MXPA00010576A - Oxyiminoalkanoic acid derivatives with hypoglycemic and hypolipidemic activity - Google Patents

Abstract

To provide a novel oxyiminoalkanoic acid derivative which has excellent hypoglycemic and hypolipidemic actions and which is used for the prevention or treatment of diabetes mellitus, hyperlipemia, insulin insensitivity, insulin resistance and impaired glucose tolerance. A compound represented by formula (a) wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;X is a bond, -CO-, -CH(OH)- or a group represented by -NR6- wherein R6 is a hydrogen atom or an optionally substituted alkyl group;n is an integer of 1 to 3;Y is an oxygen atom, a sulfur atom, -SO-, -SO2- or a group represented by -NR7- wherein R7 is a hydrogen atom or an optionally alkyl group;ring A is a benzene ring optionally having additional one to three substituents;p is an integer of 1 to 8;R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;q is an integer of 0 to 6;m is 0 or 1;R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R9 and R10 combine together to form a ring);R4 and R5 are the same or different groups which are selected from a hydrogen atom or an optionally substituted hydrocarbon group wherein R4 may form a ring with R2;provided that when R1 is a ethoxymethyl, a C1-3 alkyl, phenyl or p-methoxyphenyl and q=m=0, R3 is NR9R10;and provided that O-[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]oxime and a methyl pyruvate of [2-chloro-4-(2-quinolylmethoxy)phenylmethyl]-2-iminoxypropionic acid are excluded;or a salt thereof.

Description

DERIVATIVES OF OXIMINOALCANOICO ACID WITH HIPOGLUCEMICA AND HYPOLIPIDIC ACTIVITY Technical Field The present invention relates to novel oxyiminoalkanoic acid derivatives having hypoglycemic effect and hypolipidemic effect, a novel pharmaceutical composition and a retinoid-related receptor function adjuster comprising an oxyiminoalkanoic acid. Such novel oxyiminoalkanoic acid derivatives, pharmaceutical compositions and retinoid-related receptor function adjusters are useful as an agent for the prevention and / or treatment of diabetes mellitus. hipelipemia, impaired glucose tolerance, inflammatory disease, arteriosclerosis and the like.

Background of the Invention Examples of the known oxyiminoalkanoic acid derivatives are the intermediates used in the production of ß-lactam compounds (Japanese Patent Application KOKAI No. 49382/1983, 167576/1984, 77391/1987, 192387/1987, 47186/1991 ) and a compound having an effect that inhibits leukotriene biosynthesis (e.g., WO96 / 02507).

Ref. 123744 However, these compounds have not been reported to have hypoglycemic and hypolipidemic effects and activity as an adjunct to receptor function related to retinoid yet.

On the other hand, oxime derivatives were reported as a prophylactic and / or therapeutic agent against hyperlipidemia and hyperglycemia (for example Japanese Patent Application KOKAI No. 48779/1997, 323929/1997), but these derivatives are not a derivative of oxiiminoalcanoic acid.

Furthermore, while a phenylalkanoyl acid derivative having a substituted hydroxyl group in its 4-position (for example in O97 / 31907, O97 / 25042) is reported as a peroxisome proliferator-activated gamma receptor agonist (abbreviated occasionally as PPA? in this specification), which is one of the receptor function adjusters related to the retinoid, this derivative is not an oxyiminoalkanoic acid derivative.

The peroxisome proliferator-activated gamma receptor (PPAR?) Is a member of the superfamily of intranuclear hormone receptors, representative of which are a steroid hormone receptor and a thyroid hormone receptor, and are induced to be expressed in a very close stage of the differentiation of the fat cell, and plays an important role as a master regulator in the differentiation of the fat cell. The PPAR? it binds to a function adjuster to form a dimer with a retinoid X receptor (RXR), and also binds to the response site of a target gene in a nucleus, thereby regulating (activating) the transcription efficiency directly. Recently, a metabolite of prostaglandin D2, that is, 15-deoxy-? 12,14 prostaglandin J2, was found to be an endogenous PPARα agonist, and a certain agent that increases insulin sensitivity, such as a thiazolindione derivative, was found to have a PPARα agonistic activity, with its potency which is in parallel with its effect that reduces blood sugar and the effect that promotes the differentiation of the fat cell [Cell, Vol. 83, page 803 (1995); The Journal of Biological Chemistry, Vol. 270, page 12953 (1995); Journal of Medicinal Chemistry, Vol. 39, page 655 (1996)]. More recently, it has been shown that: 1) the PPAR? is expressed in a cell derived from human, cultured fatty sarcoma, and its growth is terminated by the addition of a PPAR agonist? [Proceedings of the National Academy of Science of The United States of America, Vol. 94, page 237 (1997)], 2) a non-steroidal anti-inflammatory agent, such as indomethacin and fenoprofen have an agonistic activity of PPAR? [The Journal of Biological Chemistry, Vol. 272, page 3406 (1997)], 3) PPAR? it is highly expressed in an activated macrophage, and the addition of its agonist serves to inhibit the transcription of a gene involved in inflammation [Nature, Vol. 39.1, p. 79 (1998)], and 4) a PPAR agonist? inhibits the production of inflammatory cytokines (TNF a, IL-1 β, IL-6) by a monocyte [Nature, Vol. 391, page 82 (1998)].

Description of the invention The aim of the present invention is to provide a novel oxyiminoalkanoic acid derivative and a retinoid-related receptor function adjuster, which has excellent hypoglycemic effect and hypolipidemic effect and which is useful as an agent for the prevention and / or treatment of diabetes mellitus, hyperlipidemia, impaired glucose tolerance, inflammatory disease and arteriesclerosis.

The present invention relates to: 1) A compound represented by the formula (1-1): (l-D RX- (C wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group, n is an integer from 1 to 3, Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkoyl group, ring A is a benzene ring having one to three additional substituents optionally, p is an integer from 1 to 8, R2 is a hydrogen atom, a substituted hydrocarbon group optionally or an optionally substituted heterocyclic group, q is an integer from 0 to 6, m is 0 or 1, R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9RX0 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, a group optionally substituted hydrocarbon, optionally substituted heterocyclic group and optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups, which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; with the proviso that when R1 is an ethoxymethyl group, a C? -3 alkyl, phenyl or p-methoxyphenyl group and q = m = 0, R3 is NR9R10; and with the proviso that O- [2-chloro-4- (2-quinolylmethoxy) phenylmethyl] methyl pyruvate oxime and [2-chloro-4- (2-quinolylmethoxy) phenylmethyl] -2- are excluded. iminoxypropionic; or a salt thereof; 2) A compound of item 1) above, wherein R1 is an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group; 3) A compound of item 1) above, wherein X is a bond or a group represented by -NR6-, wherein R6 is an optionally substituted alkyl group; 4) A compound of item 1) above, wherein n is 1 or 2; ) A compound of item 1) above, wherein Y is an oxygen atom; 6) A compound of item 1) above, wherein p is an integer from 1 to 3; 7) A compound of item 1) above, wherein R3 is a hydroxy group or -OR8 or -NR9'R10 ', wherein R8 is an optionally substituted hydrocarbon group and R9' and R10 'are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, or R9 'and R10' are combined together to form a ring; 8) A compound of item 1) above, wherein q is an integer from 0 'to 4; 9) A compound of item 1) above, wherein R2 is an optionally substituted hydrocarbon group, -10) A compound of E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino]] -4-phenylbutyric or its salt; 11) A compound which is selected from a group of E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyramide and E-8- [4- (5- methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoic acid; 12) A compound of 2) above, wherein a ring of an optionally substituted heterocyclic group or an optionally substituted cyclic hydrocarbon group of R1 is selected from the group represented by the formulas: 13) A compound of item 12) above, wherein the ring has one or two substituents optionally, which are selected from the group consisting of an optionally substituted phenyl group, an optionally substituted furyl group, an optionally substituted thienyl group and a group C? -alkyl optionally substituted; 14) A compound of part 12) above, where the ring is wherein Ph is an optionally substituted phenyl group, and R "is hydrogen or an optionally substituted C6-6 alkoyl group; ) A compound represented by the formula (1-2) wherein R 'is an optionally substituted phenyl, furyl or thienyl group; R "is hydrogen or an alkyl group C? -6, which is optionally substituted by at least one selected from a group consisting of a C1-6 alkoxy group and a halogen; R2 'is a phenyl group, which is optionally substituted by at least one selected from a group consisting of a hydrogen, an alkyl group, an alkoxy group, and a halogen; q is an integer from 1 to 6; and R3 'is a hydroxy group, a C1-6 alkoxy group or -NR9R10, in which R9 and R10 are independently selected from the group consisting of a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group and an optionally substituted acyl group, or R9 and R10 combine with each other to form a ring; ring A is a benzene ring having one to three substituents optionally; or a salt thereof; 16) A pharmaceutical composition comprising a compound represented by Formula (II) - wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a group optionally substituted heterocyclic and optionally substituted acyl group or R9 and R10 combine with each other to form a ring), - R4 and R5 are the same or different groups, which are selected from a hydrogen atom and an optionally substituted hydrocarbon group , wherein R4 can form a ring with R2; or a salt thereof; 17) A pharmaceutical composition of subsection 16) above, which is a composition for the prevention or treatment of diabetes mellitus; 18) A pharmaceutical composition of subsection 16) above, which is a composition for the prevention or treatment of hyperlipemi; 19) A pharmaceutical composition of item 16) above, which is a composition for the prevention or treatment of impaired glucose tolerance; ) A pharmaceutical composition of subsection 16) above, which is a composition for the prevention or treatment of inflammatory disease; and 21) A pharmaceutical composition of subsection 16) above, which is a composition for the prevention or treatment of arteriosclerosis; 22) An agent for controlling or adjusting the retinoid-related receptor comprising a compound represented by Formula (II) R R5 R '--XX--. { CHj) n-Y í X (C wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; And it is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkenyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q 'is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a heterocyclic group optionally substituted and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups, which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt thereof; 23) An agent of subsection 22) above, which is a ligand of the peroxisome proliferator-activated receptors; 24) An agent of subsection 22) above, which is a ligand of the retinoid X receptor; ) An agent of subsection 22) above, which is an agent that increases insulin sensitivity; 26) An agent of subsection 22) above, which is an agent that improves insulin resistance; (1) Definition of R1 A hydrocarbon group in "an optionally substituted hydrocarbon group" represented by R1 in Formulas (1-1) and (II) includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, an aromatic-aliphatic hydrocarbon group and an aromatic hydrocarbon group. The number of carbon atoms in each of these hydrocarbon groups is preferably 1 to 14. (1-1) Definition of Hydrocarbon Group for Re¬ As the aliphatic hydrocarbon group, an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferred. Such an aliphatic hydrocarbon group includes a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (eg, an alkyl group), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl , pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, and the like; an unsaturated aliphatic hydrocarbon group having 2 to 8 carbon atoms (for example, an alkenyl group, an alkadienyl group, an alkynyl group, an alkadinyl group and the like), such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2 -pentynyl, 3 -pentynyl, 4-pentynyl, 1-hexynyl, 3 -hexinyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.

As the alicyclic hydrocarbon group, an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferred. Such an alicyclic hydrocarbon group includes a saturated alicyclic hydrocarbon group (eg, a cycloalkyl group and the like), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; an unsaturated alicyclic hydrocarbon group (eg, a cycloalkenyl group, a cycloalkadienyl group and the like), such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl and the like.

As the alicyclic-aliphatic hydrocarbon group, an alicyclic hydrocarbon group indicated above is exemplified linked to an aliphatic hydrocarbon group indicated above (eg, a cycloalkyl-alkyl group, a cycloalkenyl-alkyl group and the like), and is preferred an alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms. Such an alicyclic-aliphatic hydrocarbon group includes cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, and the like.

As the aromatic-aliphatic hydrocarbon group, an aromatic-aliphatic hydrocarbon group having 7 to 13 carbon atoms (for example, an aralkyl group, an arylalkenyl group and the like) is preferred. Such araliphatic hydrocarbon group includes a phenylalkyl group having 7 to 9 carbon atoms, such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl and the like; a naphthylalkyl group having 11 to 13 carbon atoms, such as α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl and the like; a phenylalkenyl group having 8 to 10 carbon atoms, such as styryl and the like; a naphthylalkenyl group having 12 to 13 carbon atoms, such as 2- (2-naphthylvinyl) and the like.

As the aromatic hydrocarbon group, an aromatic hydrocarbon group having 6 to 14 carbon atoms (for example, an aryl group and the like) is preferred. Such an aromatic hydrocarbon group includes phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like, and, among these, preferred ones are phenyl, 1-naphthyl, 2-naphthyl and the like. (1-2) Definition of Heterocyclic Group for R1 A heterocyclic group in "an optionally substituted heterocyclic group" represented by R1 in Formulas (1-1) and (II) includes a 5- or 7-membered monocyclic or heterocyclic group having as its constituent atoms 1 to 4 hetero atoms selected The group consists of an oxygen atom, a sulfur atom and a nitrogen atom, as well as carbon atoms. As the fused heterocyclic ring, a 5- to 7-membered monocyclic heterocyclic ring condensed with a 6-membered ring containing 1 to 2 nitrogen atoms, with a benzene group, or with a 5 membered ring containing a 5-membered heterocyclic ring can be exemplified. sulfur atom.

Examples of the heterocyclic group are an aromatic heterocyclic group, such as 2-pyridyl, 3-pyridyl 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, -pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl, 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1, 2, 4-oxadiazol-5-yl, 1, 3, 4-oxadiazol-2-yl, l, 3,4 -thiaziazol-2-yl, 1, 2, 4-triazol-1-yl, 1, 2,4-triazol-3-yl, 1,2,3-triazol-l-yl, 1, 2, 3-triazole -2-yl, 1, 2, 3-triazol-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-quinazolyl, 4-quinazolyl, -quinoxalyl, 2-benzoxazolyl, 2-benzothiazolyl, benzimidazol-1-yl, benzimidazol-2-yl, indole-1-yl, indol-3-yl, lH-indazol-3-yl, lH-pyrrolo [2, 3 -b] pyrazin-2-yl, lH-pyrrolo [2, 3-b] pyridin-6-yl, lH-imidazo [4, 5-b] pyrid in-2-yl, lH-imidazo [4, 5-c] pyridin-2-yl, lH-imidazo [4, 5-b] pyrazin-2-yl and the like, as well as a non-aromatic heterocyclic group, such as 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, 1-hexamethyleneiminyl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin -3-yl, 2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl and the like.

A heterocyclic group is preferably pyridyl, oxazolyl, thiazolyl, benzoxazolyl or benzothiazolyl. (1-3) Definition of Substituents of the Hydrocarbon and / or heterocyclic group for R1 The hydrocarbon group and the heterocyclic group represented by -R1 in Formulas (1-1) and (II) each optionally have 1 to 5, preferably 1 to 3 substitutes in their possible positions. Such substituents include an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic heterocyclic group, an optionally substituted non-aromatic heterocyclic group, a halogen atom, a nitro group , an optionally substituted amino group, an optionally substituted acyl group, an optionally substituted hydroxy group, an optionally substituted thiol group, a carboxyl group derived from amide or optionally esterified. The substituents represented by "optionally substituted" are a C?-6 alkyl group, a C 1-6 alkoxy group, a halogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitro group, a halo-alkyl group C? -6, a haloalkoxy group C? -6.

Examples of the aliphatic hirdocarbide group are a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, such as an alkyl group, an alkenyl group, an alkynyl group and the like.

A preferred alkyl group includes an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl. , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.

A preferred alkenyl group includes an alkenyl group having 2 to 10 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, -methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, l-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.

A preferred alkynyl group includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl , 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.

As the alicyclic hydrocarbon group, there can be exemplified a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group.

Preferred examples of the cycloalkyl group are a cycloalkyl group having 3 to 10 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2. l] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2. l] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.1. l] nonyl, bicyclo [4.2. l] nonyl, bicyclo [4.3. l] decilo and the like.

Preferred examples of the cycloalkenyl group are a cycloalkenyl group having 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1 -ilo and the like.

Preferred examples of the cycloalkanedienyl group are a cycloalkanedienyl group having 4 to 10 carbon atoms, such as 2, 4-cyclopentadien-1-yl, 2, 4-cyclohexadien-1-yl, 2, 5-cyclohexadien-1-yl and the like.

Specific examples of the aromatic hydrocarbon group are an aromatic hydrocarbon group having 6 to 14 carbon atoms (for example, an aryl group and the like), such as phenyl, naphthale, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like , and, among these, those preferred are phenyl, 1-naphthyl, 2-naphthyl and the like.

Preferred examples of the aromatic heterocyclic group are a 5- to 7-membered monocyclic aromatic group having as its constituent atoms 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, furthermore of carbon atoms, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl , 1, 2, 3-thiadiazolyl, 1, 2,4-thiaziazolyl, 1,3,4-thiaziazolyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl , triazinyl and the like; a bicyclic or tricyclic aromatic fused heterocyclic ring having as its constituent atoms 1 to 5 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to carbon atoms, such as benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, IH-indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, IH-benzotriazolyl, quinolyl-isoquinolyl, cinnolyl, quinazolyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, puteridinyl, carbazolyl, a-carbonylil, β-carbonylyl, β-carbonyl, acridinyl, phenoxyazinyl, phenazinyl, phenazinyl, phenoxythiinyl, thiantrenyl, indolidinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1, 5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [l, 5-a] pyridyl, imidazo [l, 2-b] pyridazinyl, imidazo [1,2- a] pyrimidinyl, 1,2,4-triazolo [4, 3-a] pyridyl, 1, 2,4-triazolo [4, 3-b] pyridazinyl and the like.

Preferred examples of the non-aromatic heterocyclic group are oxilanyl, azetizinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino and the like.

Examples of the halogen atom are fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.

An optionally substituted amino group is an amino group optionally mono- or disubstituted with, for example, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an acyl group having 3 to 10 carbon atoms (for example, an alkanoyl group having 2 to 10 carbon atoms, an arylcarbonyl group having 7 to 13 carbon atoms and the like), or an aryl group having 6 to 12 carbon atoms. The acyl group has the same definition mentioned below for the acyl group in an optionally substituted acyl group.

The substituted amino group includes methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, N-methyl-N-phenylamino and the like.

The acyl group in an optionally substituted acyl group is an acyl group having 1 to 13 carbon atoms, such as formyl, as well as a carbonyl group attached to an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms and an aromatic heterocyclic group (for example , thienyl, furyl, pyridyl and the like).

Preferred examples of the acyl group are acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, oxtanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, isonicotinoyl and the like.

Such an acyl group has one to three substituents optionally at their possible positions, and such substituents include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, halogen (for example, fluorine, chlorine, iodine and the like), nitro, hydroxy, amino and the like.

Other types of acyl group are represented by a group of the formula: -COR11, -S02R14, -SOR15 or -P03R16R17, wherein R11, R14, R15, R16 and R17 are independently an optionally substituted hydrocarbon group.

Examples of the "optionally substituted hydrocarbon group" represented by R11, R14, R15, R16 and R17 are an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10. carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms.

The optionally substituted hydroxy group includes a hydroxy group, an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group, an aryloxy group and the like, each of which may be optionally substituted.

Preferred examples of the alkoxy group are an alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy , noniloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

Preferred examples of the alkenyloxy group are an alkenyloxy group having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, < 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like.

Preferred examples of the aralkyloxy group are an aralkyloxy group having 7 to 10 carbon atoms, such as phenyl-C 1 - alkyloxy (for example, benzyloxy, phenethyloxy and the like) and the like.

Preferred examples of the acyloxy group are an acyloxy group having 2 to 13 carbon atoms, preferably an alkanoyloxy group having 2 to 4 carbon atoms (for example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and the like) and similar.

Preferred examples of the aryloxy group are an aryloxy group having 6 to 14 carbon atoms, such as phenoxy, naphthyloxy and the like.

Each of an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group and an aryloxy group described above can have 1 to 2 substituents at their possible positions, and such substituents include a halogen (e.g., fluorine, chlorine, bromine) and the like), an alkoxy group having 1 to 3 carbon atoms. For example, a substituted aryloxy group can be 4-chlorophenoxy, 2-methoxyphenoxy and the like.

The substituted thiol group optionally includes a thiol, an alkylthio, a cycloalkylthio, an aralkylthio, an acylthio, an arylthio, a heteroarylthio and the like.

Preferred examples of the alkylthio group are an alkylthio group having 1 to 19 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, pentthylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio and the like.

Preferred examples of the cycloalkylthio group are a cycloalkylthio group having 3 to 10 carbon atoms, such as cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.

Preferred examples of the aralkylthio group are an aralkylthio group having 7 to 10 carbon atoms, such as phenyl-C 4 alkylthio (for example, benzylthio, phenethylthio and the like) and the like.

Preferred examples of the acylthio group are an acylthio group having 2 to 13 carbon atoms, preferably an alkanoylthio group having 2 to 4 carbon atoms (for example, acetylthio, propionylthio, butyrylthio, isobutyrylthio and the like) and similar.

Preferred examples of the arylthio group are an arylthio group having 6 to 14 carbon atoms, such as phenylthio, naphthylthio and the like.

Preferred examples of the heteroarylthio group are 2-pyridylthio, 3-pyridylthio, as well as 2-imidazolylthio, 1,2,4-triazol-5-ylthio and the like.

The esterified carboxyl group optionally includes a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like), an aralkyloxycarbonyl group having 8 to 10 carbon atoms (per example, benzyloxycarbonyl and the like), an aryloxycarbonyl group having 7 to 15 carbon atoms optionally substituted with one or two alkyl groups having 1 to 3 carbon atoms (e.g., phenoxycarbonyl, p-tolyloxycarbonyl and the like) and similar.

The substituted amide-substituted carboxyl group optionally includes a group represented by the Formula: -C0N (R12) (R13), wherein R12 and R13 may be the same or different and is hydrogen, an optionally substituted hydrocarbon group and a heterocyclic group optionally replaced.

The hydrocarbon group and the heterocyclic group in "an optionally substituted hydrocarbon group" and "an optionally substituted heterocyclic group" represented by R 12 and R 13 include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group and a group heterocyclic exemplified as the same described in points (1-1) and (1-2) above, respectively. Such hydrocarbon groups and heterocyclic groups have 1 to 3 substituents in their possible positions optionally, and such substituents include a halogen (e.g., fluorine, chlorine, bromine, iodine and the like), an alkyl group having 1 to 4 carbon atoms. carbon, an alkoxy group having 1 to 4 carbon atoms and the like.

A substituent in the hydrocarbon group and the heterocyclic group represented by R 1 in Formulas (1-1) and (II) is preferably an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 1 to 10 carbon atoms. carbon, an aromatic heterocyclic group, an aryl group having 6 to 14 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, furyl, thienyl , phenyl and naphthyl.

The substituent in the hydrocarbon group and the heterocyclic group represented by R1, when it is an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic heterocyclic group or a non-aromatic heterocyclic group, has one or more, preferably 1 to 3 optionally appropriate substituents, and such substituents include an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalguyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms (for example, phenyl, naphthyl, and the like), an aromatic heterocyclic group (for example, thienyl, furyl, pyridyl, oxazolyl, thiazolyl and the like), a non-aromatic heterocyclic group (for example, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl and the like), an aralkyl group having 7 to 9 carbon atoms, an amino group, a mono or disubstituted amino group with an alkyl group having 1 to 4 carbon atoms or with an acyl group having 2 to 8 carbon atoms (for example, an alkanoyl group and the like), an amidino group, an acyl group having 2 to 8 carbon atoms (for example, a group alkanoyl and the like), a carbamoyl group, a mono- or disubstituted carbamoyl group with an alkyl group having 1 to 4 carbon atoms, a sulfamoyl group, a mono or disubstituted sulfamoyl group with an alkyl group having 1 to 4 carbon atoms, carbon, a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, an alkenyloxy group having 2 to 5 carbon atoms, a cycloalkyl group chyloxy having 3 to 7 carbon atoms, an aralkyloxy group having 7 to 9 carbon atoms, an aryloxy group having 6 to 14 carbon atoms (for example, phenyloxy, naphthyloxy and the like), a thiol group, a alkylthio group having 1 to 6 carbon atoms, an aralkylthio group having 7 to 9 carbon atoms, an arylthio group having 6 to 14 carbon atoms (for example, phenylthio, naphthylthio and the like), a sulfo group, a cyano group, an azide group, a nitro group, a nitroso group, a halogen atom (for example, fluorine, chlorine, bromine, iodine) and the like. (1-4) Preferred Examples of R1 R1 in Formulas (1-1) and (II) is preferably an optionally substituted heterocyclic group, and more preferably pyridyl, oxazolyl, thiazolyl or triazolyl, each of which is optionally substituted. A particularly preferred R1 is pyridyl, oxazolyl, thiazolyl or triazolyl, which optionally have 1 to 2 substituents selected from the group consisting of an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms , furyl, thienyl, phenyl and naphthyl. Furyl, thienyl, phenyl and naphthyl optionally have substituents selected from an alkyl having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen (eg, fluorine, chlorine, bromine, iodine and like) and a haloalkyl group having 1 to 3 carbon atoms.

Such a preferred ring of an optionally substituted heterocyclic group or a cyclic hydrocarbon group. optionally substituted of R1 is selected from the group represented by the formulas The ring has one or two substituents optionally, which are selected from the group consisting of a phenyl group, a furyl group, a thienyl group and a C? -4 alkyl group. The group consisting of a phenyl group, a furyl group and a thienyl group has substituents selected from a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogen (e.g., fluorine, chlorine, bromine, iodine and the like). similar), a nitro group, a haloalkyl group C? -6 / a haloalkoxy group C? -6.

An additional preferred example for R1 is a group represented by the formula wherein Ph is an optionally substituted phenyl group, and R "is hydrogen or an optionally substituted C.6 alkyl group.

The substituents of Ph and the C1-6 alkyl group of R1 'are a C1-6 alkoxy group, a halogen (for example, fluorine, chlorine, bromine, iodine and the like), a nitro group, a haloalkyl group C1 -6 or a halo-C1-6 alkoxy group. (2) Definition of X In Formulas (1-1), (1-2) and (II), X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is hydrogen, a optionally substituted alguyl group, with a bond, -CH (OH) - or -NR6- being preferred, and a -NR6- bond being most preferred.

An alkyl group in "an optionally substituted alkyl group" represented by R6 includes an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like. similar. Such an alkyl group has 1 to 3 substituents optionally at their possible positions, and such substituents include a halogen (fluorine, chlorine, bromine, iodine), an alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy) , isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy and the like), a hydroxy group, a nitro group, an acyl group having 1 to 4 carbon atoms (for example, an alkanoyl group having 1 to 4 carbon atoms, such as formyl, acetyl, propionyl and the like). (3) Definition of n and Y In Formulas (1-1), (1-2) and (II), n is an integer from 1 to 3, preferably 1 to 2.

In Formulas (1-1), (1-2) and (II), Y is -O-, -S-, -SO-, -S02- or -NR7", wherein R7 is hydrogen, an alguyl group optionally substituted, with -O-, -S- or -NR7- being preferred. "An optionally substituted alkenyl group" represented by R7 includes those exemplified as "an optionally substituted alkyl group" represented by R6 described above. (4) Definition of Ring A The ring A in the formulas (1-1), (1-2) and (II) represents a ring of. benzene, and has 1 to 3 additional substituents optionally in their possible positions. Such substituents include an alkyl group, an optionally substituted hydroxy group, a halogen atom, an optionally substituted acyl group, and an optionally substituted amino group, each of which is exemplified as a substituent on a hydrocarbon group and a heterocyclic group depicted by R1.

Such a substituent is preferably an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom. Ring A is preferably an unsubstituted benzene ring.

In the Formulas (1-1), and (II), a part: (5) Definition of P In Formulas (1-1), (1-2) and (II), p is an integer from 1 to 8, preferably an integer from 1 to 3. (6) Definition of R2 In Formulas (1-1), (1-2) and (II), "an optionally substituted hydrocarbon group" represented by R 2 may be one exemplified as "an optionally substituted hydrocarbon group" represented by R 1.

"An optionally substituted heterocyclic group" represented by R 2 may be one exemplified as "an optionally substituted heterocyclic group" represented by R 1.

In Formulas (1-1), (1-2) and (II), R2 is preferably an optionally substituted hydrocarbon group. More preferably, R2 is an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic-aliphatic hydrocarbon group or an aromatic hydrocarbon group, each of which is optionally substituted, and an alkyl group having 1 to 4 is particularly preferred. carbon atoms, a phenylalkyl group having 8 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms, one of which is optionally substituted.

A substituent which optionally occurs in each of the hydrocarbon groups described above is preferably a halogen atom, an alkoxy group having 1 to 4 carbon atoms, an aryloxy group having 6 to 14 carbon atoms and an aromatic heterocyclic group (eg, furyl, thienyl). (7) Definition of q, and m In Formulas (1-1) and (1-2), q is an integer from 0 to 6, preferably 0 to 4. m is 0 or 1. In Formula (1-1) where R1 is ethoxymethyl, a C?-3 alkyl, phenyl or p-methoxyphenyl group, q is an enetro from 1 to 6.

In Formula (II), q is an integer from 0 to 6, preferably 0 to 4. m is 0 or 1. (8) Definition of R3 R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a heterocyclic group optionally substituted or optionally substituted acyl group or R9 and R10 combine with each other to form a ring).

In Formulas (1-1), (1-2) and (II), "an optionally substituted hydrocarbon group" represented by R8 includes one exemplified as "an optionally substituted hydrocarbon group" represented by R1. A particularly preferred R8 is a hydroxy group.

In Formulas (1-1), (1-2) and (II), "an optionally substituted hydrocarbon group" represented by R9 and R10 includes one exemplified as "an optionally substituted hydrocarbon group" represented by R1.

In Formulas (1-1), (1-2) and (II), "an optionally substituted heterocyclic group" represented by R9 and Rx includes one exemplified as "an optionally substituted heterocyclic group" represented by R1.

In Formulas (1-1), (1-2) and (II), "an optionally substituted acyl group" represented by R9 and R10 includes one exemplified as "an optionally substituted acyl group" represented by R1.

In Formulas (1-1), (1-2) and (II), R9 and R10 optionally combine to form a ring, such as 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl, 4-morpholino, 4-thiomorpholino. (9) Definition of R4 and R5"An optionally substituted alkyl group" represented by R 4 and R 5 in Formulas (1-1), and (II) includes the same as "an optionally substituted alkyl group" represented by R 6 described above.

"An optionally substituted hydrocarbon group" and "an optionally substituted heterocyclic group" represented by R9 and R10 in Formulas (1-1), (1-2) and (II) includes the same as "an optionally substituted hydrocarbon group" "and" an optionally substituted heterocyclic group "represented by R 12 and R 13, respectively, described above.

"An optionally substituted hydrocarbon group" represented by R 11 in Formulas (1-1), (1-2) and (II) includes an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms optionally substituted with an alkyl group having 1 to 4 carbon atoms or with a halogen atoms. Such an alkyl group having 1 to 4 carbon atoms in "an alkyl group having 1 to 4 carbon atoms" and "an aryl group having 6 to 10 carbon atoms optionally substituted with an alkyl group having 1 to 4 atoms of carbon or with a halogen atom "represented by R8 includes methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, t-butyl, and the like, with methyl and ethyl being preferred. A halogen in "an aryl group having 6 to 10 carbon atoms optionally substituted with an alkyl group having 1 to 4 carbon atoms or with a halogen atom" includes fluorine, chlorine, bromine, iodine and the like, being preferred chlorine, and an aryl group having 6 to 10 carbon atoms may include phenyl and naphthyl, with phenyl being preferred. (10) Compound of form E and form Z A compound represented by Formulas (1-1), (1-2) and (II) is presented in E and Z isomers with respect to the imino bond. The compound can be either only one of the E or Z form, or it can be the mixture of the two.

The methyl 0- [2-chloro-4- (2-quinolylmethoxy) phenylmethyl] oxime of pyruvate and [2-chloro-4- (2-quinolylmethoxy) phenylmethyl] -2-iminoxypropionic acid are known compounds described in the document WO96 / 02507, and excluded from Formula (1-1). (11) Preferred Modalities Among the compounds of Formula (1-1), one of the preferred embodiments of the present invention is a compound represented by the formula wherein R 'is a phenyl group, a furyl group or a thienyl group, which optionally have substituents selected from a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogen (e.g., fluorine, chlorine, bromine) , iodine and the like), a nitro group, a halo-C1-e alkyl group, a halo-C6-alkoxy group; R1 'is hydrogen or an optionally substituted C1-6 alkyl group (more preferably hydrogen, methyl and ethyl); R2 'is a phenyl group which is optionally substituted by at least one selected from a group consisting of hydrogen, a C1-6 alkyl group, a C1-6 alkoxy group and a halogen; q is an integer from 1 to 6; and R3 'is a hydroxy group, a C1-6 alkoxy group or -NR9R10, in which R9 and R10 are independently selected from the group consisting of a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group and an optionally substituted acyl group, or R9 and R10 combine with each other to form a ring; Ring A is an optionally substituted benzene ring; or a salt of it.

Another preferred embodiment of the present invention is a compound represented by the formula where each symbol has the same definition mentioned above; or a salt of it.

Preferred specific examples of the compound represented by Formulas (1-1), (1-2) and (II) are Compound (1) to (10) indicated below. (1) Z-2- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2-phenylacetic acid (2) Z-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (3) Z-2- (4-bromo-phenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (4) Z-2- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (4-phenoxyphenyl) acetic acid (5) Z-4- (4-fluorophenyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (6) Z-3-Methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (7) E-4- [4- (5-methyl-2-f enyl-4-oxazolylmethoxy) benzyloxyimino] -4-f-enylbutyric acid (8) E-4- (4-fluorophenyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (9) E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenyIbutyramide (10) E-8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoic acid These compounds can be abbreviated below as Compound (1), Compound (2) or the like. (12) Examples of Sales A salt of a compound represented by Formula (1-1), (1-2) or (II) (which may be abbreviated as Compound (1-1), (1-2) or (II)) is preferably a pharmacologically acceptable salt, such as a salt with an inorganic base, a salt with an organic base, a salt with an organic acid, a salt with an organic salt, a salt with a basic amino acid or acid and the like.

Preferred examples of the salt with an organic base are an alkali metal salt, such as a sodium salt and a potassium salt; an alkaline earth metal salt, such as a magnesium salt; as well as an aluminum salt and an ammonium salt and the like.

Preferred examples of the salt with an organic base are salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.

Preferred examples of the salt with an organic acid are salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

Preferred examples of the salt with an organic acid are salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, acid p-toluenesulfonic and the like.

Preferred examples of the salt with a basic amino acid are salts with arginine, lysine, ornithine, and the like, while preferred examples of a salt with an acidic amino acid are salts with aspartic acid, glutamic acid and the like.

Among the salts described above, those preferred are sodium salts, potassium salts, hydrochlorides and the like. (13) Formulation A compound represented by Formulas (1-1), (1-2) or (II) and a salt thereof (which can be abbreviated below as a compound according to the present invention) has low toxicity, and they can be formulated together with a pharmacologically acceptable carrier in a pharmaceutical composition, which can be used as an agent for the prevention and / or treatment of several diseases discussed below in mammals (e.g., human, mouse, rat, rabbit, dog , cat, cattle, horse, pig, monkey and the like).

The pharmacologically acceptable carrier employed herein is selected from various usual organic and inorganic materials used as materials for pharmaceutical formulations, and can be incorporated as excipients, glidants, binders and disintegrants in a solid formulation; vehicles, solubilizers, suspending agents, tonicity agents, buffer, analgesic agents in a liquid formulation. If necessary, it is also possible to add pharmaceutical additives, such as preservatives, antioxidants, dyes, sweeteners.

Preferred examples of the excipients are lactose, sugar, D-mannitol, D-sorbitol, starch, α-starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan, light silicic anhydride, synthetic aluminum silicate, magnesium aluminate metasilicate and the like.

Preferred examples of the glidants are magnesium stearate, calcium stearate, talc, colloidal silica and the like.

Preferred examples of the binders are α-starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sugar, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.

Preferred examples of the disintegrants are sugar, starch, carboxymethylcellulose, potassium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light silicic anhydride, low substituted hydroxypropylcellulose and the like.

Preferred examples of the vehicles are water for injection, physiological saline solution, Linger's solution, alcohols, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

Preferred examples of the solubilizers are polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and so on. similar.

Preferred examples of the suspending agents are a surfactant, such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like; a hydrophilic polymer, such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and polysorbates, hydrogenated polyoxyethylene castor oil and the like.

Preferred examples of the tonicity agents are sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.

Preferred examples of the buffer solution are solutions of phosphates, acetates, carbonates, citrates and the like.

Preferred examples of the analgesic agents include benzyl alcohol and the like.

Preferred examples of the preservatives are p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

Preferred examples of antioxidants are sulphites, ascorbates and the like.

Preferred examples of colorants are water-soluble tar pigments (for example, edible pigments, such as edible Red No. 2 and No. 3, Edible No. 4 and No. 5 Edible Color, Blue No. 1 color) and No. 2 edible), water-insoluble lacquer pigments (for example, aluminum salts of the water-soluble edible tar pigments indicated below and the like), a natural pigment (eg, β-carotene, chlorophyll, red iron oxide and the like) and the like.

Preferred examples of the sweeteners are saccharin sodium, glycyrrhizinate, Aspartame, steviolates and the like. (14) Dosage Form A dosage form of a pharmaceutical composition includes an oral formulation, such as a capsule (including a soft capsule and a microcapsule), a granule, a powder, a syrup, an emulsion, a suspension and the like; a non-oral formulation, such as a formulation for injection (eg, formulation for subcutaneous injection, formulation for intravenous injection, formulation for intramuscular injection, formulation for intraperitoneal injection and the like), a formulation for infusion by drip, a formulation for application external (eg, nasal formulation, percutaneous formulation, ointments and the like), a suppository (eg, rectal suppository, vaginal suppository and the like), a pellet, a drip infusion formulation and the like, all of which they can be given safely via an oral or a non-oral route.

The pharmaceutical composition can be produced by a conventional method in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.

A method for producing a formulation is described in detail below.

An oral formulation is, for example, prepared by mixing an active ingredient with an excipient (e.g., lactose, sugar, starch, D-mannitol and the like), a disintegrant (e.g., calcium carboxymethylcellulose and the like), a binder (for example, α-starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone and the like), or a glidant (eg, talc, magnesium stearate, polyethylene glycol 6000 and the like), followed by compacting molding, further followed, if necessary, by coating with a coating base by a known method for the purpose of masking a flavor, obtaining an enteric solution or a sustained release.

Such a coating base includes a sugar coating base, a water soluble film coating base, an enteric coating base, a sustained release film coating base, and the like.

A sugar coating base includes sugar, which can be used in combination with one or more materials selected from the group consisting of talc, settling calcium, carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like.

A water soluble film coating base includes a cellulose based polymer, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylhydroxyethylcellulose and the like; a synthetic polymer, such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (tradename), Rohm Pharma], polyvinylpyrrolidone and the like; and a polysaccharide, such as pullulan.

An enteric film coating base includes a cellulose-based polymer, such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; a polymer based on acrylic acid, such as methacrylic acid copolymer L [Eudragit L (trade name), Rohm Pharma], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma], methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma] and the like; a material that exists naturally, such as shellac.

A sustained release film coating base includes a cellulose based polymer, such as ethylcellulose; a polymer based on acrylic acid, such as RS aminoalkyl methacrylate copolymer [Eudragit RS (tradename), Rohm Pharma], ethylacrylate-methyl methacrylate copolymer suspension [Eudragit NE (tradename), Rohm Pharma] and the like.

A mixture of two or more coating bases described above may also be employed in a certain appropriate proportion. A material that protects from light, such as titanium oxide and iron dioxide or trioxide, can also be employed in the coating.

A formulation for injection can be prepared by dissolving, suspending or emulsifying an active ingredient together with a dispersant (for example, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like), polyethylene glycol, carboxymethylcellulose, sodium alginate and the like , a preservative (e.g., methylparaben, propylparaben, benzyl alcohol, chlorbutanol, phenol and the like), a tonicity agent (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like) and the like, - in an aqueous solvent (eg, distilled water, physiological saline solution, Linger's solution and the like) or a lipophilic solvent (eg, a vegetable oil, such as an olive oil, sesame oil, oil of cottonseed, corn oil and the like or propylene glycol). In this process, an additive, such as a solubilizer (e.g., sodium salicylate, sodium acetate and the like), a stabilizer (e.g., human serum albumin and the like), an analgesic agent, may also be employed if necessary. (for example, benzyl alcohol and the like). (15) Composition The other aspect of the present invention is a pharmaceutical composition comprising a compound represented by the formula (II) R 'R4 R5 A (CH p-O-N = C I- (CH,) q- (VC) m- C (= 0) -R3 (||) R -X- (CH2) p-Y wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a heterocyclic group optionally substituted and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups, which are selected from a hydrogen atom or an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it. Each of the substituents mentioned above have the same detailed definition as defined for the corresponding Formula (1-1).

Especially, the pharmaceutical composition can be used for the prevention or treatment of diseases, such as diabetes mellitus, hyperlipidemia, impaired glucose tolerance, inflammatory disease, arteriosclerosis and the like.

Among these compositions, a preferred one is a composition of a compound represented by the formula R wherein R 'is phenyl, furyl or thienyl, which optionally have substituents selected from a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogen (e.g., fluorine, chlorine, bromine, iodine and the like), a nitro group, a halo-C1-6 alkyl group, a halo-C6-6 alkoxy group; R "is a hydrogen or a C.6 aligyl group optionally substituted (more preferably, hydrogen, methyl or ethyl); R 2 is a phenyl group, which is optionally substituted by one selected from a group consisting of a hydrogen, a C 1-6 alkyl, a C 1-6 alkoxy and a halogen; q is an integer from 1 to 6; and R3 'is a hydroxy group, a C1-6 alkoxy group or -NR9R10, in which R9 and R10 are independently selected from the group consisting of a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or R9 and R10 combine with each other to form a ring; Ring A is an optionally substituted benzene ring; or a salt of it.

Another preferred composition of the present invention is a composition comprising a compound represented by the formula ? \ where each symbol has the same definition mentioned above; or a salt of it. (16) Agent According to the useful function of the compound of the present invention, the compound can be used as an agent that increases insulin sensitivity; an agent that improves insulin resistance; an agent for controlling or adjusting the receptor related to the retinoid, a ligand of the peroxisome proliferator-activated receptors; a ligand of the retinoid X receptor; etc.

A compound according to the present invention has an effect that reduces blood sugar, an effect that reduces the lipid in the blood, an effect that reduces insulin in the blood, an effect that increases the sensitivity to insulin, a effect that improves insulin resistance and activities as adjuvant of receptor function related to retinoid. A receptor related to the retinoid used herein is included in the nuclear receptors, and is a DNA-binding transcription factor that has as a function adjuster a signal molecule, such as an oil-soluble vitamin, and can be any one of a monomer receptor, a homodimer receptor and a heterodimer receptor.

A monomer receptor is exemplified by the retinoid O receptor (hereinafter abbreviated occasionally as ROR) to (Access to Genetic Bank No. L14611), RORß (Access to Genetic Bank No. L14160), ROR? (Access to the Genetic Bank No. U16997); Rev-erba (Access to the Genetic Bank No. M24898), Rev-erbß (Access to the Genetic Bank No. L31785), ERRa (Access to the Genetic Bank No. X51416); ERRß (Access to the Genetic Bank No. X51417); Ftz-FIa (Access to the Genetic Bank No. S65876), Ftz-Flß (Access to the Genetic Bank No. M81385); TIx (Access to the Genetic Bank No. S77482); GCNF (Access to the Genetic Bank No. U14666) and the like.

A homodimer receptor can be, for example, a homodimer formed from the retinoid X receptor (hereinafter abbreviated as RXR) to (Access to Genetic Bank No. X52773), RXRβ (Access to Genetic Bank No.

M84820), RXR? (Access to the Genetic Bank No. U38480); COUPa (Access to the Genetic Bank No. X12795), COUPß (Access to the Bank Genetic No. M64497), COUP? (Access to the Genetic Bank No. X12794); TR2a (Access to the Genetic Bank No. M29960), TR2ß (Access to the Genetic Bank No. L27586); or, HNF4a (Access to Genetic Bank No. X76930), HNF4? (Access to the Genetic Bank No. Z49826) and the like.

A heterodimer receptor can be, for example, a heterodimer formed from the retinoid X receptor (RXRa, RXRβ, RXRα) described above together with a receptor selected from the group consisting of retinoid A receptor (hereinafter abbreviated occasionally as RAR) a (Access to the Genetic Bank No. X06614), RARß (Access to the Genetic Bank No. Y00291), RAR? (Access to the Genetic Bank No. M24857); a thyroid hormone receptor (hereinafter abbreviated as TR) to (Access to Genetic Bank No. M24748), TRβ (Access to Genetic Bank No. M26747); a vitamin D receptor (VDR) (Access to Genetic Bank No. J03258); a receptor activated by the peroxisome proliferator (hereinafter abbreviated as PPAR occasionally) to (Access to Genetic Bank No. L02932), PPARβ (PPAR d) (Access to Genetic Bank No. U10375), PPAR? (Access to the Genetic Bank No. L40904); LXRa (Access to the Genetic Bank No. U22662), LXRß (Access to the Genetic Bank No. U14534); FXR (Access to the Bank Genetics No. U18374); MB67 (Access to the Genetic Bank No. L29263), - ONR (Access to the Genetic Bank No. X75163); and NURa (Access to the Genetic Bank No. L13740), NURß (Access to the Bank Genetics No. X75918), NUR? (Access to the Genetic Bank No. U12767).

The compound (1-1) and its salts exhibit excellent activity as a function adjuster especially towards the retinoid X receptors (RXRa, RXRβ, RXRα) and peroxisome proliferator-activated receptors (PPARα, PPARβ ((PPAR d), PPAR) ?) among those receptors related to the retinoid indicated above.

In addition to Compound (II) or its salts exhibit excellent activity as a ligand to a heterodimer receptor formed from a retinoid X receptor and a peroxisome proliferator-activated receptor, preferably a peroxisome proliferator-activated receptor as in the heterodimer receptor formed from RXRa and PPAR ?.

Accordingly, a retinoid-related receptor function adjuster according to the present invention is advantageously used as a receptor ligand activated by the peroxisome proliferator or a ligand of the retinoid X receptor. (17) Diseases that are treated Accordingly, a compound or a pharmaceutical composition according to the present invention can be used for the prevention or treatment of diabetes mellitus (for example, insulin-dependent diabetes mellitus (diabetes mellitus type 1), non-insulin dependent diabetes mellitus (diabetes mellitus of type 2), diabetes mellitus in pregnancy and the like), hyperlipidemia (eg, hypertriglycemia, hypercholesterolemia, hypoHDLemia and the like), insulin insensitivity, insulin resistance, and impaired glucose tolerance (IGT).

A compound or a pharmaceutical composition according to the present invention can also be used for the prevention or treatment of diabetic complications (eg, neuropathy, nephropathy, retinopathy, cataract, large blood vessel disorders, osteopenia and the like), obesity, osteoporosis, cachexia (e.g., carcinomatous cachexia, tuberculous cachexia, diabetic cachexia, hemophagous cachexia, endocrinophatic cachexia, infectious cachexia or cachexia induced by acquired immunoinsufficiency syndrome), adipose liver, hypertension, polycystic ovarian syndrome, renal disorders (e.g. , glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, terminal renal disorders and the like), muscular dystrophy, myocardial infarction, angina pectoris, cerebral infarction, insulin resistance syndrome, syndrome X, sensory disorder induced by hyperinsulinemia , tumors (for example, leukemia, breast cancer, prostate cancer, skin cancer and the like), inflammatory diseases (eg, rheumatoid arthritis, spondylitis deformities, osteoarthritis, lumbago, gout, inflammation and surgical wound swelling remedy, neuralgia, pharyngolaryngitis , cystitis, hepatitis, pneumonia, pancreatitis and the like), arterial sclerosis (for example, atherosclerosis and the like).

A compound according to the invention can also be used as a pharmaceutical product to control appetite, food intake, diet and anorexia.

While the dose of a compound or a pharmaceutical composition according to the present invention varies depending on several factors, such as the subject being treated, the route of administration, the disease or the condition being treated, a compound according to The present invention as an active ingredient can be, for example, given orally to an adult in a single dose of about 0.05 to 100 mg / kg of body weight, preferably about 0.1 to 10 mg / kg of body weight, so preferable one up to three times a day. (18) Combination of Drug Use A compound according to the present invention can be used in combination with an agent that treats diabetes mellitus, an agent that treats diabetic complication, an antihyperlipidemic agent, a hypotensive agent, an anti-obesity agent, a diuretic, a chemotherapeutic agent, a immunotherapeutic agent and the like (hereinafter referred to as a concomitant agent). In such a case, the periods of treatments with a compound according to the present invention and with a concomitant agent are not particularly limited, and such agents can be given to a patient simultaneously or at a certain time interval. The dose of a concomitant drug can be appropriately determined based on the usual clinical dose. The ratio between a compound according to the present invention and a concomitant agent can be appropriately determined on the basis of various factors, such as the subject being treated, the route of administration, the disease or condition being treated and the combination of the drugs. For example, when treating a human, 1 parts by weight of a compound according to the present invention is combined with 0.01 to 100 parts by weight of a concomitant agent.

Examples of an agent for treating diabetes mellitus are an insulin formulation, (eg, animal insulin formulations extracted from the pancreas of cattle or a pig, an animal insulin formulation synthesized by a genetic engineering technology using colibacilli and yeast ), an agent that increases insulin sensitivity (eg, pioglitazone, hydrochloride, troglitazone, rosiglitazone and the like), an a-glycosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate and the like), an Biguanide (for example, phenformin, metoformin, buformin and the like), or a sulphonylurea (for example, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glycopyramide, glimepiride and the like), as well as other agents that promote secretion of insulin (eg, repaglinide, senaglinide, nateglinide, mitiglinide, GLP-1 and the like), amyrin agonist (eg, pramlintid) a and the like), inhibitor of phosphotyrosine phosphatase (for example, vanadic acid and the like) and the like.

Examples of an agent to treat diabetic complications are an aldose reductase inhibitor (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidareatat, SK-860, CT-112 and the like), a neurotrophic factor (e.g. NGF, NT-3, BDNF and the like), PKC inhibitor (e.g., LY-333531 and the like), AGE inhibitor (e.g., ALT946, pimagenide, piradoxamine, phenacylthiazolium bromide (ALT766) and the like) , an active oxygen quenching agent (e.g., thioctic acid and the like), a cerebrovascular dilation agent (e.g., thiapride, mexiletene and the like). • An antihyperlipidemic agent may be, for example, a statin-based compound, which is an inhibitor of cholesterol synthesis (eg, pravastatin, simvastatin, lovastatin, atrvastatin, fluvastatin, cerivastatin, and the like), an inhibitor of squalene synthetase or a fibrate compound that has an effect that lowers triglycerides (for example, benzafibrate, clofibrate, synfibrate, clinofibrate and the like) and the like.

A hypotensive agent may be, for example, an enzyme inhibitor that converts angiotensin (eg, captropil, enalapril, delapril and the like) or an angiotensin II agonist (eg, losartan, candesartan cilexetil, eprosartan, valsartan, telmisartan, irbesartan, tasosartan and the like) and the like.

An anti-obesity agent can be, for example, a central antiobesity agent (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamfetamine, mazindol, phenylpropanolamine, clobenzorex and the like), a pancreatic lipase inhibitor (e.g., orlistat). and the like), a β3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085 and the like), an appetite-suppressing agent based on peptides (for example, leptin, CNTF and the like), a cholecystokinin agonist (for example, lintitript, FPL-15849 and the like) and the like.

A diuretic may be, for example, a xanthine derivative (eg, sodium theobryl salicylate, theobromine salicylate and the like), a thiazide formulation (for example, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylchlororthiazide, penflutizide, polythiazide, methylclothiazide and the like), antialdosterone formulation (eg, spironolactone, triamterene and the like), a decarboxylase inhibitor (eg, acetazolamide) and the like), a formulation of chlorbenzenesulfonamide (for example, chlorthalidone, mefruside, indapamide and the like), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

A chemotherapeutic agent may be, for example, an alkylating agent (for example, cyclophosphamide, ifosfamide and the like), an antagonsite-of metabolism (for example, methotrexate, 5-fluorouracil and the like), an anticancer antibiotic (e.g. , mitomycin, adriamycin and the like), an anticancer agent derived from plant plants (for example, vincristine, vindesine, taxol and the like), cisplatin, carboplatin, etoposide and the like. Among these substances, 5-fluorouracil derivatives, such as furtulon and neofurtulon, are preferred.

An immunotherapeutic agent can be, for example, a microorganism or a bacterial component (eg, derivative of muramyl dipeptide, picibanil and the like), a polysaccharide having potential immune activity (eg, lentinan, sizofilan, crestin and the like ), a cytokine obtained by a genetic engineering technology (e.g., interferon, interleukin (IL) and the like), a colony stimulation factor (e.g., granulocyte colony stimulating factor, erythropoetin and the like), and the like, between. These substances, those preferred are IL-1, IL-2, IL-12 and the like.

In addition, an agent whose effect that improves cachexia has been established in an animal model or in a clinical stage, such as a cyclooxygenase inhibitor (e.g., indomethacin and the like) [Cancer Research, Vol. 49, page 5935-5939 , 1989], a progesterone derivative (eg, megestrol acetate) [Journal of Clinical Oncology, Vol. 12, page 213-225, 1994], a glycosteroid (e.g., dexamethasone and the like), an agent based on metoclopramide, an agent based on tetrahydrocannabinol (supra), an agent that improves lipid metabolism (eg, eicosapentaenoic acid and the like) [British Journal of Cancer], Vol. 68, page 314-318, 1993], a hormone of growth, IGF-1, or an antibody against TNF-α, LIF, IL-6, oncoestatin M, which are factors that induce cachexia, can also be used concomitantly with a compound according to the present invention.

Preferred possible combinations of the agents for the prevention and / or treatment of the diseases mentioned above are as follows; (1) an agent that increases insulin sensitivity, an insulin formulation and a Biguanide; (2) an agent that increases sensitivity to insulin, a sulfonylurea agent and a Biguanide; (3) an agent that increases insulin sensitivity, a sulfonylurea agent and an a-glycosidase inhibitor; (4) an agent that increases insulin sensitivity, a Biguanide and an a-glycosidase inhibitor; (5) an agent that increases sensitivity to insulin, an agent that reduces blood sugar and other agents to treat diabetic complications; Y (6) an agent that increases sensitivity to insulin, and any of the other two types of agents mentioned above.

In the case that the compound or composition of the present invention is used in combination with the other agent, an amount of each different agent can be reduced in a range which is safe in view of its adverse effect. Especially, an agent that increases insulin sensitivity, a Biguanide and a sulfonylurea agent can be used at a lower dose than the regular dose. In this way, the adverse effect which can be caused by these agents can be safely avoided. In addition, an agent for treating diabetic complications, an anti-hyperlipidemic agent and a hypotensive agent can also be used at a lower dose, so that the adverse effect which can be caused by these agents can effectively be avoided. (19) Production Methods A method for preparing a compound according to the present invention is described below. Since Compounds (1-1) and (1-2) are included in Compound (II), a method for preparing the Compound is described below (II) - Compound (II) according to the present invention can be prepared by a method known per se, such as Method A and Method B shown below, as well as analogous methods.

[Method A] R R "HO - N: •« *,) "- ((Oc). - c II (I V) (I I) RJ = OR »-X (CH ..) 'n. l * H (CH2) D-C wherein Z is a hydroxyl group, a halogen atom or a group represented by OS02R18, wherein R18 is an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms which can be replace with an alkyl group having 1 to 4 carbon atoms, and other symbols are defined as described above.

In this scheme, an alkyl group having 1 to 4 carbon atoms in "an alkyl group having 1 to 4 carbon atoms" and "an aryl group having 6 to 10 carbon atoms, which can be substituted with an alkyl group having 1 to 4 carbon atoms "represented by R18, can be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, with methyl being preferred.

An aryl group having 6 to 10 carbon atoms in "an aryl group having 6 to 10 carbon atoms, which can be substituted with an alkyl group having 1 to 4 carbon atoms" represented by R 18 can be example, phenyl, naphthyl, with phenyl being preferred.

In this method, Compound (III) is reacted with Compound (IV) to produce Compound (II).

When Z is a hydroxy group, this reaction can be carried out by a method known per se, for example, a method described in Synthesis, page 1 (1981) or analogous methods. Therefore, this reaction is usually carried out in the presence of an organic phosphorus compound or an electrophilic reagent in a solvent which has no adverse effect on the reaction.

An organic phosphorus compound can be, for example, triphenylphosphine, tributylphosphine and the like.

An electrophilic reagent can be, for example, diethyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbonyldipiperazine and the like.

The amounts that were used of an organic phosphorus compound and an electrophilic reagent were about 1 to about 5 molar equivalents for Compound (IV).

A solvent that has no adverse effect on the reaction can be, for example, an ether, such as diethyl ether, tetrahydrofuran, dioxane and the like; a halogenated hydrocarbon, such as chloroform, dichloromethane and the like; an aromatic hydrocarbon, such as benzene, toluene, xylene and the like; an amide, such as N, N-dimethylformamide; a sulfoxide,. such as dimethyl sulfoxide and the like. These solvents can be used as a mixture in an appropriate ratio.

The reaction temperature is usually about -50 ° C to about 150 ° C, preferably about -10 ° C to about 100 ° C.

The reaction time is about 0.5 to about 20 hours.

When Z is a halogen atom or a group represented by OS02R18, this reaction is carried out by a standard method in the presence of a base in a solvent that has no adverse effect on the reaction.

A base may be, for example, an alkali metal salt, such as potassium hydroxide, sodium hydroxide, sodium acid carbonate, sodium carbonate and the like; an amine, such as pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undeca-7-en and the like; a metal hydride, such as potassium hydride, sodium hydride and the like; an alkali metal alkoxide, such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like.

The amount of a base indicated above is preferably about 1 to 5 molar equivalents for Compound (IV).

A solvent that has no adverse effect on the reaction can be, for example, an aromatic hydrocarbon, such as benzene, toluene, xylene and the like; an ether, such as tetrahydrofuran, dioxane and the like; a ketone, such as acetone, 2-butanone and the like; a halogenated hydrocarbon, such as chloroform, dichloromethane and the like; an amide, such as N, N-dimethylformamide; a sulfoxide, such as dimethyl sulfoxide and the like. These solvents can be used as a mixture in an appropriate ratio.

The reaction temperature is usually about -50 ° C to about 150 ° C, preferably about -10 ° C to about 100 ° C.

The reaction time is usually about 0.5 to about 20 hours.

Subsequently, Compound (II, R3 = OR8) is hydrolysed if necessary to produce Compound (II '').

This hydrolyzation can be carried out by a standard method, in the presence of an acid or a base, in a solvent containing water.

An acid can be, for example, hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid and the like.

A base may be, for example, an alkali metal carbonate, such as potassium carbonate, sodium carbonate and the like; a metal alkoxide, such as sodium methoxide and the like; an alkali metal hydroxide, such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like.

The amount used of an acid or a base is usually in excess relative to Compound (II). Preferably, the amount of an acid that is employed is about 2 to 50 equivalents for Compound (II), while the amount of a base that is employed is about 1.2 to 5 equivalents for Compound (II).

A solvent containing water can be, for example, a mixture of solvents consisting of water and one or more solvents selected from the group consisting of an alcohol, such as methanol, ethanol and the like; an ether, such as tetrahydrofuran, dioxane and the like; dimethyl sulfoxide and acetone and the like.

The reaction temperature is usually about -20 ° C to about 150 ° C, preferably about -10 ° C to about 100 ° C.

The reaction time is usually about 0.5 to about 20 hours.

Compound (II) and Compound (II1 ') thus obtained can be isolated and purified by a known separation and purification procedure, such as concentration, reduced low pressure concentration, solvent extraction, crystallization, recrystallization, partition and chromatography. and the like.

Compound (III) and Compound (IV) used as starting materials in Method A described above are known compounds, and, for example, Compound (III), wherein Z is a hydroxy group is described in EP -A 710659. Compound (III) is also described in EP-A 629624 (Japanese Patent Application Laid-open No. 7-53555), WO 98/03505 and the like. The compound (III) can also be prepared by a method analogous to those described in these publications.

Compound- (IV) is described for example in Journal fur Praktische Chemie, Vol. 311, page 370 (1969); Canadian Journal of Chemistry, Vol. 48, page 1948 (1970); Journal of Heterocyclic Chemistry, Vol. 25, page 1283 (1988) and the like. Compound (IV) can also be prepared by a method analogous to those described in these publications.

Among Compound (II), a compound wherein R2 is a phenyl group substituted by an aliphatic hydrocarbon group and the like can also be prepared by Method B known below.

+ W-B (0H). (V) -R (II -2) R > = 0R « wherein W is an aliphatic hydrocarbon group, an aromatic hydrocarbon group or optionally substituted aromatic heterocyclic group, and other symbols are defined as described above.

"An aliphatic hydrocarbon group" represented by W may be an aliphatic hydrocarbon group exemplified as a substituent on a hydrocarbon group and a heterocyclic group represented by R1.

Each of an aromatic hydrocarbon group and an aromatic heterocyclic group in "an aromatic hydrocarbon group or optionally substituted aromatic heterocyclic group" represented by W can be an aromatic hydrocarbon group and an aromatic heterocyclic group each exemplified as a substituent in a hydrocarbon group and a heterocyclic group represented by R1. A substituent in these aromatic hydrocarbon and heterocyclic aromatic groups may be an exemplified substituent as a substituent when a substituent on a hydrocarbon group and a heterocyclic group represented by R 1 is an alicyclic hydrocarbon group, an aromatic hydrocarbon group, a group aromatic heterocyclic or a non-aromatic heterocyclic group.

In this method, Compound (II-1) is reacted with the boronic acid compound (V) to produce Compound (H-2).

This reaction is carried out by a method known per se, such as a method described in Journal of Organic Chemistry, Vol. 58, page 2201 (1993) or in Journal of Organic Chemistry, Vol. 60, page 1060 (1995), in the presence of a metallic catalyst and a base, in a solvent that has no adverse effect on the reaction.

A metallic catalyst can be, for example, palladium metal, nickel metal and the like. A palladium metal catalyst can be, for example, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium and the like, and a nickel metal catalyst can be, for example, 1,1'-bis (diphenylphosphino) nickel. ) Ferrocene and the like.

A base may be, for example, an alkali metal bicarbonate, such as sodium bicarbonate; an alkali metal carbonate, such as sodium carbonate, potassium carbonate; an alkali metal phosphate, such as tripotassium phosphate and the like.

The amount used of a metal catalyst is about 0.01 to about 1 molar equivalent, preferably about 0.05 to about 0.5 molar equivalent for Compound (II-D.

The amount used of a base is about 1 to 20 molar equivalents, preferably about one to about 10 molar equivalents for the compound (II-1).

A solvent that has no adverse effect on the reaction can be, for example, an aromatic hydrocarbon, such as benzene, toluene and the like; an alcohol, such as methanol, ethanol and the like; an ether, such as tetrahydrofuran, dioxane and the like; water and the like. These solvents can be used in a mixture in a suitable ratio. The types of solvents can be appropriately selected depending on the types of the metal catalysts.

The amount of the boric acid compound (V) employed is about 1 to 7 molar equivalents, preferably about 1 to about 5 molar equivalents for the compound (II-1).

The reaction temperature is usually about -20 ° C to about 150 ° C, preferably about 0 ° C to about 100 ° C.

The reaction time is about 0.1 to about 24 hours.

Subsequently, Compound (II-2, R3 = OR8) is hydrolyzed to produce Compound (II '' -1).

This hydrolyzation can be carried out similarly to hydrolyzation in Method A.

Compound (II-2) and (II "-1) thus obtained can be isolated and purified by a known separation and purification process, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography and the like.

Compound (II-1) used as starting material in Method B described above can be, for example, produced by Method A described above. Compound (V) is a known compound described in Organic Synthesis, Vol. 39, page 3 (1959); Journal of American Chemical Society, Vol. 94, page 4370 (1972) and the like. The compound (V) can also be prepared by a method analogous to those described in these publications.

Compound (II) can be produced by [Method C] or [Method D] described below.

[Method C] R1-X- (CH2) n-Y-? J (CH2) pO-NH2 -0 = C f- (CH2) q-V (C) m-Cf-R3 (VI) (VII) In this method, the reaction between Compound (VI) and Compound (VII) results in Compound (II). This reaction can be carried out by a method known per se. Thus, this reaction can be carried out in the presence of an acid or a base in a solvent that has no effect on the reaction. Such acid includes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like. Such base includes sodium carbonate, potassium carbonate, sodium acetate, ammonia (aqueous) and the like. The amount used of an acid or a base is usually about 1 to 10 molar equivalents for Compound (VI). A solvent that has no effect on the reaction includes ethers, such as tetrahydrofuran, dioxane and the like, alcohols, such as methanol, ethanol and the like, as well as dimethyl sulfoxide, acetic acid, water and the like. Any of these solvents can be used in combination with each other at an appropriate ratio. The reaction temperature is usually about -50 ° C to about 150 ° C, preferably about -10 ° C to about 120 ° C.

Subsequently, if desired, Compound (II) can be hydrolyzed to form Compound (II1 1). This reaction can be carried out similar to the hydrolyzation in Method A.

Compound (II) and Compound (II '') thus obtained can be isolated and purified by a known isolation and purification method, such as concentration, concentration under reduced pressure, extraction with a solvent, crystallization, recrystallization, partition , chromatography and the like.

[Method D] In this method, the reaction between Compound (VIII) and Compound (IX) results in Compound (II). This reaction can be carried out similarly to the reaction between Compound (III) and Compound (IV) in Method A.

Subsequently, if desired, Compound (II) can be hydrolyzed to form Compound (II1 1). This reaction can be carried out similar to the hydrolyzation in Method A.

The compound (II) and Compound (II ") thus obtained can be isolated and purified by a known isolation and purification method, such as concentration, concentration under reduced pressure, extraction with a solvent, crystallization, recrystallization, partition. , chromatography and the like.

A compound wherein R3 is NR9R10 in Compound (II) can be produced by Method E shown below.

[Method E] In this method, Compound (II ") is amidated to produce Compound (II '' '). This reaction can be carried out by a method known per se, ie a direct condensation between Compounds (II ") and Compound (X) using a condensation reagent (eg, dicyclohexylcarbodiimide), or can be carried performed by an appropriate reaction of a reactive derivative of Compound (II ") with Compound (X). In such a reaction, a reactive derivative of Compound (II ") includes an acid anhydride, an acid halide (acid chloride, acid bromide), imdazole, or a mixed acid anhydride (e.g., anhydride with sodium carbonate). methyl, ethyl carbonate, isobutyl carbonate, and the like) and the like. For example, when acid halide is employed, the reaction can be carried out in the presence of a base, in a solvent that has no effect on the reaction. Such base may be, for example, triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium bicarbonate, sodium carbonate, potassium carbonate and the like. Such a solvent that has no effect on the reaction includes a halogenated hydrocarbon, such as chloroform and dichloromethane; an aromatic hydrocarbon, such as benzene and toluene; an ether, such as tetrahydrofuran and dioxane, as well as ethyl acetate and water. Any of these solvents can be used in combination with each other in an appropriate ratio. The amount of Compound (X) that is used is about 1 to 10 molar equivalents for Compound (II'1), preferably 1 to 3 molar equivalents. The reaction temperature is usually about -30 ° C to about 100 ° C, and the reaction time fluctuates from about 0.5 to 20 hours. When a mixed acid anhydride is used, the Compound (II ") is reacted with chlorocarbon ester (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) in the presence of a base (e.g., triethylamine, N-methylmorpholine, N, N-dimethylaniline, bicarbonate sodium, sodium carbonate, potassium carbonate) and furthermore is reacted with Compound (X). The amount of Compound (X) that is used is about 1 to 10 molar equivalents for Compound (II "), preferably about 1 to 3 molar equivalents. The reaction temperature is usually about -30 ° C to about 100 ° C, and the reaction time fluctuates from 0.5 to 20 hours.

Compound (II '' ') thus obtained can be isolated and purified by a known isolation and purification method, such as concentration, concentration under reduced pressure, extraction with a solvent, crystallization, recrystallization, partition, chromatography and the like .

Compound (IV) used as starting material in Method C can be produced by a method known per se, such as a method described in Journal of Organic Chemistry, Vol. 36, page 3836 (1971) or a method analogous thereto. .

Compound (IX) used as starting material in Method D can be produced by Method F shown below.

[Method F] (XI) (IV) (IX) This method is carried out similarly to the reaction between Compound (III) and Compound (IV) in Method A. The -YH part in Compound (XI) can be protected before the condensation reaction and then deprotected afterwards. of the reaction. A protecting group which may be employed are a benzyl group, a methoxymethyl group, a silyl group (for example, trimethylsilyl group, t-butyldimethylsilyl group) and the like.

BEST WAY TO CARRY OUT THE INVENTION The present invention is further detailed in the following Experiments, Reference Examples, Examples and Formulation Examples, which are not intended to limit the present invention. In the following Reference Examples and Examples, a% is one percent by weight unless otherwise specified.

The genetic engineering procedure described in the Reference Examples is in accordance with a method described in [MOLECUING CLONING (Maniatis et al., Cold Spring Harbor Laboratory), (1989)] or in a bound protocol of a reagent.

Experiments (hypoglycemic and hypolipidemic actions in mice) A test compound was added to a powder diet (CE-2, Cie Japan Inc.) at a concentration of 0.01%, and the ad libitum diet was given to KKAy mice (9 to 12 months of age, 5 animals in a group), a model with type II diabetes mellitus obese (diabettes mellitus noninsulin dependent), for 4 days. During this period, water is released ad libi tum. A blood sample was taken from the orbital venous plexus and the plasma glucose and triglyceride levels were determined enzymatically using a Wako "Glu2 L-type (Wako Puré Chemical Ind. Ltd.) and a Iatro-MA701 TG (Iatron) kit. Laboratories Inc.) or Wako TG • H type L (Wako Puré Chemical Ind. Ltd.), respectively.

- The value of each group with treatment was represented as% reduction when compared with the group without treatment, and was summarized in Table 1.

Table 1 Compound Hypoglycemic effect Effect (Example number) (% reduction) hypotriglyceridemic (% reduction) 36 35 7 42 61 10 36 45 11 49 82 17 49 59 1) 25 38 66 81 54 75 1) 106 46 2) 65 1 ) , 2 ) 1) quantified using a Wako TG • H of type L 2) dosage: 0.005% As is evident from the results, a compound according to the present invention has excellent hypoglycemic effect and hypotriglyceridemic effect, and is useful for the prevention and treatment of diabetes mellitus and hyperlipidemia.

Experiment (transactivation assay of the PPAR heterodimer -RXRa) A PPAR? Cell: RXRa: 4ERPP / CH0-K1 obtained in Reference Example 5 described below was cultured in a medium of HAM F12 (NISSUI SEIYAKU) containing 10% Fetal Bovine serum (Life Technologies, Inc. , USA) and then inoculated to a 96-well white plate (Corning Coaster Corporation, USA) at the density of 2 x 104 cells / well, and cultured in an incubator with carbonate gas at 37 ° C overnight.

After washing the 96-well white plate with PBS (Phosphate-buffered Saline), 90 μl of HAM F12 medium containing 0.1% fatty acid free bovine serum albumin (BSA) was added to the plate. μl of a test substance, which was then cultured in an incubator with carbonate gas at 37 ° C for 48 hours. After removing the medium, 40 μl of PICAGENE 7.5 (Wako Puré Chemical Ind. Ltd.) was added, and after shaking, the luciferase activity was determined using a Lumistar (BMG Labtechnologies GmBH, Germany).

An induction magnitude was calculated on the basis of the luciferase activity of each test substance with the luciferase activity in the untreated group which was considered as 1. The values of the concentration of the test substance and the magnitude of induction were determined. analyzed using a PRISM 2.01 (GraphPad Software Inc., USA) to calculate the effective concentration of EC0 of a compound for the induction of 50% of maximum activity. The results are shown in Table 2.

Table 2 Compound EC50 (Example number) (μM) 0. 024 11 0. 41 17 0. 047 25 0. 79 81 0. 26 106 0. As indicated above, a compound according to the present invention exhibits excellent activity as a heterodimer ligand of PPARγRXRa.

Eg emplos Reference Example 1 (Cloning of the human PPAR gene) A PPAR gene? human was cloned using a heart cDNA (Toyobo Co., Ltd., trade name: QUICK-clone cDNA) as a standard by a PCR method employing a primer set shown below, which was prepared with reference to the sequence of DNA of the PPAR gene? reported by Greene et al.

(Gene Expr., 1995, Vol. 4 (4-5), page 281-299).

PAG-U: 5 '-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA GAG-3' PAG-L: -GGG GTC GAC CAG GAC TCT CTG CTA GTA CAA GTC-3 ' The PCR procedure was carried out by a hot start method using a AmpliWax PCR Gem 100 unit (TARARA SHUZO CO. LTD.). First, 2 μl of 10 x LA PCR buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution and 10 μl of sterilized distilled water were mixed to obtain a lower layer solution mixture. Lμl of human heart cDNA (1 ng / ml) as standard, 3 μl of 10 x LA PCR buffer, 1 μl of 2.5 mM dNTP solution, 0.5 μl of TaKaRa LA Taq DNA polymerase (TAKARA SHUZO) were mixed. CO., LTD.) And 24.5 μl sterilized distilled water to obtain a mixture of top coat solution.

The lower layer solution mixture was received in an AmpliWax PCR Gem 100 unit (TAKARA SHUZO CO., LTD.), And treated at 70 ° C for 5 minutes and then on ice for 5 minutes, and then the mixture of Top layer solution was added to prepare the PCR reaction mixture. A tube containing the reaction mixture was placed in a thermal cycle forming device (Perkin Elmer, USA) and treated at 95 ° C for 2 minutes. After repeating the 95 ° C cycle for 15 seconds, followed by 68 ° C for 2 minutes plus 35 times, the tube was then treated at 72 ° C for 8 minutes.

The PCR product thus obtained was subjected to agarose gel electrophoresis (1%), and a DNA fragment of 1. 4 kb containing the PPAR gene? it was recovered from the gel, and then inserted into the pT7 Blue-T vector (TAKARA SHUZO CO., LTD.) to obtain a plasmid designated pTBT-hPPAR ?.

Reference Example 2 (Cloning of the human RXRa gene) A human RXRa gene was cloned using a kidney cDNA (Toyobo Co., Ltd., trade name: QUICK-clone cDNA) as a standard by a PCR method employing a primer set shown below, which was prepared with reference to the DNA sequence of the RXRa gene reported by Mangelsdorf , DJ. et al (Nature, 1990, Vol. 345 (6272), page 224-229).

XRA-U: 5 '-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC CTG-3' XRA-L: 5 '-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3' The PCR procedure was carried out by a hot start method using a Gem 100 AmpliWax PCR unit (TAKARA SHUZO CO., LTD). First, 2 μl of 10 x LA PCR buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution and 10 μl of sterilized distilled water were mixed to obtain a lower layer solution mixture. Lμl of human kidney cDNA (1 ng / ml) as a standard, 3 μl of 10 x LA PCR buffer, 1 μl of 2.5 mM dNTP solution, 0.5 μl of TaKaRa LA Taq DNA polymerase (TAKARA SHUZO) were mixed. CO., LTD.) And 24.5 μl sterilized distilled water to obtain a mixture of top coat solution.

The lower layer solution mixture was received in an AmpliWax PCR Gem 100 unit (TAKARA SHUZO CO., LTD.), And treated at 70 ° C for 5 minutes and then on ice for 5 minutes, and then the mixture of Top layer solution was added to prepare the PCR reaction mixture. A tube containing the reaction mixture was placed in a thermal cycle forming device (Perkin Elmer, USA) and treated at 95 ° C for 2 minutes. After repeating the 95 ° C cycle for 15 seconds, followed by 68 ° C for 2 minutes plus 35 times, the tube was then treated at 72 ° C for 8 minutes.

The PCR product thus obtained was subjected to agarose gel electrophoresis (1%), and a 1.4 kb DNA fragment containing RXRa gene was recovered from the gel, and then inserted into the vector pT7 Blue-T (TAKARA SHUZO CO., LTD.) To obtain a plasmid designated pTBT-hRXRa.

Reference Example 3 (Construction of plasmids to express PPAR ?, human RXRa) A 7.8 kb Fspl-Notl fragment of the pVgRXR plasmid (Invitrogen, USA) was ligated to a 0.9 kb Fspl-Notl fragment containing the RXRa gene of the plasmid pTBT-hRXRa obtained in Reference Example 2 to prepare the plasmid pVg RXR2 .

Subsequently, pVgRXR2 was digested with BstXI and then treated with T4DNA polymerase (TAKARA SHUZO CO., LTD.) To obtain an obtuse terminal. Then digestion in Kpnl gave a DNA fragment of 6.5 kb.

On the other hand, the plasmid pTBT-HPPAR? obtained in Reference Example 1 was digested with Sal I and then treated with T4DNA polymerase (TAKARA SHUZO CO., LTD.) to obtain an obtuse terminal. Then digestion in Kpnl gave a 1.4 kb DNA fragment containing the PPAR gene? human.

Then both DNA fragments were ligated to construct the plasmid pVgRXR2-hPPAR ?.

Reference Example 4 (Construction of the reporter plasmid) A DNA fragment containing a PPAR-responsive element (PPRE) of an acyl CoA oxidase was prepared using the following 5'-phosphorylated synthetic DNA.

PPRE-U: 5 '-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-3 • PPRE-L: 5 * -pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-3' First, the PPRE-U and the PPRE-L were annealed and inserted into the Sal I site of the pBluescrpt SK + plasmid. With the sequential control of the bases of the inserted fragment, the plasmid pBSS-PPRE4 was selected in which 4 PPREs are linked in front of each other.

A region of the minimal promoter of HSV thymidine kinase (TK promoter) was cloned using the pRL-TK vector (Promega, USA) as a standard by a PCR method employing a primer set shown below, which was prepared with reference to the DNA sequence of the thymidine kinase promoter region reported by Luckow, B et al. (Nucleic Acid Res., 1987, Vol.15 (13), p.5490).

TK-U: 5 '-CCCAGATCTCCCCAGCGTCTTGTCATTG-3' TK-: 5 '- CACCATGGTCAAGCTTTTAAGCGGGTC-3' The PCR procedure was carried out by a hot start method using a Gem 100 PCR AmpliWax unit (TAKARA SHUZO CO. LTD.). First, 2 μl of 10 x LA PCR buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution and 10 μl of sterile distilled water were mixed to obtain a lower layer solution mixture. . Iμl of vector pRL-TK (Promega, USA) was mixed as standard, 3 μl of 10 x LA PCR buffer, 1 μl of 2.5 mM dNTP solution, 0.5 μl of TaKaRa LA Taq DNA polymerase (TAKARA SHUZO CO ., LTD.) And 24.5 μl sterilized distilled water to obtain a mixture of top coat solution.

The lower layer solution mixture was received in a .AmpliWax PCR Gem 100 unit (TAKARA SHUZO CO., LTD.), And treated at 70 ° C for 5 minutes and then on ice for 5 minutes, and then mixing of top layer solution was added to prepare the PCR reaction mixture. A tube containing the reaction mixture was placed in a thermal cycle forming device (Perkin Elmer, USA) and treated at 95 ° C for 2 minutes. After repeating the 95 ° C cycle for 15 seconds, followed by 68 ° C for 2 minutes plus 35 times, the tube was then treated at 72 ° C for 8 minutes.

The PCR product thus obtained was subjected to agarose gel electrophoresis (1%), and a 140 b DNA fragment containing TK promoter was recovered from the gel, and then inserted into the vector pT7 Blue-T (TAKARA SHUZO CO., LTD.). By digesting the plasmid thus obtained with the restriction enzymes Bgl II and Ncol, a fragment containing TK promoter was obtained and ligated to the Bgl II-NcoI fragment of the plasmid vector pGL3-Basic (Promega, USA) to obtain the plasmid pGL3-TK.

A 4.9 kb Nhel-Xhol fragment of the pGL3-TK plasmino thus obtained was ligated to a 200 Nhel-XhoI fragment of the pBSS-PPRE4 plasmid to obtain the plasmid pGL3-4ERPP-TK.

This pGL3-4ERPP-TK plasmid thus obtained was digested with BamHI (TAKARA SHUZO CO., LTD.) And then treated with T4DNA polymerase (TAKARA SHUZO CO., LTD.) To form an obtuse terminal, thereby a DNA fragment was obtained.

On the other hand, pGFP-Cl (Toyobo Co., Ltd.) was digested with Bsu36I (NEB) and then treated with T4DNA polymerase (TAKARA SHUZO CO., LTD.) To form an obtuse terminal, thereby obtains a DNA fragment of 1.6 kb.

Both DNA fragments were ligated to construct a reporter plasmid designated pGL3-4ERPP-TK neo.

Reference Example 5 (Introduction of the plasmid expressing the PPAR? And human RXRa and reporter plasmid in a CHO-KI cell and establishment of a stably transformed cell) A CHO-Kl cell cultured in a 750 ml tissue culture flask (Corning Costar Corporation, USA) containing HAM F12 medium (NISSUI SEIYAKU) supplemented with 10% fetal bovine serum (Life Technologies, Inc., USA) ) was scraped by treating with trypsin 0.5 g / L-EDTA (ethylenediaminetetraacetic acid 0.2 g / L (Life Technologies, Inc., USA) and the cell was washed with PBS (phosphate buffered saline) (Life Technologies, Inc., USA). ) and centrifuged (100 rpm, 5 minutes) and then suspended in PBS Subsequently, a DNA was introduced into the cell under the condition shown below using a GENE ULSER (Bio-Rad Laboratories, USA).

Thus, a specimen having an aperture of 0.4 cm received 8 x 10 6 cells and 10 μg of plasmid pVgRXR2-hPPAR? obtained in Reference Example 3 and 10 μg of reporter plasmid pGL3-4ERPP-TK neo obtained in Reference Example 4 and then electroporated at the 0.25 kV voltage under the capacitance of 960 10 μF. Subsequently, the cell was transferred in a HAM F12 medium containing 10% Fetal Bovine Serum and cultured for 24 hours and then the cells were scraped again and centrifuged, and then suspended in HAM F12 medium containing Serum. of 10% fetal bovine supplemented with 500 μg / ml of GENETICIN (Life Technologies, Inc., USA) and 250 μg / ml of ZEOCIN (Invitrogen, USA) and diluted to the density of 10 4 cells / ml with inoculation to a 96-well plate (Corning Coster Corporation, USA), which was incubated in an incubator with carbonate gas at 37 ° C, which resulted in a transformant resistant to GENETICIN and ZEOCIN.

Subsequently, the cell line of the transformant thus obtained was cultured in a 24-well plate (Corning Coster Corporation, USA) and then sieved, by adding 10 μM Pioglitazone, to a cell line in which the expression of luciferase, ie, PPAR cell ?: RXRa: 4ERPP / CH0-Kl.

Reference Example 6 To a solution of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (33.42 g) in methanol (150 ml) -tetrahydrofuran (30 ml), sodium borohydride (4.31 g) was added portionwise at 0 °. C. After stirring for 30 minutes at room temperature, water was added to the reaction mixture, and the mixture was stirred for one hour. The crystals of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (32.85 g, 98% yield) were isolated by filtration. Recrystallization from ethyl acetate-diethyl ether gave pale yellow crystals, m.p. 128-129 ° C Reference Example 7 To a solution of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (5.00 g) in toluene (40 ml), thionyl chloride (1.85 ml) was added, and the mixture was stirred for 30 minutes at room temperature. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO 4) and concentrated to obtain 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (5.23 g, 99% yield) as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p. 108-109 ° C Reference Example 8 To a solution of 4- [2- (methyl-2-pyridylamino) ethoxy] benzaldehyde (15.0 g) in methanol (70 ml), sodium borohydride (1.11 g) was added at 0 ° C in portions. After stirring for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO), and then concentrated. The residue was subjected to column chromatography on silica gel, and 4 [2- (methyl-2-pyridylamino) ethoxy] benzyl alcohol (14.3 g, 94% yield) of a fraction eluted with ethyl acetate-hexane was obtained (1: 1, v / v) as an oil.

NMR (CDC13) d 31.5 (3H, s), 3.98 (2H, t, J = 5.5 Hz), 4.19 (2H, t, J = 5.5 Hz), 4.61 (2H, d, J = 5.4 Hz), 6.50- 6.59 (2H, m), 6.89 (2H, d, J = 8.8Hz), 7.27 (2H, d, J = 8.8 Hz), 7.40-7.50 (1H, m), 8.13-8.18 (2H, m).

Reference Example 9 A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (3.41 g), 3- (4-hydroxyphenyl) propanol (2.50 g), potassium carbonate (3.40 g) and N, N-dimethylformamide (25 ml) was stirred for 14 hours at 60 ° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4), and then concentrated. The residue was subjected to column chromatography on silica gel, and 3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propanol (4.46 g, 84% yield) of an eluted fraction was obtained. with ethyl acetate-hexane (1: 1, v / v) as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p. 70-71 ° C Reference Example 10 A mixture of methyl phenylglyoxylate (25.5 g), hydroxylamine hydrochloride (11.3 g), triethylamine (22.8 ml) and methanol (300 ml) was stirred for 17 hours at 60 ° C. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO 4), and then concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain methyl E-2-hydroxyimino-2-phenylacetate (3.58 grams, 13% yield) as colorless crystals, m.p. 151-153 ° C Reference Example 11 The mother liquor obtained in Reference Example 10 was concentrated and the residue was subjected to column chromatography on silica gel, and methyl Z-2-hydroxyimino-2-phenylacetate (17.8 g, 64% yield) was obtained as an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v).

NMR (CDC13) d: 3.89 (3H, s), 7.34-7.48 (3H, m), 7.52-7.60 (2H, m), 8.51 (1H, m).

Reference Example 12 To a mixture of aluminum chloride (59.0 g) and dichloromethane (500 ml), ethyl chloroglyoxylate (45.4 ml) was added dropwise at 0 ° C. After stirring for 15 minutes, anisole (40.1 ml) was added in drops at 0 ° C, and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was poured into ice (500 g), and the mixture was stirred for 1 hour at room temperature. The separated dichloromethane layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4), and then concentrated. The residue was subjected to column chromatography on silica gel, and ethyl-methoxyphenylglyoxylate (43.6 g, 60% yield) was obtained as an oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v). ).

NMR (CDC13) d: 1.42 (3H, t, J = 7.1 Hz), 3.90 (3H, s), 4.44 (2H, q, J = 7.1 Hz), 6.98 (2H, d, J = 9.0 Hz), 8.01 (2H, d, J = 9.0 Hz).

Reference Example 13 A mixture of ethyl 4-methoxyphenylglyoxylate (15.0 g), hydroxylamine hydrochloride (6.00 g), sodium acetate (8.86 g) and ethanol (150 ml) was heated under reflux for 12 hours.

The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO 4), and then concentrated. The residue was subjected to column chromatography on silica gel and ethyl Z-2-hydroxyimino-2- (4-methoxyphenyl) acetate (8.99 g, 56% yield) was obtained as crystals of a fraction eluted with ethyl acetate. -hexane (1: 2, v / v). Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p. 81-82 ° C Reference Example 14 From a fraction eluted following the form of Z in the Reference Example 13, ethyl E-2-hydroxyimino-2- (4-methoxyphenyl) acetate (4.97 g, 31% yield) was obtained as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p. 128-129 ° C Reference Example 15 A mixture of ethyl pyruvate (9.50 g), hydroxylamine hydrochloride (6.82 g), sodium acetate (10.1 g) and ethanol (150 ml) was heated under reflux for 17 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO 4), and then concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain ethyl E-2-hydroxyiminopropionate (6.33 g, 59% yield) as colorless crystals. p.f-. 98-99 ° C Reference Example 16 A mixture of methyl 3-benzoylpropionate (15.0 g), hydroxylamine hydrochloride (6.50 g), sodium acetate (9.60 g) and methanol (150 ml) was heated under reflux for 8 hours.

The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO 4), and then concentrated. The residue was subjected to column chromatography on silica gel, and methyl E-4-hydroxyimino-4-phenylbutyrate was obtained (14.7 g, 91% yield) as an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v).

NMR (CDC13) d: 2.58-2.67 (2H, m), 3.09-3.17 (2H, m), 3.66 (3H, m), 7.35-7.44 (3H, m), 7.56-7.67 (2H, m), 8.00 -8.80 (1H, br s).

Reference Example 17 From an eluted fraction following the E form in Reference Example 16, methyl Z-4-hydroxyimino-4-phenylbutyrate (1.37 g, 8% yield) was obtained as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p. 76-77 ° C Reference Example 18 A mixture of ethyl 5-oxo-5-phenylpentanoate (8.00 g), hydroxylamine hydrochloride (3.03 g), sodium acetate (4.47 g) and ethanol (70 ml) was heated under reflux for 15 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO 4), and then concentrated. The residue was subjected to column chromatography on silica gel, and ethyl E-5-hydroxyimino-5-phenylpentanoate (7.55 g, 88% yield) was obtained as crystals of a fraction eluted with ethyl acetate-hexane (1 : 3, v / v). Recrystallization with hexane gave colorless crystals. p.f. 28-30 ° C.

Reference Example 19 To a solution of diethyl oxalate (26.3 g) in diethyl ether (400 ml), a solution of butylmagnesium chloride in tetrahydrofuran (0.90 M, 100 ml) was added dropwise at -78 ° C under a nitrogen atmosphere. After stirring for 1 hour, the reaction mixture was allowed to warm to 0 ° C, and then IN hydrochloric acid was added. The diethyl ether layer was separated, washed with an aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in ethanol (150 ml), and hydroxylamine hydrochloride (7.50 g) and sodium acetate (11.1 g) were added. The mixture was heated under reflux for 13 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO), and then concentrated. The residue was subjected to column chromatography on silica gel, and ethyl E-2-hydroxyiminohexanoate (11.0 g, 71% yield) was obtained as crystals of a fraction eluted with ethyl acetate-hexane (1: 4, v). / v). Recrystallization with hexane gave colorless crystals. p.f. 49-50 ° C Example 20 Reference To a solution of diethyl oxalate (19.6 g) in diethyl ether (400 ml), a solution of isopropylmagnesium bromide in tetrahydrofuran (0.67 M, 100 ml) was added dropwise at -78 ° C under a nitrogen atmosphere. After stirring for 1 hour, the reaction mixture was allowed to warm to 0 ° C, and then IN hydrochloric acid was added. A layer of diethyl ether was separated, washed with an aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried (MgSO 4), and concentrated. The residue was dissolved in ethanol (100 ml), and hydroxylamine hydrochloride (5.59 g) and sodium acetate (8.24 g) were added. The mixture was heated under reflux for 15 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and was obtained from a fraction eluted with ethyl acetate-hexane (1: 4, v / v) ethyl 2-hydroxyimino-3-methylbutyrate (a mixture of the forms of E and Z). Recrystallization from hexane gave ethyl E-2-hydroxyimino-3-methylbutyrate (1.91 g, 18% yield) as colorless crystals, m.p. 54-55 ° C NMR (CDC13) d: 1.24 (6H, d, J = 7.0 Hz), 1.35 (3H, t, J = 7.1 Hz), 3.49 (1H, sept, J = 7.0 Hz), 4.29 (2H , q, J = 7.1 Hz), 9.79 (1H, br s).

Reference Example 21 The mother liquid of the E-form obtained in Reference Example 20 was concentrated to obtain a mixture of E: Z = 2.3: 1 (5.69 g, 53% yield).

Z: NMR (CDC13) d: 1.17 (6H, d, J = 6.6 Hz), 1.36 (3H, t, J = 7.1 Hz), 2.80 (1H, sept, J = 6.6 Hz), 4.36 (2H, q, J = 7.1 Hz), 9.75 (ÍH, br s).

Reference Example 22 To a mixture of aluminum chloride (29.3 g) and dichloromethane (250 ml), ethyl chloroglyoxylate (22.3 ml) was added dropwise at 0 ° C. After stirring for 30 minutes, diphenyl ether (63.5 ml) was added in drops for 30 minutes at 0 ° C, followed by stirring for 2 hours, the reaction mixture was poured onto ice (250 grams) and stirred for 1 hour at room temperature. The dichloromethane layer was separated, washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and ethyl 4-phenoxyphenylglyoxylate (38.0 g, 70% yield) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:10, v / l). v).

NMR (CDCl 3) d: 1.42 (3 H, t, J = 7.1 Hz), 4.44 (2 H, q, J = 7.1 Hz), 6.98-7.13 (4 H, m), 7.20-7.29 (H, m), 7.37- 7.47 (2H, m), 8.01 (2H, d, J = 9.0 Hz).

Reference Example 23 A mixture of ethyl 4-phenoxyphenylglyoxylate (37.9 g), hydroxylamine hydrochloride (11.7 grams), sodium acetate (17.3 g) and ethanol (200 ml) was heated under reflux for 15 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO 4), and then concentrated. The residual crystals were recrystallized with toluene-hexane to obtain ethyl E-2-hydroxyimino-2- (4-phenoxyphenyl) acetate (11.0 g, 28% yield) as a colorless oil, m.p. 131-132 ° C Reference Example 24 The mother liquid of the E-form obtained in Reference Example 23 was concentrated, and the residue was subjected to column chromatography on silica gel to obtain ethyl Z-2-hydroxyimino-2- (4-phenoxyphenyl) acetate ( 23.6 g, 56% yield) as an oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 1.40 (3H, t, J = 7.1 Hz), 4.46 (2H, q, J = 7.1 Hz), 6.95-7.08 (4H, m), 7.11-7.20 (ÍH, m), 7.32- 7.42 (2H, m), 7.53 (ÍH, d, J = 8.8 Hz),, 8.42-8.49 (1H, m).

Reference Example 25 To a mixture of aluminum chloride (41.6 g) and 1,2-dichloroethane (300 ml), ethyl chloroglyoxylate (32.0 ml) was added dropwise at 0 ° C. After stirring for 30 minutes, 4-fluorobenzene (25.0 g) was added at 0 ° C. After stirring for 2 hours at 40 ° C, the reaction mixture was poured onto ice (300 g), and the mixture was stirred for 1 hour at room temperature. The 1,2-dichloroethane layer was separated and washed with a saturated aqueous sodium chloride solution, dried (MgSO 4), and then concentrated. The residue was dissolved in ethanol (300 ml), and mixed with hydroxylamine hydrochloride (21.7 g) and sodium acetate (32.0 g), and then heated to reflux for 20 hours. The reaction mixture was concentrated, and the residue was diluted with water, extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2- (4-fluorophenyl) -2-hydroxyiminoacetate (3.82 g, 6% yield) as an oil of a fraction eluted with ethyl acetate- hexane (1: 3, v / v).

NMR (CDC13) d: 1.40 (3H, t, J = 7.1 Hz), 4.46 (2H, q, J = 7.1 Hz), 7.05-7.14 (2H, m), 7.52-7.61 (2H, m), 8.37 ( ÍH, s).

Reference Example 26 From an eluted fraction following the Z-form in Reference Example 25, ethyl E-2- (4-fluorophenyl) -2-hydroxyiminoacetate (2.45 g, 5% yield) was obtained as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p. 117-118 ° C Reference Example 27 To a mixture of aluminum chloride (41.6 g) and 1, 2-dichloroethane (300 ml), ethyl succinyl chloride (40.8 ml) was added dropwise at 0 ° C. After stirring for 30 minutes, 4-flurobenzene (25.0 g) was added at 0 [deg.] C. After stirring for 15 hours at 60 [deg.] C., the reaction mixture was poured onto ice (500 g), and the mixture was The mixture was stirred for 1 hour at room temperature, the 1,2-dichloroethane layer was separated and washed with a saturated aqueous sodium chloride solution, dried (MgSO.sub.4), and then concentrated.The residue was dissolved in ethanol (300 ml. ), and mixed with hydroxylamine hydrochloride (21.7 g) and sodium acetate (32.0 g), and then heated under reflux for 20 hours.The reaction mixture was concentrated, and the residue was diluted with water, extracted with acetate The ethyl acetate layer was washed with water, dried (MgSO.sub.4), and then concentrated.The residue was subjected to column chromatography on silica gel to obtain E-4- (4-fluorophenyl) -4 ethyl -hydroxyiminobutyrate (7.45 g, 12% yield) as an oil of a fraction eluted with ethyl acetate-hexan or (1: 4, v / v).

NMR (CDC13) d: 1.23 (3H, t, J = 7.1 Hz), 2.56-2.65 (2H, m), 3.05-3.14 (2H, m), 4.11 (2H, q, J = 7.1 Hz), 7.01- 7.14 (2H, m), 7.56-7.66 (2H, m), 8.05-8.40 (1H, br s).

Reference Example 28 To a solution of 3-phenoxybenzyl alcohol (25.0 g) and triethylamine (26.3 ml) in ethyl acetate (300 ml), methanesulfonyl chloride (14.6 ml) was added dropwise at 0 ° C at 0 ° C. After stirring for 1 hour, the reaction mixture was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in acetone (300 ml), mixed with sodium iodide (37.5 g) and then stirred for 1 hour. The reaction mixture was concentrated, and the residue was diluted with water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO), and then concentrated. The residue was dissolved in dimethyl sulfoxide (100 ml) and stirred with sodium cyanide (7.35 g) for 15 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel to obtain 3-phenoxyphenylacetonitrile (8.36 g, 32% yield) as an oil of a fraction eluted with ethyl acetate-hexane (1: 7, v / v).

NMR (CDC13) d: 3.72 (2H, s), 6.90-7.20 (6H, m), 7.28-7.43 (3H, m).

Reference Example 29 To a solution of sodium ethoxide prepared from sodium (1.09 g) and ethanol (20 ml-), se. added in solution a solution of 3-phenoxyphenylacetonitrile (8.30 g) in ethanol (15 ml) at 0 ° C, and then nitrite of isoamyl was added dropwise (7.99 ml). After stirring for 15 hours at room temperature, diethyl ether was added and the mixture was washed consecutively with IN HCl, an aqueous sodium bicarbonate solution and then a saturated aqueous sodium chloride solution.

The diethyl ether layer was dried (MgSO), concentrated, and the residue was subjected to column chromatography on silica gel. The crystals obtained from a fraction eluted with ethyl acetate-hexane (1: 4, v / v) were recrystallized from ethyl acetate-hexane to obtain 2-hydroxyimino-2- (3-phenoxyphenyl) acetonitrile (4.25 g, yield: 45%) as pale yellow crystals. A mixture of the E form and the Z form. P.f. 124-125 ° C Reference Example 30 A mixture of 2-hydroxyimino-2- (3-phenoxyphenyl) acetonitrile (3.00 g), potassium hydroxide (3.40 g), ethanol (15 ml) and water (15 ml) was heated under reflux for 24 hours. The reaction mixture was acidified with 1N HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The reaction mixture was dissolved in methanol (30 ml), mixed with concentrated sulfuric acid (a catalytic amount), and then heated under reflux for 24 hours. The reaction mixture was combined with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl Z-2-hydroxyimino-2- (3-phenoxyphenyl) acetate (1.14 g, 33% yield) as an oil of a fraction eluted with ethyl acetate. -hexane (1: 2, v / v).

NMR (CDC13) d: 3.95 (3H, s), 6.99-7.18 (4H, m), 7.21-7.28 (2H, m), 7.31-7.41 (3H, m), 8.33 (1H, s).

Reference Example 31 From an eluted fraction following the E form in Reference Example 30, methyl E-2-hydroxyimino-2- (3-phenoxyphenyl) acetate (746 mg, 22% yield) was obtained as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p. 122-123 ° C Reference Example 32 A solution of 4-bromophenylmagnesic bromide prepared from p-dibromobenzene (25.0 g), magnesium (2.43 g) and diethyl ether (250 ml) was added dropwise to a solution of diethyl oxalate (32.5 g) in diethyl ether (250 ml) at -78 ° C under a nitrogen atmosphere. After stirring for 1 hour, the reaction mixture was allowed to warm to 0 ° C, and IN HCl was added. The diethyl ether layer was separated, washed with an aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1:15, v / v). This oil was dissolved in ethanol (100 ml), combined with hydroxylamine hydrochloride (4.17 g) and sodium acetate (6.15 g), and then heated under reflux for 18 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystals were recrystallized from isopropyl ether-hexane to obtain ethyl E-2- (4-bromo-phenyl) -2-hydroxyiminoacetate (4.31 g, 16% yield) as crystals, m.p. 163-164 ° C Reference Example 33 From an eluted fraction following the E form in Reference Example 32, ethyl Z-2- (bromophenyl) -2-hydroxyiminoacetate (5.31 g, 20% yield) was obtained as an oil.

NMR (CDC13) d: 1.40 (3H, t, J = 7.1 Hz), 4.55 (2H, q, J = 7.1 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 8.6 Hz), 8.47 (ÍH, s).

Reference Example 34 To a solution of sodium ethoxide prepared from sodium (7.22 g) and ethanol (400 ml), ethyl phenylacetate (25.8 g) and diethyl oxalate (45.9 g) were added and the mixture was stirred for 1.5 hours at 70 ° C. C with ethanol separation. The reaction mixture was combined with ethyl acetate (500 ml) and 1N HCl (350 ml), and the ethyl acetate layer was separated. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was dissolved in dimethyl sulfoxide (150 ml) -water (15 ml), mixed with sodium chloride (9.18 g) and then the mixture was stirred for 1.5 hours at 130 ° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4), and then concentrated. The residue was dissolved in ethanol (100 ml), mixed with hydroxylamine (3.34 g) and sodium acetate (4.92 g), and then the mixture was heated under reflux for 17 hours. The reaction mixture was concentrated, and the residue was combined with water, and then extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-2-hydroxyimino-3-phenylpropionate (6.94 g, 21% yield) as crystals of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p. 54-55 ° C Reference Example 35 To a solution of diethyl ether (400 ml) of 3-bromopyridine (25.7 g) n-butyllithium (1.6N hexane solution, 108 ml) was added dropwise at -78 ° C for 1 hour under a nitrogen atmosphere. After stirring for 30 minutes, a solution of diethyl ether (100 ml) of diethyl oxalate (28.6 g) was added dropwise thereto at -78 ° C for 1 hour. The reaction mixture was further mixed for 30 minutes, allowed to warm to 0 ° C, and 1N hydrochloric acid (200 ml) was added thereto. After stirring for 30 minutes, sodium bicarbonate was added thereto to neutralize the reaction mixture. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl 3-pyridylglyoxalate (13.1 g, 45% yield) of a fraction eluted with ethyl acetate-hexane (1: 1, v / v).

RÍÍN (CDC13) d: 1.45 (3H, t, J = 7.1 Hz), 4.48 (2H, q, J = 7.1 Hz), 7.45-7.53 (ÍH, m), 8.33-8.41 (ÍH, m), 8.85- 8.90 (ÍH, m), 9.26-9.29 (ÍH, m).

Reference Example 36 A mixture of ethyl 3-pyridylglyoxylate (6.00 g), hydroxylamine hydrochloride (2.79 g), sodium acetate (4.13 g) and ethanol (80 ml) was heated to reflux for 15 hours. The reaction mixture was concentrated, water was added to the residue, and it was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate to obtain E-2-hydroxyimino-2- (3-pyridyl) -acetic acid ethyl ester (3.30 g, 51% yield) as colorless crystals, m.p. 172-173 ° C Reference Example 37 The mother liquor of Reference Example 36 was concentrated and the residue was subjected to column chromatography on silica gel to obtain the crystals of a fraction eluted with ethyl acetate-hexane (3: 2, v / v). The crystals were recrystallized from ethyl acetate-hexane to obtain ethyl Z-2-hydroxyimino-2- (3-pyridyl) acetate (1.55 g, 24% yield) as colorless crystals, m.p. 137-138 ° C.

Reference Example 38 To a solution of sodium ethoxide prepared from sodium (2.51 g) and ethanol (40 ml) was added dropwise a solution of 2- (3-bromo-phenyl) -acetonitrile (17.8 g) in ethanol (30 ml) at 0 °. C, and then it was added dropwise to the same isoamyl nitrite (18.3 ml). After stirring at room temperature for 18 hours, diethyl ether was added, and washed consecutively with IN hydrochloric acid, an aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. The diethyl ether layer was dried (MgSO4), concentrated, and the residue was subjected to column chromatography on silica gel to obtain 2- (3-bromo-phenyl) -2- (hydroxyimino) acetonitrile (19.9 grams, 97% strength). yield) as an orange paste of a fraction eluted with ethyl acetate-hexane (1: 1, v / v). Recrystallization from ethyl acetate-hexane gave orange crystals, m.p. 91-93 ° C Reference Example 39 A solution of 1,2-dibromoethane (12 ml) of bromine (5.43 ml) was added dropwise for 3 hours, while refluxing a solution of 1,2-dibromoethane (40 ml) of 3-methylbenzophenone ( 20.0 g). After heating to reflux for 30 minutes, the reaction mixture was concentrated. The residue was dissolved in dimethyl sulfoxide (100 ml) and stirred with sodium cyanide (7.50 g) at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain 2- (3-benzoylphenyl) acetonitrile (13.8 g, 61% yield) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1: 3, v / v).

NMR (CDC13) d: 3.84 (2H, s), 7.46-7.68 (5H, m), 7.73-7.83 (4H, m).

Reference Example 40 To a solution of sodium ethoxide prepared from sodium (1.70 g) and ethanol (40 ml) was added dropwise to a solution of 2- (3-benzoylphenyl) acetonitrile (13.6 g) in ethanol (30 ml) at 0 °. C, and then nitrite of isoamyl (12.4 ml) was added dropwise. After stirring at room temperature for 15 hours, the reaction mixture was diluted with ethyl acetate and washed consecutively with IN hydrochloric acid and a saturated aqueous sodium chloride solution. The ethyl acetate layer was dried (MgSO) and concentrated to obtain 2- (3-benzoylphenyl) -2- (hydroxyimino) acetonitrile (15.2 g, 99% yield) as crystals. Recrystallization from ethyl acetate-hexane gave an isomer of 2- (3-benzoylphenyl) -2- (hydroxyimino) acetonitrile as colorless crystals, m.p. 175-176 ° C Reference Example 41 The mother liquor of Reference Example 40 was concentrated, and the residue was recrystallized with ethyl acetate-hexane to obtain another isomer of 2- (3-benzoylphenyl) -2- (hydroxyimino) acetonitrile as colorless crystals. p.f. 147-148 ° C.

Reference Example 42 A mixture of 2- (3-bromophenyl) -2- (hydroxyimino) acetonitrile (19.0 g), 4N aqueous potassium hydroxide solution (100 ml) and 2-methoxyethanol (100 ml) was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, IN hydrochloric acid was added to make the acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and concentrated. The residue was dissolved in ethanol (200 ml) and concentrated sulfuric acid (catalytic amount) was added. The reaction mixture was heated under reflux for 48 hours, cooled to room temperature, poured into an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2- (3-bromophenyl) -2- (hydroxyimino) acetate (3.31 g, 14% yield) as a pale brown oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v).

NMR (CDC13) d: 1.41 (3H, t, J = 7.1 Hz), 4.47 (2H, q, J = 7.1 Hz), 7.23-7.32 (1H, m), 7.45-7.60 (2H, m), 7.72- 7.75 (ÍH, m), 8.56 (1H, br s).

Reference Example 43 From a fraction which was eluted following the Z-isomer in Reference Example 42, E-2- (3-bromophenyl) was obtained. -2- (hydroxyimino) ethyl acetate as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals (1.52 g, 7% yield), m.p. 113-114 ° C Reference Example 44 A mixture of 2- (3-benzoylphenyl) -2- (hydroxyimino) acetonitrile (14.5 g), 4N aqueous potassium hydroxide solution (80 ml) and ethanol (80 ml) was heated under reflux for 20 hours. The reaction mixture was cooled to room temperature, IN hydrochloric acid was added to make the acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in ethanol (150 ml) and concentrated sulfuric acid (catalytic amount) was added. The reaction mixture was heated under reflux for 15 hours, cooled to room temperature, poured into an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated.

The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2- (3-benzoylphenyl) -2- (hydroxyimino) acetate (2.48 g, 14% yield) as a pale brown oil of a fraction eluted with ethyl acetate-hexane (1: 2, v / v).

NMR (CDC13) d: 1.38 (3H, t, J = 7.1 Hz), 4.45 (2H, q, J = 7.1 Hz), 7.30-7.66 (4H, m), 7.70-8.00 (5H, m), 8.66 ( ÍH, br s).

Reference Example 45 From a fraction which was eluted following the Z-isomer in Reference Example 44, E-2- (3-benzoylphenyl) -2- (hydroxyimino) ethyl acetate was obtained as crystals. Recrystallization from ethyl acetate-hexane gave orange crystals (1.70 g, 10% yield), m.p. 109-110 ° C Reference Example 46 To a mixture of aluminum chloride (14.7 g) and dichloromethane (120 ml) was added dropwise ethylsuccinyl chloride (14.3 ml) at 0 ° C. After stirring for 30 minutes, it was added dropwise to a solution of diphenylether (34.0 g) in dichloromethane (50 ml) at 0 ° C. After stirring for 3 hours, the reaction mixture was poured onto ice (200 g), and stirred at room temperature for 1 hour. The dichloromethane layer was separated, washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was dissolved in ethanol (150 ml), and hydroxylamine hydrochloride (8.34 g) and sodium acetate (12.3 g) were added. After refluxing for 15 hours, the reaction mixture was concentrated, water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-4- (hydroxyimino) -4- (4-phenoxyphenyl) butyrate (10.5 g, 34% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 1.23 (3H, t, J = 7.1 Hz), 2.57-2.66 (2H, m), 3.06-3.15 (2H, m), 4.12 (2H, q, J = 7.1 Hz), 6.97- 7.19 (5H, m), 7.31-7.42 (2H, m), 7.59 (2H, d, J = 9.2 Hz), 7.90-8.60 (1H, br).

Reference Example 47 A mixture of 2-chloropyrimidine (20.8 g) and 2- (methylamino) ethanol (180 ml) was heated at 120 ° C for 15 hours and concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was distilled under reduced pressure to obtain 2- (methyl-2-pyrimidylamino) ethanol (24.6 g, 88% yield) as a colorless oil, e.g. 130-132 ° C / 1-1.5 mmHg Reference Example 48 To a solution of 2- (methyl-2-pyrimidylamino) ethanol (15.3 g) in N, N-dimethylformamide (400 ml) was added sodium hydride (60% in oil, 4.40 g) at room temperature under a nitrogen atmosphere and stirred for 1 hour. A solution of 4-fluorobenzaldehyde (13.6 g) in N, N-dimethylformamide (100 ml) was added dropwise and stirred at room temperature for 15 hours. The reaction mixture was poured into ice (200 g) and concentrated. The residue was dissolved in ethyl acetate, washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 4- [2- (methyl-2-pyrimidylamino) ethoxy-benzaldehyde (18.4 g, 72% yield) as crystals of a fraction eluted with ethyl acetate-hexane (1 : 1, v / v). Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p. 74-75 ° C.

Reference Example 49 To a solution of 4- [2- (methyl-2-pyrimidylamino) ethoxy] benzaldehyde (16.6 g) in methanol (40 ml) -tetrahydrofuran (40 ml) was added portionwise sodium borohydride (1.22 g) at 0 ° C. After stirring for 1 hour, water was added to the reaction mixture and ethyl acetate was extracted. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain 4- [2- (methyl-2-pyrimidylamino) ethoxy] benzyl alcohol (15.3 g, 91% yield) as colorless crystals, m.p. 73-74 ° C Reference Example 50 A mixture of 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (5.00 g), N-hydroxyphthalimide (2.59 g), potassium carbonate (4.40 g) and N, N-dimethylformamide (50 ml) was stirred at room temperature for 20 hours, and water (500 ml) was added. The resulting crystals were filtered, and washed with water to obtain N- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] phthalimide (6.49 g, 93% yield) as colorless crystals, m.p. 155-156 ° C Reference Example 51 To a solution of 2- (5-methyl-2-phenyl-4-oxazolyl) ethanol (3.00 g) in N, N-dimethylformamide (60 ml) was added sodium hydride (60% in oil, 649 mg) at room temperature. environment under a nitrogen atmosphere and stirred at room temperature for 1 hour. A solution of 4-fluorobenzaldehyde (2.02 g) in N, N-dimethylformamide (15 ml) was added dropwise and stirred at room temperature for 12 hours. The reaction mixture was poured into ice (50 g) and concentrated. The residue was dissolved in ethyl acetate, washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v). This was dissolved in tetrahydrofuran (20 ml) and methanol (20 ml), and sodium borohydride (321 mg) was added at 0 ° C, and then stirred for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in toluene (20 ml), thionyl chloride (0.888 ml) was added at 0 ° C and stirred for 1 hour. The reaction mixture was concentrated, and the remaining crystals were recrystallized with ethyl acetate-hexane to obtain 4- [2- (4-chloromethylphenoxy) ethyl] -5-methyl-2-phenyloxazole (2.51 grams, 52% yield) as pale yellow crystals, mp 93-94 ° C Reference Example 52 a solution of N- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] phthalimide (5.22 g) in ethanol (40 ml) -tetrahydrofuran (40 ml) was added hydrazine monohydrate (1.15 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with an aqueous potassium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (3.32 g, 90% yield) as colorless crystals, m.p. 68-69 ° C Reference Example 53 A mixture of hydrochloride -Chloro-2- (chloromethyl) imidazo [1,2-a] pyridine (3.00 g), 4-hydroxybenzaldehyde (1.81 g), potassium carbonate (6.14 g) and N, N-dimethylformamide (30 ml) was stirred Room temperature for 15 hours, poured into water and extracted with ethyl acetate.

The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain 4- (5-chloroimidazo [1,2- a] pyridin-2-ylmethoxy) benzaldehyde (3.55 g, 98% yield) as colorless crystals, m.p. 126-130 ° C Reference Example 54 To a solution of 4- (5-chloroimidazo [1,2- a] pyridin-2-ylmethoxy) benzaldehyde (3.52 g) in methanol (10 ml) -tetrahydrofuran (50 ml) was added sodium borohydride (232 mg) at 0 ° C. ° C. After stirring for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate to obtain 4- (5-chloroimidazo [1,2- a] pyridin-2-ylmethoxy) benzyl alcohol (2.34 g, 66% yield) as colorless crystals, m.p. 169-171 ° C Reference example 55 To a mixture of 4- (5-chloroimidazo [1,2- a] pyridin-2-ylmethoxy) benzyl alcohol (1.97 g), triethylamine (1.15 ml) and toluene (50 ml), thionyl chloride (0.597) was added dropwise. ml) at 0 ° C. After stirring for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 5-chloro-2- (4-chloromethylphenoxymethyl) imidazo [1,2-a] pyridine (1.10 g, 52% yield) as colorless crystals, m.p. 114-115 ° C Reference Example 56 To a solution of 2-pyridinecarboxylic acid (5.00 g) in tetrahydrofuran (200 ml) was added carbonyldiimidazole (7.25 g) at 0 ° C. After stirring at room temperature for 2 hours, the mixture was added dropwise to a solution of tert-butyl acetate combined with lithium prepared from tert-butyl acetate (17.5 ml) and lithium diisopropylamide (2N tetrahydrofuran solution). , 65 ml) at -78 ° C for 1 hour. After stirring for 15 minutes, 1N hydrochloric acid (250 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v). This was dissolved in tetrahydrofuran (100 ml), and sodium hydride (60% in oil, 1.06 g) was added at 0 ° C, and then the reaction mixture was stirred for 10 minutes. In addition, ethyl bromoacetate (2.00 ml) was added, stirred at 0 ° C for 8 hours, hydrochloric acid 0. IN (300 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 5, v / v). This was dissolved in toluene (200 ml), and p-toluenesulfonic acid (2.00 g) was added, and then the reaction mixture was stirred at 80 ° C for 20 hours. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl 4-oxo-4- (2-pyridyl) butyrate (1.56 g, 19% yield) of a fraction eluted with ethyl acetate-hexane (1: 2, v / v) as a colorless oil.

NMR (CDC13) d: 1.26 (3H, t, J = 7.1 Hz), 2.76 (2H, d, J = 6.7 Hz), 3. 57 (2H, d, J = 6.7 Hz), 4.16 (2H, q, J = 7.1 Hz), 7.48 (ÍH, dd, J = 4.8, 7.6 Hz), 7.84 (HH, dt, J = 1.8, 7.6 Hz), 8.05 (HH, d, J = 7.6 Hz), 8.69 (HH, dd, J = 1.8, 4.8 Hz).

Reference Example 57 To a solution of 2-furancarboxylic acid (5.00 g) in tetrahydrofuran (50 ml) were added oxalyl chloride (4.47 ml) and N, N-dimethylformamide (catalytic amount) at room temperature, which was stirred at room temperature for 1 hour. hour, followed by concentration. The residue was dissolved in tetrahydrofuran (20 ml) and added dropwise to a solution of tert-butyl acetate combined with lithium prepared from tert-butyl acetate (19.3 ml) and lithium diisopropylamide (2N tetrahydrofuran solution)., 72 ml) at -78 ° C for 1 hour. After stirring for 15 minutes, IN hydrochloric acid (250 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain crystals of a fraction eluted with ethyl acetate-hexane (1: 5, v / v). Recrystallization from ethyl acetate-hexane gave tert-butyl 3- (2-furyl) -3-oxopropionate (3.28 g, 35% yield) as colorless crystals, m.p. 74-75 ° C Reference Example 58 To a solution of tert-butyl 3- (2-furyl) -3-oxopropionate (3.01 g) in tetrahydrofuran (80 ml) was added sodium hydride (60% in oil, 629 mg) at 0 ° C and stirred for 10 minutes . To the mixture was added ethyl bromoacetate (1.51 ml), and then the reaction mixture was stirred at room temperature for 4 hours, hydrochloric acid 0. IN (200 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 5, v / v). This was dissolved in toluene (150 ml), and trifluoroacetic acid (2.64 ml) was added, and then the reaction mixture was stirred at 90 ° C for 6 hours. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl 4- (2-furyl) -4-oxobutyrate (2.22 g, 79% yield) as a colorless oil of a fraction eluted with ethyl acetate. hexane (1: 3, v / v).

NMR (CDC13) d: 1.27 (3H, t, J = 7.1 Hz), 2.74 (2H, t, J = 6.7 Hz), 3.18 (2H, .t, J = 6.7 Hz), 4.15 (2H, q, J = 7.1"Hz), 6.53-6.57 (HH, m), 7.23 (HH, d, J = 3.6 Hz), 7.59 (HH, d, J = 1.8 Hz).

Reference Example 59 To a solution of nicotinic acid (5.00 g) in tetrahydrofuran (100 ml) was added carbonyldiimidazole (7.25 g) at 0 ° C. After stirring at room temperature for 2 hours, the mixture was added dropwise to a solution of tert-butyl acetate combined with lithium prepared from tert-butyl acetate (17.5 ml) and lithium diisopropylamide (2N tetrahydrofuran solution). , 65 ml) at -78 ° C for 1 hour. After stirring for 15 minutes, 1N hydrochloric acid (250 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO) and concentrated. The residue was dissolved in tetrahydrofuran (100 ml), sodium hydride (60% in oil, 1.38 g) was added at 0 ° C and stirred for 10 minutes. To the mixture was added ethyl bromoacetate (3.33 ml), and the reaction mixture was stirred at room temperature for 3 hours, hydrochloric acid 0. IN (350 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 1, v / v). This oil was dissolved in toluene (150 ml), and trifluoroacetic acid (7.68 ml) was added and then the reaction mixture was stirred at 90 ° C for 4 hours. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl 4-oxo-4- (3-pyridyl) butyrate (3.39 g, 38% yield) as a colorless oil of a fraction eluted with ethyl acetate- hexane (2: 1, v / v).

NMR (CDC13) d: 1.28 (3H, t, J = 7.1 Hz), 2.79 (2H, t, J = 6.6 Hz), 3.33 (2H, t, J = 6.6 Hz), 4.17 (2H, q, J = 7.1 Hz), 7.43 (HH, dd, J = 4.8, 8.0 Hz), 8.23-8.30 (HH, m), 8.80 (HH, dd, J = 1.6, 4.8 Hz), 9.22 (HH, d, J = 2.2 Hz).

Reference Example 60 To a solution of 4-pyridinecarboxylic acid (5.00 g) in tetrahydrofuran (80 ml) was added carbonyldiimidazole (7.25 g) at 0 ° C. After stirring at room temperature for 2 hours, the mixture was added dropwise to a solution of tert-butyl acetate combined with lithium prepared from tert-butyl acetate (17.5 ml) and lithium diisopropylamide (2N tetrahydrofuran solution)., 65 ml) at -78 ° C for 1 hour. After stirring for 15 minutes, 1N hydrochloric acid (250 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (2: 3, v / v). This oil was dissolved in tetrahydrofuran (100 ml), and sodium hydride (60% in oil, 1.16 g) was added at 0 ° C, and then the reaction mixture was stirred for 10 minutes. To the mixture was added ethyl bromoacetate (2.88 ml), and the reaction mixture was stirred at room temperature for 24 hours, hydrochloric acid 0. IN = 300 ml was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 1, v / v). This oil was dissolved in toluene (120 ml), and stirred with trifluoroacetic acid (5.64 ml) at 90 ° C. 6 hours. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated.

The residue was subjected to column chromatography on silica gel to obtain ethyl 4-oxo-4- (4-pyridyl) butyrate (2.61 g, 31% yield) of a fraction eluted with ethyl acetate-hexane (2: 1, v / v) as a pale brown oil.

NMR (CDC13), d: 1.27 (3H, t, J = 7.1 Hz), 2.78 (2H, t, J = 6.5 Hz), 3.30 (2H, t, J = 6.5 Hz), 4.17 (2H, q, J = 7.1 Hz), 7.76 (2H, d, J = 6.2 Hz), 8.83 (2H, d, J = 6.2 Hz).

Reference Example 61 To a solution of 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (18.3 g) in methanol (50 ml) -tetrahydrofuran (100 ml) was added portionwise sodium borohydride (1.18 g) at 0 ° C. . After stirring for 30 minutes, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (15.5 g, 84% yield) as colorless crystals, m.p. 101-102 ° C.

Reference Example 62 To a mixture of 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (15.0 g) and toluene (200 ml) was added dropwise thionyl chloride (4.45 ml) at 0 ° C. After stirring at room temperature for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4- (3-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (13.4 g, 84% yield) as pale yellow crystals, m.p. 79-80 ° C Reference Example 63 A mixture of 4- (3-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (8.00 g), N-hydroxyphthalimide (4.13 g), potassium carbonate (7.05 g) and N, N-dimethylformamide (80 ml) was stirred at room temperature for 20 hours and water (800 ml) was added. The resulting crystals were filtered and washed with water to obtain N- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] phthalimide (10.1 g, 90% yield) as pale brown crystals, m.p. 146-147 ° C Reference Example 64 a solution of N- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] phthalimide (3.00 g) in ethanol (25 ml) -tetrahydrofuran (25 ml) was added hydrazine monohydrate (0.661 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, an aqueous potassium carbonate solution was added and it was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (2.04 g, 97% yield) as pale yellow crystals, m.p. 81-82 ° C.

Reference Example 65 A mixture of 2-aminopyridine (12.5 g), 1,3-dichloro-2-propanone (17.7 g) and acetonitrile (100 ml) was heated under reflux for 2 hours and concentrated. An aqueous saturated sodium bicarbonate solution was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain crystals of a fraction eluted with ethyl acetate-hexane (3: 2, v / v). Recrystallization from ethyl acetate-hexane gave 2-chloromethylimidazo [1,2-a] pyridine (7.52 g, 34% yield) as pale yellow crystals, m.p. 93-94 ° C Reference Example 66 To a solution of 6-oxo-6-phenylhexanoic acid (1.00 g) in tetrahydrofuran (15 ml) were added oxalyl chloride (0.508 ml) and N, N-dimethylformamide (catalytic amount) at room temperature, which was stirred at room temperature. room temperature for 1 hour and concentrated. The residue was dissolved in ethyl acetate (25 ml) and added dropwise to a stirred mixture of 25% aqueous ammonia (20 ml) and ethyl acetate (25 ml) at 0 ° C. After stirring at room temperature for 2 hours, water (200 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain 6-oxo-6-phenylhexanamide (885 mg, 89% yield) as colorless crystals, m.p. 113-114 ° C Reference Example 67 A mixture of acetophenone (25.0 ml) and diethyl oxalate (58.3 ml) was added to a solution of sodium ethoxide prepared from sodium (9.85 g) and ethanol (300 ml) and heated under reflux for 1 hour. The reaction mixture was concentrated, diluted with IN hydrochloric acid (450 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in ethanol (250 ml), and hydroxylamine hydrochloride (44.6 g) was added, and then the reaction mixture was refluxed for 1 hour. The reaction mixture was concentrated, water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain ethyl 5-phenylisoxazole-3-carboxylate (31.5 g, 70% yield) as pale brown crystals, m.p. 46-47 ° C Reference Example 68 To a solution of oxime of a-chlorobenzaldehyde (4.04 g) and 2-propyn-1-ol (1.66 ml) in tetrahydrofuran (130 ml) was added triethylamine (7.28 ml) and stirred at room temperature for 4 days. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain (3-phenyl-5-isoxazolyl) methanol (3.42 g, 75% yield) as colorless crystals, m.p. 48-49 ° C Reference Example 69 A solution of ethyl 5-phenylisoxazole-3-carboxylate (20.0 g) in diethyl ether (50 ml) was added dropwise to a mixture of lithium aluminum hydride (2.62 g) in diethyl ether (50 ml) at 0 ° C. After stirring for 1 hour, water was carefully added to the reaction mixture, followed by the addition of IN hydrochloric acid (200 ml) and extraction with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain (5-phenyl-3-isoxazolyl) methanol (15.2 g, 94% yield) as pale brown crystals, m.p. 101-102 ° C Reference example 70 To a solution of (3-phenyl-5-isoxazolyl) methanol (2.89 g) in toluene (10 ml) was added thionyl chloride (2.41 ml) and stirred at 60 ° C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate.

The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain 5- (chloromethyl) -3-phenylisoxazole (2.75 g, 86% yield) as pale brown crystals.

Reference Example 71 To a solution of (5-phenyl-3-isoxazolyl) methanol (12.1 g) in toluene (50 ml) was added thionyl chloride (7.55 ml) and stirred at 80 ° C for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate-hexane to obtain 3- (chloromethyl) -5-phenylisoxazole (11.8 g, 88% yield) as pale yellow crystals. p.f. 46-47 ° C Reference Example 72 To a mixture of 4-hydroxybenzaldehyde (50.0 g), potassium carbonate (84.9 g) and N, N-dimethylformaldehyde (150 ml) was added chloromethyl methyl ether (34.2 ml) at 0 ° C and stirred at room temperature for 11 hours . Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was dissolved in tetrahydrofuran (300 ml) and methanol (50 ml) and sodium borohydride (7.76 g) was added portionwise at 0 ° C. After stirring for 30 minutes, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain 4-methoxymethoxybenzyl alcohol (56.7 g, 82% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 3, v / v) .

NMR (CDC13) d: 3.48 (3H, s), 4.63 (2H, s), 5.18 (2H, s), 7.03 (2H, d, J = 8.8 Hz), 7.30 (2H, d, J = 8.8 Hz) .

Reference Example 73 To a solution of 4-methoxymethoxybenzyl alcohol (50.0 g), N-hydroxyphthalimide (44.1 g) and triphenylphosphine (83.7 g) in tetrahydrofuran (900 ml) was added dropwise to diethyl azodicarboxylate (40% toluene solution, 142 g) at room temperature and stirred for 1 hour. The reaction mixture was concentrated. To remove the triphenylphosphine oxide, the residue was subjected to silica gel column chromatography to obtain crystals of a fraction eluted with ethyl acetate-hexane (1: 5, v / v). The crystals were washed with ethyl acetate-hexane (1: 5, v / v) and then dissolved in tetrahydrofuran (200 ml) and ethanol (50 ml). To this solution was added hydrazine monohydrate (33.7 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, an aqueous potassium carbonate solution was added and it was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. To the residue, isopropyl ether was added and filtered to remove the insoluble substances. The filtrate was concentrated to obtain 4-methoxymethoxybenzyloxyamine (28.9 g, 58% yield) as a colorless oil.

R] N (CDCl3) d: 3.48 (3H, s), 4.63 (2H, s), 5.18 (2H, s), 7.04 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz).

Reference Example 74 A mixture of 4-methoxymethoxybenzyloxyamine (4.99 g), methyl 4-oxo-4-phenylbutyrate (5.71 g), acetic acid (5.10 ml), sodium acetate (4.87 g) and methanol (200 ml) was heated under reflux for 15 hours. The reaction mixture was cooled to room temperature, dilute hydrochloric acid was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in tetrahydrofuran (50 ml) and methanol (5 ml). To this solution was added IN hydrochloric acid (10 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl E-4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (4.24 g, 50% yield) as a colorless oil of a fraction eluted with ethyl acetate. -hexane (2: 5, v / v).

NMR (CDC13) d: 2.50-2.59 (2H, m), 3.01-3.10 (2H, m), 3.63 (3H, s), 4.97-5.05 (H, m), 5.14 (2H, s), 6.82 (2H , d, J = 8.8 Hz), 7.25-7.38 (5H, m), 7.59-7.65 (2H, m).

Reference Example 75 To a solution of ethyl benzoylacetate (10.0 g) in N, N-dimethylformamide (100 ml) was added sodium hydride (60% in oil, 2.18 g) at 0 ° C and stirred for 30 minutes. To this mixture was added methyl iodide (3.89 ml) and stirred for 1 hour. To the mixture was added sodium hydride (60% in oil, 2.18 g), and stirred for 30 minutes. In addition, methyl iodide (3.89 ml) was added and stirred for 1 hour. The reaction mixture was poured into 0.05N hydrochloric acid (1000 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl 2, 2-dimethyl-3-oxo-phenylpropionate (7.37 g, 64% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1:20, v / v).

NMR (CDC13) d: 1.05 (3H, t, J = 7.1 Hz), 1.55 (6H, s), 4.12 (2H, q, J = 7.1 Hz), 7.37-7.58 (3H, m), 7.81-7.87 ( 2H, m).

Reference Example 76 A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (15.6 g), methyl 4-hydroxyphenylacetate (12.5 g), potassium carbonate (20.8 g) and N, N-dimethylformamide (80 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenylacetate (23.8 g, 94% yield) as crystals of a fraction eluted with ethyl acetate. ethylhexane (1: 4, v / v). The crystals were recrystallized with ethyl acetate-hexane to obtain colorless crystals, m.p. 74-75 ° C Reference Example 77 A mixture of methyl 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenylacetate (23.2 g), lithium hydroxide monohydrate (4.33 g), tetrahydrofuran (100 ml), water (60 ml) and methanol (40 ml). ml) was stirred at room temperature for 1 hour. IN hydrochloric acid (103 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The remaining crystals were recrystallized with acetone to obtain 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenylacetic acid (21.9 g, 98% yield), m.p. 181-183 ° C Reference Example 78 To a mixture of methyl 8-chloro-8-oxooctanoate (2.00 g) and anisole (5 ml) was added aluminum chloride (2.58 g) at 0 ° C. After stirring at room temperature for 14 hours, the reaction mixture was poured onto ice (50 g), stirred at room temperature for 1 hour and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl 8- (4-methoxyphenyl) -8-oxooctanoate (2.37 g, 88% yield) as crystals. The crystals were recrystallized with ethyl acetate-hexane to obtain colorless crystals, m.p. 57-58 ° C Example 79 Reference To a mixture of 4-hydroxybenzaldehyde (17.8 g), imidazole (19.8 g) and N, N-dimethylformamide (100 ml) was added tert-butyldimethylsilyl chloride (24.1 g). After stirring at room temperature for 2 hours, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in tetrahydrofuran (300 ml) and methanol (40 ml), and then sodium borohydride (11.1 g) was added portionwise at 0 ° C. After stirring for 30 minutes, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain 4- (tert-butyldimethylsilyloxy) benzyl alcohol (27.7 g, 79% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 4). , v / v).

NMR (CDC13) d: 0.19 (6H, s), 0.98 (9H, s), 4.61 (2H, s), 6.83 (2H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz) .

Reference Example 80 To a solution of 4- (tert-butyldimethylsilyloxy) benzyl alcohol (27.5 g), N-hydroxyphthalimide (16.8 g) and triphenylphosphine (31.1 g) in tetrahydrofuran (450 ml) was added dropwise to diethyl azodicarboxylate (40% toluene solution). %, 54.0 g) at room temperature and stirred for 18 hours. After the reaction mixture was concentrated, diisopropyl ether (200 ml) was added and the residual crystals were removed by filtration. The filtrate was concentrated, and the residue was subjected to column chromatography on silica gel to obtain N- [4- (tert-Butyldimethylsilyloxy) benzyloxy] phthalimide (17.4 g, 43% yield) as crystals of a fraction eluted with ethyl acetate-hexane-toluene (1:10:10, v / v). The crystals were recrystallized with ethyl acetate-hexane to obtain colorless crystals, m.p. 76-77 ° C Reference Example 81 To a solution of N- [4- (tert-butyldimethylsilyloxy) benzyloxy] phthalimide (5.00 g) in ethanol (10 ml) -tetrahydrofuran (40 ml) was added hydrazine monohydrate (1.25 ml) and stirred at 60 ° C for 1 hour.

The reaction mixture was cooled to room temperature, an aqueous potassium carbonate solution was added and it was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated to obtain 4- (tert-butyldimethylsilyloxy) benzyloxyamine (3.15 g, 95% yield) as a colorless oil.

NMR (CDC13) d: 0.19 (6H, s), 0.98 (9H, s), 4.62 (2H, s), 5.20-5.50 (2H, br), 6.83 (2H, d, J = 8.6 Hz), 7.24 ( 2H, d, J = 8.6 Hz).

Reference Example 82 A mixture of 4- (tert-butyldimethylsilyloxy) benzyloxyamine (3.10 g), ethyl 8-oxo-8-phenyloctanoate (6.32 g), acetic acid (2.07 ml), sodium acetate (1.98 g) and ethanol (80 ml) are heated under reflux for 20 hours. The reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in tetrahydrofuran (60 ml), tetrabutylammonium fluoride trihydrate was added (3.98 g) and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-8- (4-hydroxybenzyloxyimino) -8-phenyloctanoate (3.55 g, 77% yield) as a colorless oil of a fraction eluted with ethyl acetate -hexane (2: 7, v / v).

NMR (CDC13) d: 1.20-1.65 (11H, m), 2.18-2.27 (2H, m), 2.69-2.78 (2H, m), 4.12 (2H, q, J = 7.1 Hz), 5.13 (2H, s) ), 5.39 (ÍH, br s), 6.83 (2H, d, J = 8.4 Hz), 7.25-7.38 (5H, m), 7.57-7.63 (2H, m).

Reference Example 83 A mixture of benzonitrile (26.2 g), hydroxylamine hydrochloride (17.7 g), potassium carbonate (17.6 g) and ethanol 70% (250 ml) was stirred at 80 ° C for 2 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture and extracted with ethyl acetate.

The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated.

The residue was dissolved in acetone (250 ml) and potassium carbonate (19.0 g) was added. This mixture was cooled to 0 ° C and chloroacetyl chloride (21.9 ml) was added dropwise. After stirring for 1 hour, the reaction mixture was concentrated. To the residue was added water, the residual crystals were filtered, washed with water and dissolved in ethyl acetate. This solution was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in xylene (250 ml), and refluxed with water separation. After 2 hours, the solution was concentrated and the remaining crystals were washed with hexane to obtain 5- (chloromethyl) -3-phenyl-1,2,4-oxadiazole (25.2 g, 51% yield) as yellow crystals. pale, mp 38-39 ° C Reference Example 84 A mixture of 4- (tert-butyldimethylsilyloxy) benzyloxyamide (5.31 g), ethyl 6-oxo-6-phenylhexanoate (6.76 g), acetic acid (3.54 ml), sodium acetate (3.38 g) and ethanol (150 ml) are heated to reflux for 18 hours. The reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in tetrahydrofuran (100 ml), tetrabutylammonium fluoride trihydrate was added (10.0 g) and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated.

The residue was subjected to silica gel column chromatography to obtain ethyl E-6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (5.64 g, 77% yield) as a colorless oil of a fraction eluted with ethyl acetate. -hexane (2: 7, v / v).

NMR (CDC13) d: 1.22 (3H, t, J = 7.1Hz), 1.45-1.75 (4H, m), 2.23-2.31 (2H, m), 2.73-2.81 (2H, m), 4.09 (2H, q , J = 7.1 Hz), 5.04 (ÍH, s), 5.13 (2H, s), 6.82 (2H, d, J = 8.2 Hz), 7.25-7.38 (5H, m), 7.58-7.64 (2H, m) .

Reference Example 85 To a solution of 3-benzoylpropionic acid (10.0 g) in tetrahydrofuran (100 ml) were added oxalyl chloride (5.39 ml) and N, N-dimethylformamide (catalytic amount) at room temperature, which was stirred at room temperature for 1 hour. hour and concentrated. The residue was dissolved in tetrahydrofuran (100 ml) and added dropwise to 25% aqueous ammonia (100 ml) at 0 ° C. After stirring at room temperature for 30 minutes, water (1000 ml) and hexane (500 ml) were added, and then the residual crystals were filtered and washed with hexane to obtain 4-oxo-4-butyramide (2.67 g, 27% of performance) as orange crystals, mp 126-127 ° C Reference Example 86 A solution of 2- [2- (methoxycarbonyl) ethyl] -2-phenyl-1,3-dioxolane (5.00 g) in diethyl ether (15 ml) was added dropwise to a mixture of lithium aluminum hydride (949 mg. ) and diethyl ether (30 ml) at 0 ° C. After stirring for 30 minutes, water was carefully added to the reaction mixture and the precipitates were removed by filtration. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to silica gel column chromatography to obtain 2- (3-hydroxypropyl) -2-phenyl-1,3-dioxolan (3.81 g, 87% yield) as a colorless oil of a fraction eluted with acetate of ethylhexane (2: 3, v / v).

NMR (CDC13) d: 1.61-1.72 (2H, m), 2.02 (2H, t, J = 6.4 Hz), 3.63 (2H, t, J = 6.3 Hz), 3.74-3.87 (2H, m), 3.95- 4.08 (2H, m), 7.24-7.49 (5H, m).

Reference Example 87 To a solution of 2- (3-hydroxypropyl) -2-phenyl-1,3-dioxolane (3.75 g) and triethylamine (5.05 ml) in ethyl acetate (100 ml) was added methanesulfonyl chloride (1.81 ml) at 0 ° C. ° C.

After stirring for 30 minutes, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was dissolved in acetone (100 ml), sodium iodide (5.40 g) was added and stirred at 60 ° C for 2 hours. The reaction mixture was concentrated, water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain 2- (3-iodopropyl) -2-phenyl-1,3-dioxolane (5.41 g, 94% yield) as colorless crystals, m.p. 71-73 ° C Reference Example 88 To a solution of diisopropylamine (0.529 ml) in tetrahydrofuran (5 ml) was added dropwise N-butyllithium (1.6N hexane solution, 2.16 ml) at 20 ° C under a nitrogen atmosphere. After stirring for 20 minutes, the mixture was cooled to -78 ° C, and methyl isobutyrate (0.397 ml) in tetrahydrofuran (5 ml) was added dropwise over 30 minutes. The reaction mixture was further stirred for 20 minutes, 2- (3-iodopropyl) -2-phenyl-1,3-dioxolane (1.00 g) and hexamethylphosphoramide (0.602 ml) were added. After stirring at -40 ° C for 3 hours, dilute hydrochloric acid was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was dissolved in acetone (30 ml), INN sulfuric acid (10 ml) was added and it was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl 2,2-dimethyl-6-oxo-6-phenylhexanoate (350 mg, 45% yield) as a colorless oil of a fraction eluted with ethyl acetate. -hexane (1: 7, v / v).

NMR (CDC13) d: 1.20 (6H, s), 1.55-1.80 (4H, m), 2.96 (2H, t, J = 6.8 Hz), 3.65 (3H, s), 7.41-7.61 (3H, m), 7.92-8.02 (2H, m).

Example 89 Reference To a solution of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (5.00 g) in tetrahydrofuran (30 ml) -methanol (30 ml) was added sodium borohydride (325 g) at 0 ° C. After stirring for 1 hour, the reaction mixture was poured into water to give crystals.

Recrystallization from acetone-ethyl acetate gave 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (4.17 g, 83% yield) as colorless prisms, m.p. 155-156 ° C.

Reference Example 90 To a stirred suspension of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (4.00 g) in toluene (60 ml) was added dropwise thionyl chloride (1.69 g) at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residual crystals were dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution and water. The ethyl acetate layer was separated, dried (MgSO 4), and concentrated to give 4- (2-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole as crystals. Recrystallization from ethyl acetate-hexane gave colorless needles (3.50 g, 82% yield), m.p. 103-104 ° C.

Reference Example 91 To a solution of 3,5-dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (10.0 g) in tetrahydrofuran (70 ml) -methanol (30 ml) was added sodium borohydride (540 g) at 0 ° C. After stirring for 1 hour, the reaction mixture was poured into water to give 3,5-dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (9.25 g, 92% yield) as crystals. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p. 113 -114 ° C.

Reference Example 92 To a stirred suspension of 3,5-dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) -benzyl alcohol (9.00 g) in tetrahydrofuran (50 ml) -toluene (150 ml) was added dropwise chloride. thionyl (3.62 g) at 0 ° C. After stirring at room temperature for 3 hours, the reaction mixture was concentrated. The residual crystals were dissolved in ethyl acetate and washed with a solution of aqueous sodium bicarbonate and water. The ethyl acetate layer was separated, dried (MgSO), and concentrated to give 4- (4-chloromethyl-2,6-dimethoxyphenoxymethyl) -5-methyl-2-phenyloxazole as crystals. Recrystallization from acetone-hexane gave colorless needles (7.00 g, 74% yield), m.p. 118-119 ° C.

Reference Example 93 To a solution of 4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzaldehyde (6.48 g) in tetrahydrofuran (50 ml) -methanol (50 ml) was added sodium borohydride (825 mg) ) at 0 ° C. After stirring for 1 hour, the reaction mixture was poured into water to give 4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyl alcohol (6.98 g, 92% yield) as crystals.

NMR (CDC13) d: 2.41 (3H, s), 3.88 (3H, s), 4.63 (2H, s), 5.06 (2H, s), 6.5-6.55 (H, m), 6.85-6.95 (H, m) ), 6.95-7.05 (3H, m), 7.5-7.55 (1H, m).

Reference Example 94 To a stirred suspension of 4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyl alcohol (6.30 g) in tetrahydrofuran (100 ml) was added dropwise thionyl chloride (2.59 g) at 0 ° C. After stirring at room temperature for 1 hour, the reaction mixture was poured on ice to give 4- (4-chloromethyl-2-methoxyphenoxymethyl) -2- (2-furyl) -5-methyloxazole as crystals (5.67 g, 85 % of performance).

NMR (CDC13) d: 2.40 (3H, s), 3.88 (3H, s), 4.56 (2H, s), 5.05 (2H, s), 6.5-6.55 (2H, m), 6.9-7.05 (4H, m ), 7.5-7.55 (ÍH, m).

Reference Example 95 In the same manner substantially as in Reference Example 93, 3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (6.47 g) is reduced by sodium borohydride (760 mg) to obtain alcohol 3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl ester (6.11 g, 93% yield) as crystals.

NMR (CDC13) d: 2.32 (3H, s), 3.79 (3H, s), 4.54 (2H, s), 4.96 (2H, s), 6.7-7.0 (3H, m), 7.3-7.4 (3H, m ), 7.9-8.0 (2H, m).

Reference Example 96 In the same manner substantially as in Reference Example 94, the 3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (6.00 g) is reacted with thionyl chloride (1.58). g) to obtain 4- (4-chloromethyl-2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole (5.77 g, 91% yield) as crystals.

NMR (CDC13) d: 2.32 (3H, s), 3.79 (3H, s), 4.47 (2H, s), 4.97 (2H, s), 6.7-7.0 (3H, m), 7.3-7.4 (3H, m ), 7.9-8.0 (2H, m).

Example 1 To a solution of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (1.32 g) in toluene (10 ml), thionyl chloride (0.488 ml) was added and the mixture was stirred for 30 minutes at room temperature. 60 ° C. The reaction mixture was concentrated and the residue was dissolved in N, N-dimethylformamide (5 ml), and then added under a nitrogen atmosphere to a mixture of methyl Z-2-hydroxyimino-2-phenylacetate (800 mg). sodium hydride (60% in oil, 178 mg) and N, N-dimethylformamide (5 ml) and the mixture was stirred for 1.5 hours at room temperature. After adding IN HCl (7 ml) and then an aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in methanol (10 ml) -solution of aqueous sodium hydroxide IN (7 ml) and the mixture was heated under reflux for 1 hour. After adding IN HCl (7.5 ml) to the reaction mixture, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2-phenylacetic acid (1.07 g, 54% yield) as colorless crystals. p.f. 171-172 ° C (decomposition) Example 2 To a solution of 3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propanol (1.00 g) and triethylamine (0.866 ml) in ethyl acetate (30 ml), chloride was added dropwise. methanesulfonyl (0.478 ml) at 0 ° C, and the mixture was stirred for 1 hour. The reaction mixture was washed with a saturated aqueous sodium chloride solution, dried (MgSO), and then concentrated. The residue was dissolved in N, N-dimethylformamide (10 ml), and methyl Z-2-hydroxyimino-2-phenylacetate (830 mg) and sodium hydride (60%, in oil, 185 mg) were added and the mixture was added. it was stirred for 2 hours at room temperature. After adding IN HCl (7 ml) and then an aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain a colorless oil of a fraction eluted with ethyl acetate-hexane-toluene (1: 5: 5, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and a solution of aqueous sodium hydroxides IN (5 ml) was added, and then the mixture was stirred for 2 hours at 40 ° C. After adding IN HCl (5.5 ml) to the reaction mixture, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propoxyimino] -2-phenylacetic acid (1.13 g, 78 % yield) as colorless crystals, mp 165-166 ° C (decomposition) Example 3 To a solution of 4- [2- (methyl-2-pyridylamino) ethoxy] benzyl alcohol (1.50 g) in toluene (15 ml), thionyl chloride (0.636 ml) was added at 0 ° C and the mixture was stirred for 30 minutes. The reaction mixture was concentrated and the residue dissolved in N, N-dimethylformamide (10 ml), and then mixed with methyl Z-2-hydroxyimino-2-phenylacetate (1.04 g) and sodium hydride (60% in oil, 511 mg) and stirred for 14 hours at room temperature under a nitrogen atmosphere. After adding 1N HCl (20 ml) and then an aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 2, v / v). This oil was dissolved in tetrahydrofuran (20 ml) -methanol (20 ml), and an aqueous sodium hydroxide solution IN (10 ml) was added and the mixture was stirred at 40 ° C for 1 hour. To the reaction mixture was added IN HCl to adjust to pH 4, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain Z-2- [4- [2- (methyl-2-pyridylamino) ethoxy] benzyloxyimino] -2-phenylacetic acid (959 mg, 41% yield) as colorless crystals, pf 93-94 ° C Example 4 a solution of 4- [2- (methyl-2-pyridylamino) ethoxy] benzyl alcohol (1.50 g) in toluene (15 ml), thionyl chloride (0.636 ml) was added at 0 ° C and the mixture was stirred for 30 minutes. minutes The reaction mixture was concentrated and the residue was dissolved in N, N-dimethylformamide (10 ml), and then mixed with methyl E-4-hydroxyimino-2-phenylbutyrate (1.20 g) and sodium hydride (60%, oil, 511 mg) and stirred for 3 hours at room temperature under a nitrogen atmosphere. After adding IN HCl (20 ml) and then an aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 2, v / v). This oil was dissolved in tetrahydrofuran (20 ml) -methanol (20 ml), and an aqueous sodium hydroxide solution IN (10 ml) was added and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added IN HCl to adjust to pH 4, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and then concentrated to obtain E-4- [4- [2- (methyl-2-pyridylamino) ethoxy] benzyloxyimino acid] -2-phenylbutyric (1.04 g, 41% yield) as a colorless oil.

NMR (CDC13) d: 2.51-2.62 (2H, m), 3.00-3.09 (2H, m), 3.13 (3H, s), 3.97 (2H, t, J = 5.6 Hz), 4.19 (2H, t, J = 5.6 Hz), 5.14 (2H, s), 6.50-6.59 (2H, m), 6.87 (2H, d, J = 8.8 Hz), 7.24-7.51 (6H, m), 7.59-7.65 (2H, m), 8.13-8.18 (H) , m).

Example 5 To a solution of methyl E-2-hydroxyimino-2-phenylacetate (548 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (960 mg) in N, N-dimethylformamide (10 ml) was added under a nitrogen atmosphere sodium hydride (60%, in oil, 122 mg) at room temperature and the mixture was stirred for 1 hour. After addition of 1N HCl (5 ml), a solution of aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 2, v / v). This oil was dissolved in methanol (5 ml) -solution of aqueous sodium hydroxide IN (5 ml) and the mixture was heated under reflux for 3 hours. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-isopropyl ether to obtain E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2-phenylacetic acid (948 mg, 70% yield) as colorless crystals, mp 142-143 ° C (decomposition) Example 6 To a solution of ethyl E-2-hydroxyimino-3-phenylpropionate (661 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) was sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and a 1N aqueous sodium hydroxide solution (4 ml) was added and the mixture was stirred at room temperature for 1.5 hours. INN HCl (4.5 ml) was added to the reaction mixture., and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residual crystal was recrystallized from ethyl acetate-isopropyl ether to obtain E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionic acid (844 mg, 58% yield) as colorless crystals. p.f. 143-144 ° C (decomposition) Example 7 To a solution of methyl E-4-hydroxyimino-4-phenylbutyrate (661 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) were added. sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and an aqueous sodium hydroxide solution IN (5 ml) was added and the mixture was stirred at room temperature for 1.5 hours. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (907 mg, 60% yield) as colorless crystals. p.f. 126-127 ° C (decomposition) Example 8 To a solution of ethyl E-2-hydroxyiminohexanoate (553 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) was added under an atmosphere of nitrogen, sodium hydride (60% in oil, 127 mg) at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and an aqueous sodium hydroxide solution IN (5 ml) was added and the mixture was stirred at room temperature for 30 minutes. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] hexanoic acid (922 mg, 68% yield) as colorless crystals. p.f. 112-114 ° C Example 9 To a solution of ethyl E-2-hydroxyiminopropionate (418 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) was added under a nitrogen atmosphere sodium hydride (60% in oil, 127 mg) at room temperature and the mixture was stirred for 1 hour.

After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and an aqueous sodium hydroxide solution IN (5 ml) was added and the mixture was stirred at room temperature for 1 hour. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-isopropyl ether to obtain E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] propionic acid (849. mg, 70% yield) as crystals. colorless, pf 147-148 ° C Example 10 To a solution of ethyl Z-2- (4-bromophenyl) -2-hydroxyiminoacetate (868 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide ( 10 ml) sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 2, v / v). This oil was dissolved in tetrahydrofuran (5 ml) -methanol (10 ml), and a 0.5N aqueous sodium hydroxide solution (10 ml) was added and the mixture was heated under reflux for 1.5 hours. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain Z-2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (1.34 g, 81% strength). yield) as colorless crystals. p.f. 189-190 ° C (decomposition) Example 11 To a solution of ethyl Z-2-hydroxyimino-2- (4-phenoxylphenyl) acetate (910 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (20 ml) -methanol (10 ml), and a solution of 1N aqueous sodium hydroxide (10 ml) was added and the mixture was stirred at 40 ° C for 2 hours. INN HCl (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (4-phenoxyphenyl) acetic acid (1.51 g, 89%). % yield) as colorless crystals, mp 184-185 ° C (decomposition) Example 12 To a solution of ethyl E-2-hydroxyimino-2- (4-phenoxyphenyl) acetate (910 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and an aqueous sodium hydroxide solution IN (5 ml) was added and the mixture was stirred at 40 ° C for 2 hours. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (4-phenoxyphenyl) acetic acid (1.38 g, 81%). % yield) as colorless crystals, mp 152-153 ° C (decomposition) Example 13 To a solution of methyl Z-2-hydroxyimino-2- (3-phenoxypheyl) acetate (605 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (700 mg) in N, N-dimethylformamide (10 ml) Sodium hydride (60% in oil, 107 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and a 1N aqueous sodium hydroxide solution (5 ml) was added and the mixture was stirred at 40 ° C for 2 hours.

INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain acid Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-phenoxyphenyl) acetic acid (738 mg, 62% yield) as colorless crystals, m.p. 173-174 ° C (decomposition) Example 14 To a solution of methyl E-2-hydroxyimino-2- (3-phenoxyphenyl) acetate (605 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (700 mg) in N, N-dimethylformamide ) (10 ml) was added under a nitrogen atmosphere sodium hydride (60% in oil, 107 mg) at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and an aqueous sodium hydroxide solution IN (5 ml) was added and the mixture was stirred at 40 ° C for 2 hours. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-phenoxyphenyl) acetic acid (745 mg, 62%). % yield) as a colorless amorphous material, mp 55-65 ° C NMR (CDC13) d: 2.45 (3H, s), 5.10 (2H, s), 5.22 (2H, s), 6.98-7.48 (16H, m), 7.98-8.05 (2H, m).

Example 15 To a solution of ethyl Z-2- (4-fluorophenyl) -2-hydroxyiminoacetate (920 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.37 g) in N, N-dimethylformamide ( 10 ml) was added under a nitrogen atmosphere sodium hydride (60% in oil, 209 mg) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (7 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (20 ml) -methanol (10 ml), and an aqueous sodium hydroxide solution IN (10 ml) was added and the mixture was stirred at 40 ° C for 2 hours. INN HCl (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain Z-2- (4-fluorophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (1.66 g, 83% strength). yield) as colorless crystals. p.f. 182-183 ° C (decomposition) Example 16 To a solution of ethyl E-2- (4-fluorophenyl) -2-hydroxyiminoacetate (920 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.37 g) in N, N-di-ethylformamide (10 ml) Sodium hydride (60% in oil, 209 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (7 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (20 ml) -methanol (10 ml), and an aqueous sodium hydroxide solution IN (10 ml) was added and the mixture was stirred at 40 ° C for 2 hours. INN HCl (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain E-2- (4-fluorophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (1.08 g, 54% strength). yield) as colorless crystals. p.f. 150-151 ° C (decomposition) Example 17 To a solution of ethyl E-4- (4-fluorophenyl) -4-hydroxyiminobutyrate (763 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide ( 10 ml) sodium hydride (60% * in oil, 153 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (7 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v). This oil was dissolved in tetrahydrofuran (20 ml) -methanol (10 ml), and an aqueous sodium hydroxide solution IN (10 ml) was added and the mixture was stirred at room temperature for 1 hour. INN HCl (7.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-4- (4-fluorophenyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (727 mg, 47%). % yield) as colorless crystals, mp 139-140 ° C Example 18 To a solution of ethyl E-5-hydroxyimino-5-phenylpentanoate (751 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) was added under a nitrogen atmosphere sodium hydride (60% in oil, 153 mg) at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v). This oil was dissolved in tetrahydrofuran (20 ml) -methanol (10 ml), and a 1N aqueous sodium hydroxide solution (10 ml) was added and the mixture was stirred at room temperature for 2 hours. INN HCl (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -5-phenylpentanoic acid (1.24 g, 80% yield) as colorless crystals, mp 129-130 ° C Example 19 To a solution of ethyl Z-2-hydroxyimino-2- (4-methoxyphenyl) acetate (711 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (5 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2- (4-methoxyphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (1.50 g , yield: 94%) as crystals of a fraction eluted with ethyl acetate-hexane (1: 2, v / v). The recrystallization was carried out with ethyl acetate-hexane. p.f. 102-103 ° C Example 20 To a solution of ethyl 2-hydroxyimino-3-methylbutyrate (Z: E = 2.3: 1, 1.01 g) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (2.00 g) in N, N- dimethylformamide (20 ml) was added under a nitrogen atmosphere sodium hydride (60% in oil, 225 mg) at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (10 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain as a first product Z-3-methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl butyrate (640 mg , 23% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane-dichloromethane (1:10:10, v / v).

NMR (CDC13) d: 1.14 (6H, d, J = 6.8 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 2.70 (ΔI, sept, J = 6.8 Hz), 4.29 (2H, q, J = 7.1Hz), 4.99 (2H, s), 5.03 (2H, s), 6.98 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.41 -7.49 (3H, m), 7.97-8.05 (2H, m).

Example 21 From an eluted fraction following the Z-form in Example 20, ethyl E-3-methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate, (1.34 g, 48% yield) as a colorless oil.

NMR (CDC13) d: 1.17 (6H, d, J = 7.0 Hz), 1.35 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 3.40 (ÍH, sept, J = 7.0 Hz), 4.30 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.17 (2H, s), 7.01 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.8 Hz), 7.40 -7.48 (3H, m), 7.97-8.05 (2H, m).

Example 22 To a solution of ethyl E-2- (4-bromophenyl) -2-hydroxyiminoacetate (1.73 g) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (2.00 g) in N, N-dimethylformamide ( 20 ml) sodium hydride (60% in oil, 225 mg) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. After adding IN HCl (10 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-2- (4-bromo-phenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (2.54 g. , 73% yield) as crystals of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). The recrystallization was carried out with ethyl acetate-hexane. p.f. 105-106 ° C Example 23 To a solution of ethyl Z-2- (4-bromo-phenyl) -2-hydroxyiminoacetate (2.50 g) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (3.03 g) in N, N-dimethylformamide ( 25 ml) was added under a nitrogen atmosphere sodium hydride (60% in oil, 368 mg) at room temperature and the mixture was stirred for 1 hour. After addition of IN HCl (12 ml), an aqueous sodium bicarbonate solution was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (3.12 g). , 61% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v).

R1VIN. { CDC13) d: 1.33 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.19 (2H, s), 7.01 (2H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.37-7.54 (7H, m), 7.97-8.05 (2H, m).

Example 24 In a mixture of tetrahydrofuran (5 ml) -methanol (10 ml), Z-2- (4-methoxyphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl acetate was dissolved. (1.20 g) and a 0.5N aqueous sodium hydroxide solution (10 ml) was added and the mixture was heated to reflux for 1 hour. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain Z-2- (4-methoxyphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (1.02 g, 90% strength). yield) as colorless crystals, mp 183 -184 ° C Example 25 In a mixture of tetrahydrofuran (6 ml) -methanol (3 ml) was dissolved Z-3-methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl butyrate (580 mg). ) and an aqueous sodium hydroxide solution IN (3 ml) was added and the mixture was stirred for 3 hours at room temperature. INN HCl (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residual crystals were recrystallized with ethyl acetate-hexane to obtain Z-3-methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (523 mg, 96% yield) as colorless crystals, mp 140-142 ° C Example 26 In a mixture of tetrahydrofuran (10 ml) -methanol (5 ml) was dissolved E-3-methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl butyrate (1.27 g) and an aqueous sodium hydroxide solution IN (5 ml) was added and the mixture was stirred for 2 hours at room temperature. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-3-methyl-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (1.02 g, yield: 85%) as colorless crystals, mp 128-129 ° C Example 27 In a mixture of tetrahydrofuran (6 ml) -methanol (3 ml) was dissolved E-2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl acetate (600 mg) and a 1N aqueous sodium hydroxide solution (3 ml) was added and the mixture was stirred for 1 hour at 40 ° C. To the reaction mixture was added 1N HCl (3.3 ml), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystals were recrystallized with ethyl acetate to obtain E-2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (516 mg, 99% strength). yield) as colorless crystals. p.f. 159-160 ° C (decomposition) Example 28 A mixture of E-2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl acetate (800 mg), phenylboronic acid (213 mg), potassium carbonate (604 mg), toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under an argon atmosphere for 30 minutes at room temperature. Tetrakis (triphenylphosphine) palladium metal (101 mg) was added and the mixture was heated under reflux for 15 hours. The reaction mixture was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (6 ml) -methanol (3 ml), and an aqueous sodium hydroxide solution IN (3 ml) was added and the mixture was stirred for 2 hours at 40 ° C. INN HCl (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-2- (4-biphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyiminoacetic acid (642 mg, 85% yield) as colorless crystals. p.f. 148-149 ° C (decomposition) Example 29 A mixture of Z-2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl acetate (1.43 g), phenylboronic acid (476 mg), potassium carbonate (1.44 g), toluene (30 ml), ethanol (3 ml) and water (3 ml) was stirred under an argon atmosphere for 30 minutes at room temperature. Tetrakis (triphenylphosphine) palladium metal (180 mg) was added and the mixture was heated under reflux for 13 hours. The reaction mixture was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane-dichloromethane (1:10:10, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and an aqueous sodium hydroxide solution IN (5 ml) was added and the mixture was stirred for 2 hours at 40 ° C. To the reaction mixture was added 1N HCl (5.5 ml), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-isopropyl ether to obtain Z-2- (4-biphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (807 mg, 60% yield) as colorless crystals. p.f. 193 -194 ° C (decomposition) Example 30 A mixture of ethyl Z-2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (800 mg), thienylboronic acid (224 mg), potassium carbonate (604 mg), toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under an argon atmosphere for 30 minutes at room temperature. Tetrakis (triphenylphosphine) palladium metal (101 mg) was added and the mixture was heated under reflux for 14 hours. The reaction mixture was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and a 1N aqueous sodium hydroxide solution (5 ml) was added and the mixture was stirred for 2 hours at 40 ° C. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [4- (3-thienyl) phenyl] acetic acid. (442 mg, 58% yield) as pale yellow crystals, mp 205-206 ° C (decomposition) Example 31 A mixture of ethyl Z-2- (4-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (830 mg), 4- (E-2-phenylethenyl) ) phenylboronic acid (268 mg), potassium carbonate (626 mg), toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under an argon atmosphere for 30 minutes at room temperature. Tetrakis (triphenylphosphine) palladium metal (105 mg) was added and the mixture was heated under reflux for 14 hours. The reaction mixture was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residues were subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), and an aqueous sodium hydroxide solution IN (5 ml) was added and the mixture was stirred for 2 hours at 40 ° C. INN HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [4- (E-2-phenylethenyl) phenyl] acid. ] acetic acid (634 mg, yield: 77%) as pale yellow crystals. p.f. 194-195 ° C (decomposition) Example 32 To a solution of ethyl Z-2-hydroxyimino-2- (3-pyridyl) acetate (619 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 153 mg) at room temperature under a nitrogen atmosphere and stirred for 3 hours. INN hydrochloric acid (7 ml) was added to the reaction mixture, an aqueous saturated sodium bicarbonate solution was added and it was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-pyridyl) ethyl acetate (1.12 g , 74% yield) as a pale yellow oil of a fraction eluted with ethyl acetate-hexane (1: 1, v / v).

NMR (CDC13) d: 1.35 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 4.42 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.22 (2H, s) , 7.01 (2H, d, J = 8.8 Hz), 7.25-7.37 (3H, m), 7.40-7.48 (3H, m), 7.86-7.93 (HI, m), 7.99-8.05 (2H, m), 8.61 -8.65 (lH, "m), 8.75-8.78 (ÍH, m).

Example 33 To a solution of ethyl E-2-hydroxyimino-2- (3-pyridyl) acetate (619 mg) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) in N, N-dimethylformamide (10 ml) was added sodium hydride (60%, in oil, 153 mg) at room temperature under a nitrogen atmosphere and stirred for 3 hours.

INN hydrochloric acid (7 ml) was added to the reaction mixture, an aqueous saturated sodium bicarbonate solution was added and it was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-pyridyl) ethyl acetate (1.02 g , 68% yield) as a pale yellow oil of a fraction eluted with ethyl acetate-hexane (1: 1, v / v).

NMR (CDC13) d: 1.36 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 4.37 (2H, q, J = 7.1 Hz), 4.99 (2H, s), 5.27 (2H, s) , 7.00 (2H, d, J = 8.8 Hz), 7.25-7.38 (3H, m), 7.41-7.48 (3H, m), 7.72-7.80 (HI, m), 7.98-8.05 (2H, m), 8.57 -8.62 (ÍH, m), 8.66-8.70 (ÍH, m).

Example 34 To a solution of ethyl Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-pyridyl) acetate (450 mg) in tetrahydrofuran (10 ml) was added acid m-chloroperoxybenzoic acid (70%, 282 mg) at room temperature and stirred for 17 hours. To the reaction mixture was added an aqueous saturated sodium thiosulfate solution (10 ml) and a saturated aqueous potassium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-methanol (10: 1, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), a solution of saturated aqueous sodium hydroxide IN (5 ml) was added and stirred at 40 ° C for 2 hours. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized with acetone-diisopropyl ether to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (pyridin-1-oxide-3-yl) acetic acid ( 282 mg, 64% yield) as colorless crystals, mp 181-182 ° C (decomposition) Example 35 a solution of ethyl Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-pyridyl) acetate (520 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at 40 ° C for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. r The residue was recrystallized from ethyl acetate to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-pyridyl) acetic acid (321 mg, 66% yield) as colorless crystals, mp 156-157 ° C (decomposition) Example 36 To a solution of E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-pyridyl) ethyl acetate (450 mg) in tetrahydrofuran (10 ml) was added m-chloroperoxybenzoic acid (70%, 282 mg) at room temperature and stirred for 17 hours. To the reaction mixture were added a saturated aqueous sodium thiosulfate solution (10 ml) and a saturated aqueous potassium carbonate solution (10 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-methanol (10: 1, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), a solution of saturated aqueous sodium hydroxide IN (5 ml) was added and stirred at 40 ° C for 2 hours. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (pyridin-1-oxide-3-yl) acetic acid. (228 mg, 52% yield) as colorless crystals. p.f. 161-162 ° C (decomposition) Example 37 a solution of E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-pyridyl) ethyl acetate (520 mg) in tetrahydrofuran (10 ml) -methanol (5 ml). ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at 40 ° C for 1 hour. To the reaction mixture was added IN hydrochloric acid (5.5 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and concentrated. The residue was recrystallized with acetone-diisopropyl ether to obtain E-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (3-pyridyl) acetic acid (427 mg, 88% yield). yield) as colorless crystals. p.f. 130-131 ° C (decomposition) Example 38 To a solution of ethyl Z-2- (3-bromo-phenyl) -2-hydroxyiminoacetate (1.15 g) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.33 g) in N, N-dimethylformamide ( 15 ml) was added sodium hydride (60%, in oil, 203 mg) at room temperature under a nitrogen atmosphere and stirred for 1 hour. To the reaction mixture was added IN hydrochloric acid (7 ml), an aqueous sodium bicarbonate solution was added, and it was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2- (3-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (1.12 g). , 48% yield) as a pale yellow oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 1.33 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 4.41 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.20 (2H, s) , 7.01 (2H, d, J = 8.8 Hz), 7.20-7.56 (8H, m), 7.73-7.76 (HI, m), 7.99-8.06 (2H, m).

Example 39 To a solution of ethyl Z-2- (3-benzoylphenyl) -2-hydroxyiminoacetate (2.47 g) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (2.61 g) in N, N-dimethylformamide ( 15 ml) was added sodium hydride (60% in oil, 399 mg) at room temperature under a nitrogen atmosphere and stirred for 1 hour. INN hydrochloric acid (15 ml) was added to the reaction mixture, an aqueous sodium bicarbonate solution was added, and it was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2- (3-benzoylphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (1.97 g. , 41% yield) as a pale yellow oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v).

NMR (CDC13) d: 1.31 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 4.99 (2H, s), 5.20 (2H, s) , 7.00 (2H, d, J = 8.8 Hz), 7.25-7.72 (11H, m), 7.76-7.86 (3H, m), 7.96-8.05 (2H, m).

Example 40 To a solution of ethyl Z-2- (3-benzoylphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (800 mg) in tetrahydrofuran (14 ml) -methanol ( 7 ml) was added a solution of saturated aqueous sodium hydroxide IN (7 ml) and stirred at 40 ° C for 1 hour. INN hydrochloric acid (7.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2- (3-benzoylphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (608 mg, 80%). of performance) as orange crystals, mp 185-186 ° C (decomposition) Example 41 To a mixture of methyltriphenylphosphonium bromide (1.14 g) and tetrahydrofuran (10 ml) was added potassium tert-butoxide (328 mg) under a nitrogen atmosphere and stirred at room temperature for 1 hour. A solution of Z-2- (3-benzoylphenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] ethyl acetate was dropwise added to the reaction mixture. (1.12 g) in tetrahydrofuran (10 ml), further stirred for 3 hours, dilute hydrochloric acid was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [3- (1-phenylvinyl) phenyl] acetate. of ethyl (880 mg, 79% yield) as a pale brown oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 1.27 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 4.36 (2H, q, J = 7.1 Hz), 4.99 (2H, s), 5.18 (2H, s) , 5.48 (2H, d, J = 6.4 Hz), 6.99 (2H, d J = 8.6 Hz), 7.25-7.55 (14H, m), 7.99-8.05 (2H, m).

Example 42 A mixture of ethyl Z-2- (3-bromophenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (780 mg), E-styrylboronic acid (252 mg), potassium carbonate. (589 mg), toluene (20 ml), water (2 ml) and ethanol (2 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. To this was added metal tetrakis (triphenylphosphine) palladium (98 mg) and heated to reflux for 15 hours. After the mixture was cooled to room temperature, the organic layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (E-styryl) ethyl acetate (610 mg , 75% yield) as a pale brown oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 1.35 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 4.43 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.23 (2H, s) , 7.01 (2H, d, J = 8.4 Hz), 7.11 (2H, s), 7.25-7.60 (13H, m), 7.69 (IH, br s), 7.99-8.05 (2H, m).

Example 43 To a solution of ethyl Z-2- (3-bromo-phenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetate (430 mg) in tetrahydrofuran (10 ml) -methanol ( 5 ml) was added an aqueous saturated sodium hydroxide solution IN (5 ml) and stirred at 40 ° C for 2 h. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2- (3-bromo-phenyl) -2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid (370 mg, 91% of performance) as colorless crystals. p.f. 181-182 ° C (decomposition) Example 44 To a solution of ethyl Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [3- (1-phenylvinyl) phenyl] acetate (780 mg) in tetrahydrofuran (10 mg). ml) -methanol (5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at 40 CC for 2 hours. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- [3- (1-phenylvinyl) phenyl] acetic acid ( 701 mg, 95% yield) as colorless crystals, mp 171-172 ° C Example 45 a solution of Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (E-3-styryl) ethyl acetate (500 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at 40 ° C for 2 hours. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -2- (E-3-styryl) acetic acid (474 mg, 95% yield) as colorless crystals, mp 178-179 ° C Example 46 To a solution of ethyl E-4- (hydroxyimino) -4- (4-phenoxyphenyl) butyrate (1.50 g) and 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.50 g) in N, N dimethylformamide (15 ml) was added sodium hydride (60% in oil, 211 mg) at room temperature under a nitrogen atmosphere and stirred for 1 hour. INN hydrochloric acid (7 ml) was added to the reaction mixture, an aqueous saturated sodium bicarbonate solution was added and it was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain crystals of a fraction eluted with ethyl acetate-hexane (1: 4, v / v). The crystals were recrystallized from ethyl acetate-hexane to obtain ethyl E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (4-phenoxyphenyl) butyrate (1.87 g, 66%). % yield) as colorless crystals. p.f. 118-119 ° C Example 47 To a solution of ethyl E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (4-phenoxyphenyl) butyrate (1.60 g) in tetrahydrofuran (20 ml) -methanol ( 10 ml) was added a solution of saturated aqueous sodium hydroxide IN (10 ml) and stirred at room temperature for 1 hour. INN hydrochloric acid (10.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. . The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) bensyloxyimino] -4- (4-phenoxyphenyl) butytic acid (1.50 g, 99% of performance) as colorless crystals, mp 131-132 ° C Example 48 To a solution of methyl E-4- (hydroxyimino) -4-phenylbutyrate (632 mg) and 4- [2- (4-chloromethylphenoxy) ethyl] -5-methyl-2-phenyloxazole (1.00 g) in N, N dimethylformamide (10 ml) was added sodium hydride (60% in oil, 134 mg) at room temperature under a nitrogen atmosphere and stirred for 1 hour. To the reaction mixture was added IN hydrochloric acid (5 ml), an aqueous saturated sodium bicarbonate solution was added and it was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain crystals of a fraction eluted with ethyl acetate-hexane (1: 3, v / v) The crystals were recrystallized with ethyl acetate-hexane to obtain E- Ethyl 4- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyloxyimino] -4-phenylbutyrate (650 mg, 43% yield) as colorless crystals, mp 73-74 ° C Example 49 To a solution of 4- [2- (methyl-2-pyrimidylamino) ethoxy] benzyl alcohol (1.50 g) in toluene (25 ml) was added dropwise thionyl chloride (0.633 ml) at 0 ° C, which was stirred for 30 minutes and concentrated. The residue was dissolved in N, N-dimethylformamide (10 ml), methyl E-4- (hydroxyimino) -4-phenylbutyrate (1.20 g) was added, sodium hydride (60% in oil, 509 mg) was further added to ambient temperature under a nitrogen atmosphere and stirred for 1 hour. INN hydrochloric acid (20 ml) was added to the reaction mixture, an aqueous saturated sodium bicarbonate solution was added and it was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4- [4- [2- (methyl-2-pyrimidylamino) ethoxy] benzyloxyimino] -4-phenylbutyrate (1.32 g, 51% yield) as a dark red oil of a fraction eluted with ethyl acetate-hexane (1: 2, v / v).

NMR (CDC13) d: 2.49-2.58 (2H, m), 3.00-3.09 (2H, m), 3.30 (3H, s), 3.62 (3H, s), 4.02 (2H, t, J = 5.7 Hz), 4.21 (2H, t, J = 5.7 Hz), 5.14 (2H, s), 6.48 (ÍH, t, J = 4.8 Hz), 6.90 (2H, d, J = 8.4 Hz), 7.29-7.38 (5H, m), 7.59-7.65 (2H, m), 8.31 (2H, d, J = 4.8 Hz).

Example 50 To a solution of methyl E-4- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyloxyimino] -4-phenylbutyrate (460 mg) in tetrahydrofuran (10 ml) -methanol ( 5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyloxyimino] -4-phenylbutyric acid (443 mg, 99% of performance) as colorless crystals, mp 106-107 ° C Example 51 To a solution of methyl E-4- [4- [2- (methyl-2-pyrimidylamino) ethoxy] benzyloxyimino] -4-phenylbutyrate (1.22 g) in tetrahydrofuran (10 ml) -methanol (5 ml) was added a Aqueous saturated sodium hydroxide solution IN (5 ml) and stirred at room temperature for 1 hour. To the reaction mixture was added IN hydrochloric acid (5 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- [2- (methyl-2-pyrimidylamino) ethoxy] benzyloxyimino] -4-phenylbutyric acid (1.09 g, 92% yield) as colorless crystals. , pf 72-73 ° C Example 52 A mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (1.00 g), ethyl benzoylacetate (0.612 ml), acetic acid (0.554 ml), sodium acetate (528 mg) and ethanol (20 ml) ) was refluxed for 12 hours and cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionate (1.29 g, 83% yield). ) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v) NMR (CDC13) d: 1.15 (3H, t,, J = 7.1 Hz), 2.44 (3H, s), 3.76 (2H, s), 4.09 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.20 (2H, s), 7. 01 (2H, d, J = 8.4 Hz), 7.30-7.50 (8H, m), 7.61-7.67 (2H, m), 7.97-8.05 (2H, m).

Example 53 a solution of ethyl E-3- [4- (5-methyl-2-phenyl-4-oxaz-9-ylmethoxy) benzyloxyimino] -3-phenylpropionate (1.16 g) in tetrahydrofuran (60 ml) -water (40 ml) was added hydroxide of lithium monohydrate (402 mg) and stirred at room temperature for 18 hours. Dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized to obtain 3 - [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionic acid (1.08 g, 99% yield) as colorless crystals, m.p. 107-108 ° C Example 54 To a solution of methyl E-4- (hydroxyimino) -4-phenylbutyrate (676 mg) and 5-chloro-2- (4-chloromethylphenoxymethyl) imidazo [l, 2-a] pyridine (1.00 g) in N, N dimethylformamide (10 ml) was added sodium hydride (60%, in oil, 143 mg) at room temperature and stirred for 1 hour. INN hydrochloric acid (7 ml) was added to the reaction mixture, an aqueous saturated sodium bicarbonate solution was added and it was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain E-4- [4- (5-chloroimidazo [1,2- a] pyridin-2-ylmethoxy) benzyloxyimino] -4-methyl-phenylbutyrate (1.04 g, 67% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 1, v / v).

NMR (CDC13) d: 2.50-2.60 (2H, m), 3.01-3.11 (2H, m), 3.62 (3H, s), 5.17 (2H, s), 5.31 (2H, s), 6.90 (HI, d) , J = 7.4 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.19 (HH, dd, J = 7.4, 8.8 Hz), 7.30-7.39 (5H, m), 7.55-7.66 (3H, m) , 7.85 (ÍH, s).

Example 55 To a solution of methyl E-4- [4- (5-chloroimidazo [l, 2-a] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyrate (400 mg) in tetrahydrofuran (10 ml) -methanol (5 mg). ml) was added an aqueous saturated sodium hydroxide solution IN (5 ml) and stirred at room temperature for 1 hour. To the reaction mixture was added 1N hydrochloric acid (5.5 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- (5-chloroimidazo [1,2- a] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyric acid (313 mg, 78% yield) as colorless crystals, mp 160-161 ° C Example 56 A mixture of methyl E-4- [4- (5-chloroimidazo [l, 2-a] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyrrate (550 mg), phenylboronic acid (168 mg), sodium bicarbonate ( 348 mg), toluene (20 ml), water (2 ml) and methanol (2 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. To this was added metal tetrakis (triphenylphosphine) palladium (80 mg) and heated to reflux for 36 hours. The reaction mixture was cooled to room temperature, the organic layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4- [4- (5-phenylimidazo [l, 2-a] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyrate (490 mg, 82% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (3: 2, v / v).

NMR (CDC13) d: 2.49-2.58 (2H, m), 3.00-3.10 (2H, m), 3.61 (3H, s), 5.15 (2H, s), 5.24 (2H, s), 6.75 (HI, d) , J = 7.0 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.24-7.37 (6H, m), 7.51-7.63 (8H, m), 7.72 (1H, s).

Example 57 To a solution of methyl E-4- [4- (5-phenylimidazo [l, 2-a] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyrate (400 mg) in tetrahydrofuran (10 ml) -methanol (5 mg). ml) was added an aqueous saturated sodium hydroxide solution IN (5 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- (5-phenylimidazo [1,2- a] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyric acid (365 mg, 94% strength). yield) as colorless crystals, mp 160-161 ° C Example 58 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), ethyl 6-oxo-6-phenylhexanoate (415 mg), acetic acid (0.276 ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 13 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (620 mg, 73% yield ) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 1.22 (3H, t, J = 7.1 Hz), 1.45-1.73 (4H, m), 2.28 (2H, t, J = 7.3 Hz), 2.44 (3H, s), 2.78 (2H, t, J = 7.5 Hz), 4.09 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 7.01 (2H, d, J = 8.4 Hz), 7.33-7.48 ( 8H, m),. 7.58-7.64 (2H, m), 7.99-8.05 (2H, m).

Example 59 From a fraction which was eluted following the compound of E in Example 58, ethyl Z-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (120 mg, 14% yield) as a colorless oil.

NMR (CDC13) d: 1.22 (3H, t, J = 7.1 Hz), 1.38-1.71 (4H, m), 2.26 (2H, t, J = 7.3 Hz), 2.43 (3H, s), 2.53 (2H, t, J = 7.5 Hz), 4.09 (2H, q, J = 7.1 Hz), 4.99 (2H, s), 5.02 (2H, s), 6.97 (2H, d, J = 8.4 Hz), 7.23-7.47 (10H, m), 7.97-8.05 ( 2H, m).

Example 60 To a solution of ethyl E-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (530 mg) in tetrahydrofuran (6 ml) -methanol (3 ml) was added a solution of saturated aqueous sodium hydroxide IN (3 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoic acid (451 mg, 90% yield) as colorless crystals, mp 112 -113 ° C Example 61 a solution of ethyl Z-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (120 mg) in tetrahydrofuran (6 ml) -methanol (3 ml) was added a solution of saturated aqueous sodium hydroxide IN (3 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoic acid (113 mg, 99% yield) as crystals. colorless, pf 101-102 ° C Example 62 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), 3-oxo-l-indanecarboxylic acid (284 mg), acetic acid (0.276 ml), sodium acetate ( 264 mg) and ethanol (20 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -l-indanecarboxylic acid (522 mg, 69% yield) as crystals. colorless, pf 148-149 ° C Example 63 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), ethyl 4-oxo-4- (2-pyridyl) butyrate (367 mg), acetic acid (0.276) ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 20 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (2-pyridyl) butyrate (600 mg , 75% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 7, v / v).

NMR (CDC13) d: 1.23 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 2.55-2.64 (2H, m), 3.19-3.28 (2H, m), 4.07 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.19 (2H, s), 7.01 (2H, d, J = 8.8 Hz), 7.19-7.24 (ÍH, m), 7.36 (2H, d, J = 8.8 Hz ), 7.39-7.46 (3H, m), 7.64 (ÍH, dt, J = 1.8, 7.6 Hz), 7.87 (1H, d, J = 8.0 Hz), 7.99-8.05 (2H, m), 8.54-8.59 ( 1H, m).

Example 64 To a solution of ethyl E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (2-pyridyl) butyrate (520 mg) in tetrahydrofuran (10 ml) -methanol ( 5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (2-pyridyl) butyric acid (425 mg, 87% of performance) as colorless crystals, mp 116-117 ° C Example 65 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), ethyl 4- (2-furyl) -4-oxobutyrate (347 mg), acetic acid (0.276 ml) ), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 96 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-4- (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (190 mg , 24% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (t: 4, v / v).

NMR (CDC13) d: 1.25 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 2.62-2.71 (2H, m), 2.95-3.04 (2H, m), 4.13 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.14 (2H, s), 6.45-6.49 '(ÍH, m), 7.01 (2H, d, J = 8.8 Hz), 7.25-7.28 (ÍH, m), 7.34 (2H, d, J = 8.8 Hz), 7.39-7.48 (4H, m), 7.99-8.05 (2H, m).

Example 66 From a fraction which was eluted following the compound of E in Example 65, Z-4- (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate was obtained. ethyl (510 mg, 65% yield) as a colorless oil.

NMR (CDC13) d: 1.21 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 2.53-2.62 (2H, m), 2.89-2.98 (2H, m), 4.09 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.17 (2H, s), 6.43 (IH, dd, J = 1.8, 3.2 Hz), 6.68 (1H, d, J = 1.8 Hz), 7.01 (2H, d , J = 8.8 Hz), 7.34 (2H, d, J = 8.8 Hz), 7.38-7.47 (4H, m), 7.97-8.05 (2H, m).

Example 67 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), ethyl 4-oxo-4- (3-pyridyl) butyrate (367 mg), acetic acid (0.276) ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 20 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 4- (4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (3-pyridyl) butyrate (590 mg, 73%). % yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (3: 2, v / v).

NMR (CDC13) d: 1.16-1.30 (3H, m), 2.44 (3H, s), 2.51-2.64 (2H, m), 2.86 (0.4H, t, J = 6.9 Hz), 3.05 (1.6H, t, J = 7.9 Hz), 4.02-4.18 (2H, m), 5.00 (2.4H, s similar), 5.18 (1.6H, s), 6. 95-7.06 (2H, m), 7.23-7.48 (6H, m), 7.71-7.78 (0.2H, m), 7. 91-8.05 (2.8H, m), 8.53-8.61 (ÍH, m), 8.66-8.69 (0.2H, m), 8.85-8.88 (0.8H, m).

Example 68 To a solution of ethyl Z-4- (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (460 mg) in tetrahydrofuran (10 ml) -methanol ( 5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-4- (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (402 mg, 93%). of performance) as colorless crystals, mp 131-133 ° C Example 69 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), ethyl 4-oxo-4- (4-pyridyl) butyrate (367 mg), acetic acid (0.276) ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 15 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain 4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (4-pyridyl) butyrate ethyl (740 mg, 92%). % yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (3: 2, v / v).

NMR (CDC13) d: 1.16-1.31 (3H, m), 2.44 (3H, s), 2.48-4.63 (2H, m), 2.77-2.86 (0.5H, m), 3.02 (1.5H, t, J = 7.9 Hz), 4.02-4.18 (2H, m), 5.00 (2.5H, s similar), 5.20 (1.5H, s), 6.95-7.22 (2H, m), 7.20-7.56 (7H, m), 7.99- 8.05 (2H, m), 8.59-8.66 (2H, m).

Example 70 To a solution of ethyl 4- (4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (3-pyridyl) butyrate (520 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) a solution of saturated aqueous sodium hydroxide IN (5 ml) was added and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (3-pyridyl) butyric acid (378 mg, 77% of performance) as colorless crystals, mp 158-159 ° C Example 71 To a solution of ethyl 4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (4-pyridyl) butyrate (670 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- (4-pyridyl) butyric acid (475 mg, 75 % yield) as colorless crystals, mp 161-162 ° C Example 72 To a solution of ethyl E-4- (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (190 mg) in tetrahydrofuran (10 ml) -methanol ( 5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- (2-furyl) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (140 mg, 78% of performance) as colorless crystals, mp 124 -125 ° C Example 73 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (500 mg), methyl 9-oxo-9-phenylnonanoate (464 mg), IN hydrochloric acid (3 ml), acetate Sodium (264 mg) and methanol (20 ml) was heated to reflux for 72 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil of a fraction eluted with ethyl acetate-hexane (1: 6, v / v). This oil was dissolved in tetrahydrofuran (10 ml) -methanol (5 ml), a solution of saturated aqueous sodium hydroxide IN (5 ml) was added and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-9- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -9-phenylnonanoic acid (323 mg, 37% yield) as crystals. colorless, pf 67-68 ° C Example 74 After a mixture of 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), methyl 4-oxo-4-phenylbutyrate (371 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and methanol (20 ml) was heated to reflux for 40 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl E-4- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (570 mg, 61% yield ) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 2.43 (3H, s), 2-53-2.62 (2H, m), 3.04-3.13 (2H, m), 3.62 (3H, s), 5.01 (2H, s), 5.22 (2H, s), 6.94-7.08 (3H, m), 7.28-7.48 (7H, m), 7.60-7.66 (2H, m), 7.97-8.05 (2H, m).

Example 75 After a mixture of 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 6-oxo-6-phenylhexanoate ethyl (452 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 15 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-6- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexansate (590 mg, 58% yield ) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 9, v / v).

NMR (CDC13) d: 1.21 (3H, t, J = 7.1 Hz), 1.47-1.80 (4H, m), 2.29 (2H, t, J = 7.5 Hz), 2.43 (3H, s), 2.80 (2H, t, J = 7.5 Hz), 4.08 (2H, q, J = 7.1 Hz), 5.01 (2H, s), 5.20 (2H, s), 6.93-7.08 (3H, m), 7.25-7.47 (7H, m), 7.58-7.64 (2H, m), 7.97-8.05 (2H, m).

Example 76 To a solution of ethyl E-6- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (520 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoic acid (432 mg, 88% yield) as crystals. colorless, pf 114-115 ° C Example 77 To a solution of methyl E-4- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (500 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (395 mg, 82% yield) as. colorless crystals, mp 108-109 ° C Example 78 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 7-oxo-7-phenylheptanoate ethyl (959 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-7- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -7-phenylheptanoate (800 mg, 72% yield ) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 5, v / v).

NMR (CDC13) d: 1.08-1.70 (9H, m), 2.24 (2H, t, J = 7.5 Hz), 2.44 (3H, s), 2.76 (2H, t, J = 7.5 Hz), 4.11 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 7.02 (2H, d, J = 8.8 Hz), 7.33-7.48 (8H, m), 7.57-7.63 (2H, m ), 7.99-8.05 (2H, m).

Example 79 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (1.50 g), 8-oxo-8-phenyloctanoic acid ethyl ester (2.54 g), acetic acid (0.830 ml), sodium acetate (793 mg) and ethanol (40 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoate (2.02 g, 76% yield ) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 5, v / v).

NMR (CDC13) d: 1.18-1.65 (11H, m), 2.25 (2H, t, J = 7.5 Hz), 2.44 (3H, s), 2.75 (2H, t, J = 7.5 Hz), 4.12 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 7.01 (2H, d, J = 8.8 Hz), 7.33-7.48 (8H, m), 7.58-7.64 (2H, m), 7.99-8.05 (2H, m ).

Example 80 From a fraction which was eluted following the compound of E in Example 79, ethyl Z-8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoate (408 mg, 15% yield) as a colorless oil.

NMR (CDC13) d: 1.20-1.65 (11H, m), 2.25 (2H, t, J = 7.5 Hz), 2.43 (3H, s), 2.50 (2H, t, J = 7.2 Hz), 4.12 (2H, q, J = 7.1 Hz), 4.99 (2H, s), 5.02 (2H, s), 6.97 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.6 Hz), 7.27-7.48 (8H, m), 7.99-8.04 ( 2H, m).

Example 81 To a solution of ethyl E-8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoate (660 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at room temperature for 1 hour. To the reaction mixture was added 1N hydrochloric acid (5.5 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoic acid (580 mg, 92% yield) as crystals. colorless, pf 116-117 ° C Example 82 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), '6-oxo-6-phenylhexanamide (396 mg), acetic acid (0.331 ml), sodium acetate ( 317 mg) and ethanol (20 ml) was heated to reflux for 18 hours, the mixture was heated. cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain crystals of a fraction eluted with ethyl acetate-hexane (3: 1, v / v). The crystals were recrystallized from ethyl acetate-hexane to obtain E-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanamide (651 mg, 68% yield) as colorless crystals. , pf 95-96 ° C Example 83 A mixture of 4- (chloromethyl) 2- (2-furyl) -5-methyloxazole (340 mg), ethyl E-8- (4-hydroxybenzyloxyimino) -8-phenyloctanoate (600 mg), potassium carbonate (432 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-8- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoate (717 mg, 84% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 9, v / v).

NMR (CDC13) d: 1.20-1.65 (11H, m), 2.25 (2H, t, J = 7.5 Hz), 2.42 (3H, s), 2.70-2.79 (2H, m), 4.11 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 6.51-6.54 (HI, m), 6.96-7.03 (3H, m), 7.31-7.40 (5H, m), 7.53-7.56 ( ÍH, m), 7.58-7.64 (2H, m).

Example 84 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (1.00 g), methyl 4 -oxo-4-phenylbutyrate (619 mg), acetic acid (0.553 ml), sodium acetate (528 mg) and methanol (20 ml) was heated to reflux for 19 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.18 g, 76% yield). ) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 9, v / v).

NMR (CDC13) d: 2.44 (3H, s), 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.62 (3H, s), 5.01 (2H, s), 5.17 (2H, s) ), 7.01 (2H, d, J = 8.8 Hz), 7.33-7.48 (8H, m), 7.60-7.66 (2H, m), 7.99-8.06 (2H, m).

Example 85 From a fraction which was eluted following the compound of E in Example 84, methyl Z-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (222 mg, 14% yield) as a colorless oil.

NMR (CDC13) d: 2.43 (3H, s), 2.57 (2H, t, J = 7.0 Hz), 2.84 (2H, t, J = 7.0 Hz), 3.62 (3H, s), 5.00 (4H, s similar), 6.98 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.30-7.48 (8H, m), 7. 99-8.05 (2H, m).

Example 86 A mixture of 5- (chloromethyl) -3-phenylisoxazole (238 mg), Methyl 4- (4-hydroxybenzylsimymino) -4-phenylbutyrate (350 mg), potassium carbonate (310 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours.

Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4-phenyl-4- [4- (3-phenyl-5-isoxazolylmethoxy] benzyloxyimino] butyrate (358 mg, 62% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.62 (3H, s), 5.17 (2H, s), 5.22 (2H, s), 6.66 (1H, s) ), 6.99 (2H, d, J = 8.8 Hz), 7.34-7.49 (8H, m), 7.59-7.65 (2H, m), 7.78-7.84 (2H, m).

Example 87 To a solution of methyl E-4-phenyl-4- [4- (3-phenyl-5-isoxazolylmethoxy) benzyloxyimino] butyrate (326 mg) in tetrahydrofuran (6 ml) -water (4 ml) was added lithium hydroxide. monohydrate (58.3 mg) and stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid (1.4 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4- [4- (3-phenyl-5-isoxazolylmethoxy) benzyloxyimino] butyric acid (306 mg, 97% yield) as colorless crystals, m.p. 96-97 ° C Example 88 A mixture of 3- (chloromethyl) -5-phenylisoxazole (340 mg), methyl E-4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide ( 10 ml) was stirred at room temperature for 72 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4-phenyl-4- [4- (5-phenyl-3-isoxazolylmethoxy) benzyloxyimino] butyrate (472 mg, 63% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 9, v / v).

NMR (CDC13) d: 2.50-2.59 (2H, m), 3.01-3.11 (2H, m), 3.62 (3H, s), 5.16 (2H, s), 5.21 (2H, s), 6.66 (HI, s), 7.01 (2H, d, J = 8.8 Hz), 7.34-7.53 (8H, m), 7.57-7.65 (2H, m), 7.74-7.82 (2H, m).

Example 89 A mixture of 4- (chloromethyl) -5-methyl-2-phenylthiazole (394 mg), methyl E-4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 72 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl E-4- [4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (570 mg, 71% yield). ) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 5, v / v).

NMR (CDC13) d: 2.50-2.60 (5H, m), 3.02-3.11 (2H, m), 3.62 (3H, s), 5.17 (2H, s), 5.18 (2H, s), 7.04 (2H, d) , J = 8.6 Hz), 7.33-7.51 (8H, m), 7.58-7.66 (2H, m), 7.85-7.93 (2H, m).

Example 90 To a solution of methyl E-4-phenyl-4- [4- (5-phenyl-3-isoxazolylmethoxy) benzyloxyimino] butyrate (412 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 ml) ) lithium hydroxide monohydrate (73.5 mg) was added and stirred at room temperature for 2 hours. IN hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized with ethyl acetate-hexane to obtain E-4-phenyl-4- [4- (5-phenyl-3-isoxazolylmethoxy) benzyloxyimino] butyric acid (320 mg, 80% yield) as colorless crystals, m.p. 100-101"C Example 91 To a solution of methyl E-4- [4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (500 mg) in tetrahydrofuran (10 ml) -water (4 ml) -methanol (8 ml) was added lithium hydroxide monohydrate (83.6 mg) and stirred at room temperature for 2 hours. INN hydrochloric acid (2.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (363 mg, 75% yield) as crystals. colorless, pf 99-100 ° C Example 92 A mixture of 4- (chloromethyl) -2- (2-furyl) -5-methyl-oxazole (348 mg), methyl E-4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -4-phenylbutyrate (507 mg, 67% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 3, v / v).

R * 4N (CDC13) d: 2.42 (3H, s), 2.50-2.59 (2H, m), 3.01-3.11 (2H, m), 3.62 (3H, s), 5.00 (2H, s), 5.16 (2H, s), 6.51-6.54 (HH, m), 6.95-7.02 (3H, m), 7.28-7.40 (5H, • m), 7.52-7.55 (HH, m), 7.59-7.66 (2H, m).

Example 93 A mixture of 4- (chloromethyl) -5-methyl-2- (2-thienyl) oxazole (376 mg), methyl E-4 - [(4-hydroxybenzyloxy) imino] -4-phenylbutyrate (500 mg), carbonate Potassium (442 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 40 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -4-phenylbutyrate (495 mg, 63% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 5, v / v).

NMR (CDC13) d: 2.41 (3H, s), 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.63 (3H, s), 4.98 (2H, s), 5.16 (2H, s) ), 6.99 (2H, d, J = 8.8 Hz), 7.10 (ÍH, dd, J = 3.6, 5.0 Hz), 7.32-7.42 (6H, m), 7.59-7.66 (3H, m).

Example 94 To a solution of methyl E-4- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -4-phenylbutyrate (430 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (76.0 mg) and stirred at room temperature for 2 hours. IN hydrochloric acid (1.9 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -4-phenylbutyric acid (328 mg, 79% strength). yield) as colorless crystals, mp 124-125 ° C Example 95 A mixture of 4- (chloromethyl) -5-methyl-2- (2-thienyl) oxazole (368 mg), ethyl E-8- (4-hydroxybenzyloxyimino) -8-phenyloctanoate (600 mg), potassium carbonate (432 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-8- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoate (762 mg, 95% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 5, v / v).

NMR (CDC13) d: 1.20-1.65 (11H, m), 2.25 (2H, t, J = 7.3 Hz), 2.41 (3H, s), 2.70-2.79 (2H, m), 4.11 (2H, q, J = 7.1 Hz), 4.98 (2H, s), 5.15 (2H, s), 6.99 (2H, d, J = 8.8 Hz), 7.07-7.12 (HI, m), 7.30-7.42 (6H, m), 7.58 -7.65 (3H, m).

Example 96 A mixture of benzyl bromide (0.209 ml), methyl E-4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4- (4-benzyloxybenzyloxyimino) -4-phenylbutyrate (400 mg, 62% yield) as a colorless oil of a fraction eluted with ethyl acetate. -hexane (1: 7, v / v).

NMR (CDC13) d: 2.50-2.59 (2H, m), 3.01-3.10 (2H, m), 3.62 (3H, s), 5.07 (2H, s), 5.15 (2H, s), 6.97 (2H, d) , J = 8.8 Hz), 7.30-7.46 (10H, m), 7.60-7.66 (2H, m).

Example 97 To a solution of methyl E-4- [4- [5-methyl-2- (2-thienyl) -4- [xazolylmethoxy] benzyloxyimino] -4-phenylbutyrate (430 mg) in tetrahydrofuran (6 ml) -water ( 4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (73.6 mg) and stirred at room temperature for 2 hours. IN hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -4-phenylbutyric acid (366 mg, 88% strength). yield) as colorless crystals, mp 142-143 ° C Example 98 To a solution of methyl E-4- (4-benzyloxybenzyloxyimino) -4-phenylbutyrate (340 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (7O). .7 mg) and stirred at room temperature for 2 hours. IN hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- (4-benzyloxybenzyloxyimino) -4-phenylbutyric acid (238 mg, 72% yield) as colorless crystals. p.f. 86-87 ° C Example 99 A mixture of 2-chloromethylimidazo [1,2-a] pyridine (293 mg), methyl E-4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N- dimethylformamide (10 ml) was stirred at room temperature during 17 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4- [4- (imidazofl, 2-a] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyrate (321 mg, 45% yield). ) as a colorless oil of a fraction eluted with ethyl acetate-hexane (3: 2, v / v).

NMR (CDC13) d: 2.50-2.59 (2H, m), 3.01-3.10 (2H, m), 3.62 (3H, s), 5.16 (2H, s), 5.30 (2H, s), 6.78 (1H, dt , J = 1.0, 6.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.13-7.40 (7H, m), 7.56-7.66 (3H, m), 8.08 (H, d, J = 6.8 Hz) .

Example 100 A mixture of 4- (chloromethyl) -2-phenyloxazole (250 mg), methyl E-4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (369 mg), potassium carbonate (325 mg) and N, N-dimethylformamide ( 7 ml) was stirred at room temperature for 17 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4-phenyl-4- [4- (2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (320 mg, 58% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 9, v / v).

NMR (CDC13) d: 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.62 (3H, s), 5.10 (2H, s), 5.17 (2H, s), 7.01 (2H, d) , J = 8.8 Hz), 7. 32-7.40 (5H, m), 7.41-7.49 (3H, m), 7.60-7..66 (2H, m), 7.74 (H, s), 8.03-8.09 (2H, m).

Example 101 To a solution of methyl E-4- [4- (imidazofl, 2-a] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyrate (280 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (53.0 mg) and stirred at room temperature for 2 hours. To the reaction mixture was added IN hydrochloric acid (1.3 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4- [4- (imidazo [1,2- a] pyridin-2-ylmethoxy) benzyloxyimino] -4-phenylbutyric acid (206 mg, 76% yield) as colorless crystals, mp 180-182 ° C Example 102 To a solution of methyl E-4-phenyl-4- [4- (2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyrate (280 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 ml) ) lithium hydroxide monohydrate (49.9 mg) was added and stirred at room temperature for 2 hours. To the reaction mixture was added IN hydrochloric acid (1.3 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4- [4- (2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid (237 mg, 87% yield) as colorless crystals, m.p. 144-145 ° C Example 103 A mixture of 2-chloromethylquinoline hydrochloride (488 mg), methyl E-4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (650 mg), potassium carbonate (1.00 g) and N, N-dimethylformamide (10 ml) was added. stirred at room temperature during 13 hours . Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4-phenyl-4- [4- (2-quinolinylmethoxy) benzyloxyimino] butyrate (655 mg, 70% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 2.49-2.58 (2H, m), 3.01-3.10 (2H, m), 3.61 (3H, s), 5.15 (2H, s), 5.40 (2H, s), 7.02 (2H, d) , J = 8.4 Hz), 7.31-7.38 (5H, m), 7.50-7.85 (6H, m), 8.09 (H, d, J = 8.4 Hz), 8.19 (H, d, J = 8.4 Hz) ..

Example 104 To a solution of methyl E-4-phenyl-4- [4- (2-quinolinylmethoxy) benzyloxyimino] butyrate (585 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol (4 ml) was added hydroxide of lithium monohydrate (108 mg) and stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid (2.6 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4- [4- (2-quinolinylmethoxy) benzyloxyimino] butyric acid (469 mg, 83% yield) as colorless crystals, m.p. 133 -134 ° C Example 105 A mixture of 4- (chloromethyl) -2-phenylthiazole (368 mg), methyl E-4- (4-hydroxybenzyloxyimino) -4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N, N-dimethylformamide ( 10 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-4-phenyl-4- [4- (2-phenyl-4-thiazolylmethoxy) benzyloxyimino] butyrate (494 mg, 63% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 9, v / v).

NMR (CDC13) d: 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.62 (3H, S), 5.17 (2H, s), 5.28 (2H, s), 7.02 (2H, d) , J = 8.8 Hz), 7.31-7.49 (9H, m), 7.59-7.65 (2H, m), 7.93-7.99 (2H, m).

Example 106 To a solution of E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 ml) were added oxalyl chloride (0.156 ml) and N, N-dimethylformamide (catalytic amount) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (10 ml) and added dropwise to a mixture of 25% aqueous ammonia (15 ml) and ethyl acetate (20 ml) at 0 ° C. After stirring at room temperature for 1 hour, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with ethyl acetate to obtain E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyramide (315 mg, 45% yield) as colorless crystals, pf 164 -165 ° C Example 107 To a solution of E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (941 mg) in methanol (5 ml) was added sodium methoxide (108 mg), which was stirred at room temperature for 1 hour and concentrated. The remaining crystals were recrystallized with methanol-diethyl ether to obtain sodium E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (456 mg, 46% yield) as crystals colorless, pf 64-70 ° C Example 108 a solution of methyl E-4-phenyl-4- [4- (2-phenyl-4-thiazolylmethoxy) benzyloxyimino] butyrate (424 mg) in tetrahydrofuran (10 ml) -water (4 ml) -methanol (4 ml) Lithium hydroxide monohydrate (54.8 mg) was added and stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid (1.4 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4- [4- (2-phenyl-4-thiazolylmethoxy) benzyloxyimino] butyric acid (369 mg, 90% yield) as colorless crystals, pf 104-105 ° C Example 109 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 2, 2-dimethyl-3-oxo-3-phenylpropionate ethyl (468 mg), acetic acid ( 0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 5 days, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2, 2-dimethyl-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionate (273 mg, 28% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 9, v / v).

NMR (CDC13) d: 1.11 (3H, t, J = 7.1 Hz), 1.31 (6H, s), 2.44 (3H, s), 3.96 (2H, q, J = 7.1 Hz), 5.00 (2H, s) , 5.07 (2H, s), 7.00 (2H, d, J = 8.6 Hz), 7.26-7.46 (10H, m), 8.00-8.06 (2H, m).

Example 110 To a solution of ethyl Z-2, 2-dimethyl-3- [4- (5-methyl-2-phenyl-3-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionate (265 mg) in tetrahydrofuran (3 ml) -water (3 ml) -methanol (6 ml) was added potassium hydroxide (1.83 g), the mixture was heated to reflux for 3 days and cooled to room temperature. Dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain Z-2, 2-dimethyl-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionic acid (130 mg, 52% yield) as pale yellow or color crystals, mp 142-143 ° C (decomposition) Example 111 A mixture of E-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropionic acid (600 mg), 1-hydroxybenzotriazole ammonia complex (260 mg), hydrochloride ethyl-3- (3-dimethylaminopropyl) carbodiimide (328 mg) and N, N-dimethylformamide (5 ml) was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed consecutively with an aqueous potassium carbonate solution and an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized with tetrahydrofuran-hexane to obtain E-3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -3-phenylpropanamide (512 mg, 86% yield) as colorless crystals, pf 164-165 ° C.

Example 112 To a solution of E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 ml) were added oxalyl chloride (0.156 ml) and N, N-dimethylformamide (catalytic amount) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a mixture of 40% aqueous dimethylamine (20 ml) and ethyl acetate (20 ml) at 0 ° C. After stirring at room temperature for 2 hours, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain EN, N-dimethyl-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutanamide (511 mg, 69% of yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 1, v / v).

NMR (CDC13) d: 2.43-2.55 (5H, m), 2.83 (3H, s), 2.88 (3H, s), 3.01-3.10 (2H, m), 5.00 (2H, s), 5.17 (2H, s) ), 7.01 (2H, d, J = 8.6 Hz), 7.30-7.48 (8H, m), 7.63-7.71 (2H, m), 7.97-8.05 (2H, m).

Example 113 To a solution of E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 ml) were added oxalyl chloride (0.156 ml) and N, N-dimethylformamide (catalytic amount) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a mixture of 40% aqueous methylamine (20 ml) and ethyl acetate (30 ml) at 0 ° C. After stirring at room temperature for 1 hour, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain EN-methyl-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutanamide (466 mg, 65% yield) as colorless crystals, mp 141-142 ° C Example 114 To a solution of E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (500 mg) in methanol (10 ml) was added lithium hydroxide monohydrate (44.6 mg ), which was stirred at room temperature for 30 minutes and concentrated. The remaining crystals were recrystallized with methanol-diethyl ether to obtain E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate lithium (485 mg, 96% yield) as colorless crystals, mp 201-203 ° C Example 115 To a solution of ethyl E-7- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -7-phenylheptanoate (730 mg) in tetrahydrofuran (10 ml) -methanol (5 ml) was added a solution of saturated aqueous sodium hydroxide IN (5 ml) and stirred at room temperature for 1 hour. IN hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-7- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -7-phenylheptanoic acid (569 mg, 82% yield) as crystals. colorless, pf 84-85 ° C Example 116 a solution of ethyl Z-8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoate (340 mg) in tetrahydrofuran (6 ml) -water (4 ml) -methanol ( 4 ml) was added lithium hydroxide monohydrate (159 mg) and stirred at room temperature for 1 hour. IN hydrochloric acid (3.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoic acid (293 mg, 91% yield) as crystals. colorless, pf 88-89 ° C Example 117 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), methyl 8- (4-methoxyphenyl) -8-oxooctanoate (538 mg), acetic acid (0.331 ml) ), sodium acetate (317 mg) and methanol (20 ml) was heated to reflux for 16 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-8- (4-methoxyphenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (650 mg , 59% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 7, v / v).

NMR (CDC13) d: 1.20-1.65. (8H, m), 2.26 (2H, t, J = 7.5 Hz), 2.44 (3H, s), 2.72 (2H, t, J = 7.7 Hz), 3.65 (3H, s), 3.82 (3H, s) , 5.00 (2H, s), 5.13 (2H, s), 6.88 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.35 (2H, d, J = 8.8 Hz) , 7.39-7.48 (3H, m), 7.56 (2H, d, J = 8.8 Hz), 7.99-8.05 (2H, m).

Example 118 To a solution of methyl E-8- (4-methoxyphenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (580 mg) in tetrahydrofuran (10 ml) -water ( 4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (128 mg) and stirred at room temperature for 1 hour. INN hydrochloric acid (3.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8- (4-methoxyphenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (528 mg, 93% of performance) as colorless crystals, mp 69-70 ° C Example 119 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 8- (4-chlorophenyl) -8-oxooctanoic acid (546 mg), acetic acid (0.331 ml)Sodium acetate (317 mg) and methanol (20 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl E-8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (828 mg , 75% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 6, v / v).

NMR (CDC13) d: 1.20-1.65 (8H, m), 2.26 (2H, t, J = 7.5 Hz), 2.44 (3H, s), 2.67-2.76 (2H, m), 3.65 (3H, s), 5.00 (2H, s), 5.14 (2H, s), 7.01 (2H, d, J = 8.8 Hz), 7.29-7.37 (4H, m), 7.40-7.47 (3H, m), 7.55 (2H, d, J = 8.8 Hz), 7.99-8.05 (2H, m).

Example 120 From a fraction which was eluted following the compound of E in Example 119 was obtained as a colorless oil Z-8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octaneats of methyl (215 mg, 19% yield).

NMR (CDC13) d: 1.20-1.65 (8H, m), 2.27 (2H, t, J = 7.4 Hz), 2.41-2.53 (5H, m), 3.65- (3H, s), 4.99 (2H, s) , 5.01 (2H, s), 6.98 (2H, d, J = 8.8 Hz), 7.22-7.37 (6H, m), 7.40-7.46 (3H, m), 7.99-8.05 (2H, m).

Example 121 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (600 mg), 8- (4-fluorophenyl) -8-oxooctanoic acid (514 mg), acetic acid (0.331 ml) Sodium acetate (317 mg) and methanol (20 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl E-8- (4-fluorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (771 mg , 71% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 6, v / v).

NMR (CDC13) d: 1.20-1.65 (8H, m), 2.26 (2H, t, J = 7.5 Hz), 2.44 (3H, s), 2.68-2.76 (2H, m), 3.65 (3H, s), 5.00 (2H, s), 5.14 (2H, s), 6.97-7.10 (4H, m), 7.35 (2H, d, J = 8.8 Hz), 7.39-7.48 (3H, m), 7.54-7.63 (2H, m), 7.97-8.05 (2H, m).

Example 122 From a fraction which was eluted following the compound of E in Example 121 was obtained as a colorless oil Z-8- (4-fluorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] methyl octanoate (205 mg, 19% yield).

NMR (CDC13) d: 1.20-1.65 (8H, m), 2.27 (2H, t, J = 7.5 Hz), 2.43 (3H, s), 2.45-2.53 (2H, m), 3.65 (3H, s), 4.99 (2H, s), 5.01 (2H, s), 6.95-7.09 (4H, m), 7.23-7.46 (7H, m), 7.98-8.04 (2H, m).

Example 123 To a solution of methyl E-8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (730 mg) in tetrahydrofuran (10 ml) -water ( 4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (160 mg) and stirred at room temperature for 3 hours. INN hydrochloric acid (3.9 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (632 mg, 89% of performance) as colorless crystals, mp 90-91 ° C Example 124 To a solution of methyl Z-8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) bensyloxyimino] octanoate (200 mg) in tetrahydrofuran (10 ml) -water ( 4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (43.7 mg) and stirred at room temperature for 3 hours. INN hydrochloric acid (1.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (169 mg, 87%). of performance) as colorless crystals, mp 54-57 ° C Example 125__ To a solution of methyl E-8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (700 mg) in tetrahydrofuran (10 ml) -water ( 4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (157 mg) and stirred at room temperature for 3 hours. To the reaction mixture was added 1N hydrochloric acid (3.8 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8- (4-slorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (608 mg, 89% of performance) as colorless crystals, mp 79-80 ° C Example 126 To a solution of methyl Z-8- (4-chlorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoate (190 mg) in tetrahydrofuran (10 ml) -water ( 4 ml) -methanol (4 ml) was added lithium hydroxide monohydrate (42.8 mg) and stirred at room temperature for 3 hours. INN hydrochloric acid (1.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-8- (4-fluorophenyl) -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] octanoic acid (59 mg, 32%). of performance) as colorless crystals, mp 56-57 ° C Example 127 A mixture of 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (335 mg), ethyl E-8- (4-hydroxybenzyloxyimino) -8-phenyloctanoate (600 mg), potassium carbonate (432 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl E-8-phenyl-8- [4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] octanoate (267 mg , 32% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 5, v / v).

NMR (CDC13) d: 1.20-1.65 (11H, m), 2.24 (2H, t, J = 7.5 Hz), 2.70-2.79 (2H, m), 4.11 (2H, q, J = 7.1 Hz), 5.15 ( 2H, s), 5.26 (2H, s), 7.05 (2H, d, J = 8.8 Hz), 7.30-7.40 (5H, m), 7.48-7.66 (5H, m), 8.17 (2H, d, J = 8.2 Hz).

Example 128 To a solution of ethyl E-8-phenyl-8- [4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] octanoate (236 mg) in tetrahydrofuran (6 ml) -water ( 4 ml) -ethanol (4 ml) was added lithium hydroxide monohydrate (54.9 mg) and stirred at room temperature for 4 hours. INN hydrochloric acid (1.4 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-phenyl-8- [4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] octaneic acid (208 mg, 93%). of performance) as colorless crystals, mp 76-77 ° C Example 129 To a solution of ethyl E-8- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoate (618 mg) in tetrahydrofuran (6 ml) -water (4 ml) -ethanol (4 ml) was added lithium hydroxide monohydrate (143 mg) and stirred at room temperature for 4 hours. INN hydrochloric acid (3.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoic acid (523 mg, 90% strength). yield) as colorless crystals, mp 75-77 ° C Example 130 To a solution of ethyl E-8- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoate (682 mg) in tetrahydrofuran (6 ml) -water (4 ml) -ethanol (4 ml) was added lithium hydroxide monohydrate (153 mg) and stirred at room temperature for 4 hours. INN hydrochloric acid (3.7 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -8-phenyloctanoic acid (567 mg, 87% yield). yield) as colorless crystals, mp 106-108 ° C Example 131 A mixture of 4-chloromethyl-2- (2-furyl) -5-methyloxazole (368 mg), Ethyl E-6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (600 mg), potassium carbonate (467 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 13 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-6- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoate (770 mg, 88% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 7, v / v).

NMR (CDC13) d: 1.22 (3H, t, J = 7.1 Hz), 1.45-1.75 (4H, m), 2.28 (2H, t, J = 7.1 Hz), 2.42 (3H, s), 2.73-2.82 ( 2H, m), 4.09 (2H, q, J = 7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 6.51-6.54 (HI, m), 6.95-7.03 (3H, m), 7.30 -7.39 (5H, m), 7.53-7.64 (3H, m).

Example 132 To a solution of ethyl E-6- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoate (670 mg) in tetrahydrofuran (6 ml) -water (4 ml) -ethanol (4 ml) was added lithium hydroxide monohydrate (163 mg) and stirred at room temperature for 4 hours. To the reaction mixture was added 1N hydrochloric acid (3.9 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoic acid (625 mg, 98% yield). yield) as colorless crystals, mp 112-113 ° C Example 133 A mixture of 4-chloromethyl-5-methyl-2- (2-thienyl) -oxazole (397 mg), ethyl E-6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (600 mg), potassium carbonate (467 mg) ) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-6- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoate (856 mg, 95% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 1.22 (3H, t, J = 7.1 Hz), 1.45-1.75 (4H, m), 2.28 (2H, t, J = 7.1 Hz), 2.41 (3H, s), 2.77 (2H, t, J = 7.4 Hz), 4.09 (2H, q, J = 7.1 Hz), 4.98 (2H, s), 5.15 (2H, s), 6.99 (2H, d, J = 8.8 Hz), 7.09 (ÍH, dd, J = 3.6, 5.0 Hz), 7.31-7.42 (6H, m), 7. 58-7.65 (3H, m).

Example 134 A mixture of 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (362 mg), ethyl E-6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (600 mg), potassium carbonate (467 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 6-phenyl-6- [4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] hexanoate (649 mg , 75% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 4, v / v).

NMR (CDC13) d: 1.22 (3H, t, J = 7.1 Hz), 1.45-1.75 (4H, m), 2.28 (2H, t, J = 7.2 Hz), 2.77 (2H, t, J = 7.5 Hz) , 4.09 (2H, q, J = 7.1 Hz), 5.16 (2H, s), 5.27 (2H, s), 7.06 (2H, d, J = 8.8 Hz), 7.31-7.40 (5H, m), 7.49- 7.66 (5H, m), 8.14-8.20 (2H, m).

Example 135 To a solution of ethyl E-6- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoate (747 mg) in tetrahydrofuran (6 ml) -water (4 ml) -ethanol (4 ml) was added lithium hydroxide monohydrate (177 mg) and stirred at room temperature for 4 hours. IN hydrochloric acid (4.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyloxyimino] -6-phenylhexanoic acid (653 mg, 92% yield). yield) as colorless crystals, mp 101-102 ° C Example 136 To a solution of ethyl 6-phenyl-6- [4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] hexanoate (545 mg) in tetrahydrofuran (6 ml) -water ( 4 ml) -ethanol (4 ml) was added lithium hydroxide monohydrate (134 mg) and stirred at room temperature for 4 hours. IN hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-phenyl-6- [4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyloxyimino] hexanoic acid (465 mg, 90% of performance) as colorless crystals, mp 88-89 ° C Example 137 A mixture of 5-chloromethyl-3-phenyl-1,2,4-oxadiazole (362 mg), ethyl E-6- (4-hydroxybenzyloxyimino) -6-phenylhexanoate (600 mg), potassium carbonate (467 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 6-phenyl-6- [4- (3-phenyl-1,2,4-oxadiazol-5-ylmethoxy) benzyloxyimino] hexanoate (789 mg , 92% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (2: 9, v / v).

NMR (CDC13) d: 1.22 (3H, t, J = 7.1 Hz), 1.45-1.75 (4H, m), 2.28 (2H, t, J = 7.4 Hz), 2.77 (2H, t, J = 7.4 Hz) , 4.09 (2H, q, J = 7.1 Hz), 5.16 (2H, s), 5.36 (2H, s), 7.02 (2H, d, J = 8.6 Hz), 7.28-7.65 (10H, m), 8.06- 8.15 (2H, m).

Example 138 To a solution of ethyl 6-phenyl-6- [4- (3-phenyl-1,2,4-oxadiazol-5-ylmethoxy) benzyloxyimino] hexanoate (790 mg) in tetrahydrofuran (6 ml) -water ( 4 ml) -ethanol (4 ml) was added lithium hydroxide monohydrate (194 mg) and stirred at room temperature for 4 hours. IN hydrochloric acid (4.7 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-phenyl-6- [4- (3-phenyl-1,2,4-oxadiazol-5-ylmethoxy) benzyloxyimino] hexanoic acid (637 mg, 85% of performance) as colorless crystals, mp 91-92 ° C Example 139 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (1.00 g), 4-oxo-4-phenylbutanamide (571 mg), acetic acid (0.553 ml), sodium acetate (528) mg) and ethanol (20 ml) was heated to reflux for 10 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel and a portion of an eluted fraction was concentrated with ethyl acetate-hexane (3: 1, v / v), which was eluted following the compound of E, to obtain crystals. . The crystals were recrystallized from ethanol to obtain Z-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutanamide (120 mg, 8% yield) as colorless crystals, m.p. 110-112 ° C Example 140 After a mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamine (467 mg), 2,2-dimethyl-6-oxo-6-phenylhexanoate methyl (340 mg), acetic acid ( 0.259 ml), sodium acetate (248 mg) and methanol (15 ml) was heated to reflux for 15 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain methyl E-2, 2-dimethyl-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (348 mg, 47% yield) as a colorless oil of a fraction eluted with ethyl acetate-hexane (1: 5, v / v).

NMR (CDC13) d: 1.10 (6H, s), 1.35-1.65 (4H, m), 2.44 (3H, s), 2. 73 (2H, t, J = 7.3 Hz), 3.55 (3H, s), 5.00 (2H, s), 5.15 (2H, s), 7.02 (2H, d, J = 8.8 Hz), 7.33-7.48 (8H, m), 7.57-7.63 (2H, m), 7.99-8.05 (2H, m).

Example 141 To a solution of methyl E-2, 2-dimethyl-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (340 mg) in tetrahydrofuran (5 ml) -methanol (5 ml) was added a solution of 4N aqueous potassium hydroxide (5 ml), which was heated to reflux for 2 hours and cooled to room temperature. Dilute hydrochloric acid was added to the reaction mixture to neutralize it and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain E-2, 2-dimethyl-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoic acid (275 mg , 83% yield) as colorless crystals, mp 111-112 ° C Example 142 a solution of E-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanoate (600 mg) in tetrahydrofuran (5 ml) was added oxalyl chloride (0.126 ml) and N , N-dimethylformamide (catalytic amount) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (10 ml) and methanesulfonamide (137 mg) and N, N-dimethylaminopyridine (293 mg) were added. After the reaction mixture was stirred at room temperature for 18 hours, IN hydrochloric acid was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried (MgSO 4) and concentrated. The residue was subjected to column chromatography on silica gel to obtain crystals of a fraction eluted with ethyl acetate-hexane (1: 1, v / v). The crystals were recrystallized from ethyl acetate-hexane to obtain EN-methanesulfonyl-6- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -6-phenylhexanamide (458 mg, 66% yield) as colorless crystals, mp 130-132 ° C Example 143 To a stirred solution of 4- (2-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (1.50 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (990 mg) in N, N-dimethylformamide (40 ml) Sodium hydride (60% in oil, 200 mg) was added at 0 ° C. After stirring for 2 hours, the reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1: 4, v / v) gave methyl E-4- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.65 g, 71% yield) as a colorless oil.

NMR (CDC13) d: .2.43 (3H, s), 2.5-2.65 (2H, m), 3.0-3.15 (2H, m), 3. 61 (3H, s), 5.07 (2H, s), 5.33 (2H, s), 6.98 (ÍH, dd, J = 7.5, 1.0 Hz), 7.25-7.5 (8H, m), 7.55-7.7 (2H, m), 7.95-8.1 (2H, m).

Example 144 A mixture of methyl Er4- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.60 g), methanol (5 ml), tetrahydrofuran (10 ml) and sodium hydroxide solution IN aqueous (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO 4), and concentrated to give E-4- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (1.42 g, 91%). % yield) as crystals. Recrystallization with ethyl acetate-hexane gave colorless needles, m.p. 116-117 ° C.

Example 145 To a stirred solution of 4- (4-chloromethyl-2,6-dimethoxyphenoxymethyl) -5-methyl-2-phenyloxazole (1.00 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (585 mg) in N, N dimethylformamide (40 ml) was added sodium hydride (60% in oil, 115 mg) at 0 ° C. After stirring for 2 hours, the reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1: 3, v / v) gave E-4- [3,5-dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate of methyl (970 mg, 65% yield) as a colorless oil.

NMR (CDC13) d: 2.32 (3H, s), 2.5-2.65 (2H, m), 3.05-3.15 (2H, m), 3.63 (3H, s), 3.84 (6H, s), 4.97 (2H, s) ), 5.16 (2H, s), 6.63 (2H, s), 7.3-7.5 (6H, m), 7.6-7.7 (2H, m), 7.95-8.05 (2H, m).

Example 146 A mixture of methyl E-4- [3,5-dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (970 mg), methanol (5 ml), tetrahydrofuran ( 10 ml) and IN aqueous sodium hydroxide solution (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO 4), and concentrated to give E-4- [3,5-dimethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4- acid. phenylbutyric (880 mg, 93% yield) as crystals. Recrystallization with ethyl acetate-isopropyl ether gave colorless needles, m.p. 89-90 ° C.

Example 147 To a stirred solution of 4- (4-chloromethyl-2-methoxyphenoxymethyl) -2- (2-furyl) -5-methyloxazole (1.65 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (1.04 g) in N , N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 200 mg) at 0 ° C. After stirring for 1 hour, the reaction mixture was poured into water, neutralized with IN hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO), and concentrated. The residue was purified by column chromatography on silica gel.

Elution with ethyl acetate-hexane (1: 4, v / v) gave E-4- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxyimino] -4- methyl phenylbutyrate (1.60 g, 64% yield) as crystals. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, m.p. 67-69 ° C.

Example 148 A mixture of methyl E-4- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxyimino] -4-phenylbutyrate (1.55 g), ethanol (10 ml), and Aqueous sodium hydroxide solution IN (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and acidified with IN hydrochloric acid to give E-4- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyloxyimino] -4- acid. phenylbutyric as crystals (1.40 g, 93% yield). Recrystallization with ethanol-isopropyl ether gave colorless prisms, m.p. 131-132 ° C.

Example 149 In the same manner substantially as in Example 147, 4- (4-chloromethyl-2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole was reacted with E-4-hydroxyimino-4-phenylbutyrate (1.10 g) to obtain -4- [3-Methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-methyl-phenylbutyrate (1.20 g, 44% yield) as crystals. Recrystallization from ethyl acetate-isopropyl ether gave pale yellow prisms, m.p. 112-114 ° C.

Example 150 In the same manner substantially as in Example 148, methyl E-4- [3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyrate (1.00 g) was reacted with a 1N aqueous sodium hydroxide solution to obtain E-4- [3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid (790 mg, 80% yield) . Recrystallization with ethanol-isopropyl ether gave colorless prisms, m.p. 134-135 ° C.

Pharmaceutical Composition Example 1 (Production of capsules) 1) compound (7) 30 mg 2) cellulose powder 10 mg 3) lactose 19 mg 4) magnesium stearic acid 1 mg Sum 60 mg Components 1), 2), 3), 4) are mixed and packaged in gelatin capsules.

Example 2 of Pharmaceutical Composition (Production of tablets) 1) compound (7) 30 g 2) lactose 50 g 3) corn starch 15 g 4) carboxymethyl cellulose calcium 44 g 5) magnesium stearic acid 1 g 1000 tablets Sum 140 g The total amounts of Components 1), 2) and 3) and 30 g of Component 4) are beaten with water, dried by freezing and then sprayed. The powdered powder is mixed with 14 g of Component 4) and 1 g of Component 5), and compacted into tablets. In this way, 1000 tablets are produced, each of which contains 30 mg of Component (7).

Effects of the Invention A compound or a pharmaceutical composition according to the present invention has lower toxicity, and can be used for the prevention or treatment of diabetes mellitus (for example, insulin-dependent diabetes mellitus (diabetes mellitus type 1), non-insulin-dependent diabetes mellitus (diabetes mellitus type 2), diabetes mellitus in pregnancy and the like), hyperlipidemia (for example, hypertriglycemia, hypercholesterolemia, hypoHDLemia and the like ), insensitivity to insulin, insulin resistance, and impaired glucose tolerance (IGT).

A compound or a pharmaceutical composition according to the present invention can also be used for the prevention or treatment of diabetic complications (e.g., neuropathy, Nephropathy, retinopathy, cataract, microangiopathy, osteopenia and the like), obesity, osteoporosis, cachexia (e.g., carcinomatous cachexia, tuberculous cachexia, diabetic cachexia, hemofática cachexia, endocrinofática cachexia, infectious cachexia or cachexia induced immunodeficiency syndrome acquired), fatty liver, hypertension, polycystic ovary syndrome, renal disorders (e.g., glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, renal disorders terminals and like), muscular dystrophy, myocardial infarction, angina pectoris, myocardial brain syndrome insulin resistance, syndrome X, sensory disorder induced hyperinsulinemia, tumors (e.g., leukemia, breast cancer, prostate cancer, skin cancer and like), inflammatory diseases (eg rheumatoid arthritis , deforming spondylitis, osteoarthritis, lumbago, gout, remedy d and inflammation and swelling of surgical wound, pharyngolaryngitis, cystitis, hepatitis, pneumonia, pancreatitis and the like), arterial sclerosis (e.g., atherosclerosis and similar).

A compound according to the invention can also be used as a pharmaceutical to control appetite or food intake, diet and anorexia.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (40)

1. A compound represented by Formula (I) characterized in that R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkenyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a heterocyclic group optionally substituted and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups, which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; with the proviso that when R1 is an ethoxymethyl group, a C1-3 alkyl group, a phenyl group or a p-methoxyphenyl group and q = m = 0, R3 is NR9R10; and with the proviso that O- [2-chloro-4- (2-quinolylmethoxy) phenylmethyloxime of methyl pyruvate and [2-chloro-4- (2-quinolylmethoxy) phenylmethyl] -2-iminoxypropionic acid are excluded; or a salt thereof;

2. A compound according to claim 1, characterized in that R1 is an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group;

3. A compound according to claim 1, characterized in that X is a bond or a group represented by -NR6-, wherein R6 is an optionally substituted alkyl group;

4. A compound according to claim 1, characterized in that n is 1 or 2;

5. A compound according to claim 1, characterized in that Y is an oxygen atom;

6. A compound according to claim 1, characterized in that p is an integer from 1 to 3;

7. A compound according to claim 1, characterized in that R3 is a hydroxy group or -OR8 or -NR9'R10 ', wherein R8 is an optionally substituted hydrocarbon group and' R9 'and R10' are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, or R9 'and R10' are combined together to form a ring;

8. A compound according to claim 1, characterized in that q is an integer from 0 to 4, -

9. A compound according to claim 1, characterized in that R2 is an optionally substituted hydrocarbon group;

10. A compound according to claim 1, characterized in that the compound is E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid or its salt;

11. A compound according to claim 1, characterized in that the compound is selected from a group consisting of E-4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyramide and acid E -8- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -8-phenyloctanoic acid;

12. A compound according to claim 2, characterized in that a ring of an optionally substituted heterocyclic group or an optionally substituted cyclic hydrocarbon group of R 1 is selected from the group represented by the formulas:

13. A compound according to claim 12, characterized in that the ring optionally has one or two substituents, which are selected from the group consisting of an optionally substituted phenyl, an optionally substituted furyl, an optionally substituted thienyl and a substituted C? _4 alkyl optionally;

14. A compound according to claim 12, characterized in that the ring is: wherein Ph is an optionally substituted phenyl group, and R1 'is hydrogen or an optionally substituted C1-6 alkyl group;

15. A compound according to claim 1 represented by the formula: R R characterized in that R 'is an optionally substituted phenyl, furyl or thienyl group; R1 'is hydrogen or an alkyl group C1-6 optionally substituted; R2 'is a phenyl group, which is optionally substituted by at least one selected from a group consisting of hydrogen, a C1-6 alkyl group, a C1-6 alkoxy group, and a halogen; q is an integer from 1 to 6; and R3 'is a hydroxy group, a C6-6 alkoxy group or -NR9R10, in which R9 and R are independently selected from the group consisting of a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group and an optionally substituted acyl group, or R9 and R10 combine with each other to form a ring; or a salt thereof;

16. The pharmaceutical composition, characterized in that it comprises a compound represented by the formula wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a heterocyclic group optionally substituted and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups, which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it.

17. A pharmaceutical composition according to claim 16, characterized in that it is a composition for the prevention or treatment of diabetes mellitus;

18. A pharmaceutical composition according to claim 16, characterized in that it is a composition for the prevention or treatment of hyperlipidemia;

1 . A pharmaceutical composition according to claim 16, characterized in that it is a composition for the prevention or treatment of impaired glucose tolerance;

20. A pharmaceutical composition according to claim 16, characterized in that it is a composition for the prevention or treatment of an inflammatory disease.

21. A pharmaceutical composition according to claim 16, characterized in that it is a composition for the prevention or treatment of atherosclerosis;

22. An agent for controlling retinoid related receptors, characterized in that it comprises a compound represented by the formula R 'R4 R5 wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a heterocyclic group optionally substituted and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups, which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it.

23. An agent according to claim 22, characterized in that it is a ligand of the peroxisome proliferator-activated receptors;

24. An agent according to claim 22, characterized in that it is a ligand of the retinoid X receptor;

25. An agent according to claim 22, characterized in that it is an agent that increases the sensitivity to insulin;

26. An agent according to claim 22, characterized in that it is an agent that improves insulin resistance;

27. A method of prevention and treatment of diabetes mellitus, characterized in that it comprises administering a pharmaceutically effective amount of the compound represented by the formula: R R C- (CH.) Q- (VC) fli-C00) -R " wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkenyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a heterocyclic group optionally substituted and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups, which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it.

28. A method of prevention and treatment of hyperlipidemia, characterized in that it comprises administering a pharmaceutically effective amount of the compound represented by the formula: R * R C- (CH,) q- (VC) m-C (= 0) -R wherein R 1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a heterocyclic group optionally substituted and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups, which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it.

29. A method for increasing insulin sensitivity, characterized in that it comprises administering a pharmaceutically effective amount of the compound represented by the formula: R R wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer of 1. up to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it.

30. A method for improving insulin resistance, characterized in that it comprises administering a pharmaceutically effective amount of the compound represented by the formula: R4 R5 wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkenyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it.

31. A method of prevention and treatment of impaired glucose tolerance, characterized in that it comprises administering a pharmaceutically effective amount of the compound represented by the formula: R4 R5 wherein it is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer of 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it.

32. A method of preventing and treating an inflammatory disease, characterized in that it comprises administering a pharmaceutically effective amount of the compound represented by the formula: wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it.

33. A method of prevention and treatment of arterial sclerosis, characterized in that it comprises administering a pharmaceutically effective amount of the compound represented by the formula: R R ' wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer of 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it.

34. Use of the compound or a salt thereof for the manufacture of a medicament for the prevention and treatment of diabetes mellitus, whose compound is represented by the formula: R4 RS wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2.

35. Use of the compound or a salt thereof for the manufacture of a medicament for the prevention and treatment of hyperlipidemia, whose compound is represented by the formula: wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; Ring A is a benzene ring that has one to three - additional substituents optionally; p is an integer of 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2.

36. Use of the compound or a salt thereof for the manufacture of a medicament to increase the sensitivity to insulin, whose compound is represented by the formula: R4 R5 CH2) p- O- -N = C- (CH2) q- (VC) m-C (= 0) -R ' wherein it is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2.

37. Use of the compound or a salt thereof for the manufacture of a medicament for improving insulin resistance, whose compound is represented by the formula: R4 R5 R -X- (CH2) n-Y X A-J- (CH,) p-0-N = C '• (CHz) q- (VC) m- C (= 0) -R wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkenyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2.

38. Use of the compound or a salt thereof for the manufacture of a medicament for the prevention and treatment of impaired glucose tolerance, whose compound is represented by the formula: wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups whare selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups whare selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2.

39. Use of the compound or a salt thereof for the manufacture of a medicament for the prevention and treatment of an inflammatory disease, whose compound is represented by the formula: R 'R4 R5 N = C- (CH,) q- (V VC) n? - C (= 0) -R3 wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or a substituted heterocyclic group • optionally; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups whare selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups whare selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2.

40. Use of the compound or a salt thereof for the manufacture of a medicament for the prevention and treatment of arterial sclerosis, whose compound is represented by the formula: R * R3 wherein it is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a substituted heterocyclic group optionally and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2; or a salt of it. SUMMARY OF THE INVENTION The present invention relates to an oxyiminoalkanoic acid derivative, which has excellent hypoglycemic and hypolipidemic actions and which is used for the prevention or treatment of diabetes mellitus, hyperlipidemia, insulin insensitivity, insulin resistance and glucose tolerance. worsened A compound represented by the form wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, -CO-, -CH (OH) - or a group represented by -NR6-, wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer from 1 to 3; Y is an oxygen atom, a sulfur atom, -SO-, -S02- or a group represented by -NR7-, wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring having one to three additional substituents optionally; p is an integer from 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer from 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group) or NR9R10 (R9 and R10 are the same or different groups, which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, a heterocyclic group optionally substituted and an optionally substituted acyl group or R9 and R10 combine with each other to form a ring); R4 and R5 are the same or different groups, which are selected from a hydrogen atom and an optionally substituted hydrocarbon group, wherein R4 can form a ring with R2, - with the proviso that when R1 is an ethoxymethyl, an alkyl C1-3, phenyl or p-methoxyphenyl and q = m = 0, R3 is NR9R10; and with the proviso that 0- [2-chloro-4- (2-quinolylmethoxy) phenylmethyl] methyl pyruvate oxime and [2-chloro-4- (2-quinolylmethoxy) phenylmethyl] -2-iminoxypropionic acid are excluded.; or a salt thereof;