H/K 2 ⁇ g of plasmid pZeoSN was fully restricted with restriction enzymes Hindlll and Kpnl in ⁇ EB buffer 2, and a nucleic acid fragment of about 3.5 kb was seperated and purified in 1% agarose gel.
  • fragment pZeoSN-H/K 2 ⁇ g of plasmid pZeoSN was fully restricted with restriction enzymes Hindlll and Kpnl in ⁇ EB buffer 2, and a nucleic acid fragment of about 3.5 kb was seperated and purified in 1% agarose gel.
  • Primer GLBD-r (5'-CC ACGCGT CTA GTA CAA GTC CTT GTA GAT CTC C -3') contains the sequence encoding from Glu 472 to Tyr 478 of human PPAR ⁇ gene and the termination codon, allowing the termination of translation at the 478* amino acid, and also the restriction enzyme Mlul - recognition domain.
  • a DNA fragment encoding from Ser 176 to Tyr 478 containing the human PPAR ⁇ ligand-binding domain was amplified by PCR using the above described primer and also using the full- length cDNA of human PPAR ⁇ , isolated from human liver cDNA library, as a template.
  • fragment pZeoGAL-K/M 2 ⁇ g of plasmid pZeo-GAL obtained above was fully restricted with restriction enzymes Kpnl and Mlul in NEB buffer 2, and a nucleic acid fragment of 4.0 kb was seperated and purified in 1% agarose gel.
  • this fragment is referred to as "fragment pZeoGAL-K/M”.
  • the product was transformed into E.coli HB101 (ATCC 33694) to obtain the expression vector as desired in which the DNA fragment encoding human PPAR ⁇ ligand-binding domain is inserted into DNA encoding the GAL4 DNA-binding domain of pZeoGAL (hereinafter, referred to as "pZeo-GAL- PPAR ⁇ LBD").
  • Primer ALBD-f (5'-GG GGTACC TCA CAC AAC GCG ATT CGT T-3') contains the sequence encoding from Ser 167 to Arg 175 of human PPAR ⁇ and also the restriction enzyme Kpnl - recognition domain.
  • Primer ALBD-r (5'-CC ACGCGT TCA GTA CAT GTC CCT GTA GAT CTC CTG C-3') contains the sequence encoding from Gin 461 to Tyr 468 including the human PPAR ⁇ ligand-binding domain and fh the termination codon, allowing the termination of translation at the 468 amino acid, and also the restriction enzyme Mlul - recognition domain.
  • 'fragment ALBD-K/M' The nucleic acids thus seperated and purified (hereinafter, referred to as 'fragment ALBD-K/M') were fully restricted with restriction enzymes Kpnl and Mlul in NEB buffer 2, and extracted with phenol/chloroform, then eluted with 20 ⁇ l of TE solution.
  • the product was transformed into E.coli HB101 (ATCC 33694) to obtain the expression vector as desired in which the DNA fragment encoding human PPAR ⁇ ligand-binding domain is inserted into DNA encoding the GAL4 DNA-binding domain of pZeoGAL (hereinafter, referred to as "pZeo-GAL- PPAR ⁇ LBD").
  • Transformation CN-1 cells derived from monkey kidney were aliquoted into each well of 24- well plate at a density of 6.0x10 4 per/well, suspended in DMEM medium (Life Technologies Inc) supplemented with 10%) FBS, and cultured for 24 hours at 37°C in 5% CO atmosphere. After culturing, the growth medium was replaced with 200 ⁇ l of OptiMEMTM medium (Life Technologies Inc) and the cells were used for transformation.
  • the amount of D ⁇ A was 480 ng of ⁇ GL3-GAL4, 48 ng of pZeo-GAL-PPAR ⁇ LBD or pZeo-GAL-PPAR ⁇ LBD and 128 ng of pCHHO (Amersham, Cat. ⁇ o.
  • Example 3 and the compounds of Examples 1 to 128 were suspended in DMSO and added in DMEM medium supplemented with 5% FBS, then the resulting mixture was added to each well, followed by culturing at 37°C in 5% CO 2 atmosphere for 24 hours. After the culturing, the culture media was removed and cells were washed twice with PBS (Life Technologies Inc). To each well, 100 ⁇ l of Passive Lysis Buffer (PLB) solution (Promega Corporation) was added and then gently stirred for 20 minutes at room temperature. 20 ⁇ l of cell lysate taken from each well was removed to a Costar 96-well Luminometer and luciferase activity was determined using Luciferase Assay SystemTM kit (Promega Corporation) following the instructions of the manufacturer.
  • PBS Passive Lysis Buffer
  • the compound of Formula 1 according to the present invention is very effective for accelerating the activity of PPAR ⁇ and PPAR ⁇ . Accordingly, the compound according to the present invention can be used as a drug for treatment or prevention of diseases involving human PPAR ⁇ and PPAR ⁇ , for example, diabetes mellitus, complications associated with diabetes mellitus, inflammation, etc.
  • diseases involving human PPAR ⁇ and PPAR ⁇ for example, diabetes mellitus, complications associated with diabetes mellitus, inflammation, etc.
  • Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the scope of particular embodiments of the invention indicated by the following claims.

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Abstract

L'invention concerne de nouveaux composés accélérant l'activité des récepteurs activés par le proliférateur Peroxisome gamma (PPARη) et alpha (PPARα), des méthodes servant à préparer ces composés, ainsi que des compositions pharmaceutiques contenant ces composés en tant qu'agents actifs.
PCT/KR2004/002729 2003-10-27 2004-10-27 Nouveaux composes agonistes de ppar$g(g) et ppar$g(a), leur methode de preparation et composition pharmaceutique les contenant WO2005040127A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100383131C (zh) * 2005-06-15 2008-04-23 浙江大学 2-对三氟甲苯-4-甲基-5-噻唑甲酸乙酯的合成方法
WO2013041468A1 (fr) 2011-09-23 2013-03-28 F. Hoffmann-La Roche Ag Dérivés d'acide benzoïque en tant qu'inhibiteurs d'eif4e
JP2013537913A (ja) * 2010-09-24 2013-10-07 ブリストル−マイヤーズ スクイブ カンパニー 置換オキサジアゾール化合物およびそれらのｓ１ｐ１アゴニストとしての使用
US20150291536A1 (en) * 2012-11-22 2015-10-15 Sanofi Method for preparing phenyloxymethyl-nitro-imidazole derivatives and use of same
WO2017027312A1 (fr) * 2015-08-12 2017-02-16 Janssen Pharmaceutica Nv Agonistes de gpr40 pour le traitement du diabète de type 2
US9908873B2 (en) 2015-08-12 2018-03-06 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes
US9920040B2 (en) 2015-08-12 2018-03-20 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes

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US20020099035A1 (en) * 2001-01-24 2002-07-25 Sandanayaka Vincent P. Method for preparing alpha-sulfonyl hydroxamic acid derivatives
WO2002085844A1 (fr) * 2001-04-20 2002-10-31 Astrazeneca Ab Nouveaux composes
WO2003027108A1 (fr) * 2001-09-21 2003-04-03 Les Laboratoires Servier Derives heterocycliques et leur utilisation en tant qu'agents hypoglycemiants et hypolipemiants
US6620813B1 (en) * 2002-06-21 2003-09-16 Medinox, Inc. Hydroxamate derivatives of non-steroidal anti-inflammatory drugs
WO2003082777A2 (fr) * 2002-04-02 2003-10-09 Karo Bio Ab Nouveaux composes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020099035A1 (en) * 2001-01-24 2002-07-25 Sandanayaka Vincent P. Method for preparing alpha-sulfonyl hydroxamic acid derivatives
WO2002085844A1 (fr) * 2001-04-20 2002-10-31 Astrazeneca Ab Nouveaux composes
WO2003027108A1 (fr) * 2001-09-21 2003-04-03 Les Laboratoires Servier Derives heterocycliques et leur utilisation en tant qu'agents hypoglycemiants et hypolipemiants
WO2003082777A2 (fr) * 2002-04-02 2003-10-09 Karo Bio Ab Nouveaux composes
US6620813B1 (en) * 2002-06-21 2003-09-16 Medinox, Inc. Hydroxamate derivatives of non-steroidal anti-inflammatory drugs

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100383131C (zh) * 2005-06-15 2008-04-23 浙江大学 2-对三氟甲苯-4-甲基-5-噻唑甲酸乙酯的合成方法
JP2013537913A (ja) * 2010-09-24 2013-10-07 ブリストル−マイヤーズ スクイブ カンパニー 置換オキサジアゾール化合物およびそれらのｓ１ｐ１アゴニストとしての使用
WO2013041468A1 (fr) 2011-09-23 2013-03-28 F. Hoffmann-La Roche Ag Dérivés d'acide benzoïque en tant qu'inhibiteurs d'eif4e
US20150291536A1 (en) * 2012-11-22 2015-10-15 Sanofi Method for preparing phenyloxymethyl-nitro-imidazole derivatives and use of same
US9758488B2 (en) * 2012-11-22 2017-09-12 Sanofi Method for preparing phenyloxymethyl-nitro-imidazole derivatives and use of same
WO2017027312A1 (fr) * 2015-08-12 2017-02-16 Janssen Pharmaceutica Nv Agonistes de gpr40 pour le traitement du diabète de type 2
US9856245B2 (en) 2015-08-12 2018-01-02 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes
US9908873B2 (en) 2015-08-12 2018-03-06 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes
US9920040B2 (en) 2015-08-12 2018-03-20 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes

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