WO1997000249A1 - Heterocyclic compounds, their production and use - Google Patents

Heterocyclic compounds, their production and use Download PDF

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Publication number
WO1997000249A1
WO1997000249A1 PCT/JP1996/001643 JP9601643W WO9700249A1 WO 1997000249 A1 WO1997000249 A1 WO 1997000249A1 JP 9601643 W JP9601643 W JP 9601643W WO 9700249 A1 WO9700249 A1 WO 9700249A1
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Prior art keywords
group
optionally substituted
stands
oxazolidinedione
compound
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PCT/JP1996/001643
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French (fr)
Inventor
Takashi Sohda
Etsuya Matsutani
Yu Momose
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Takeda Chemical Industries, Ltd.
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Priority to AU60168/96A priority Critical patent/AU6016896A/en
Publication of WO1997000249A1 publication Critical patent/WO1997000249A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/44—Two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C07D233/78—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • TECHNICAL FIELD This invention relates to a novel heterocyclic compound useful as a medicine especially an antitumor agent, a method of producing it and a preparation comprising it.
  • R stands for an alkyl group, a cycloalkyl group, a phenylalkyl group, phenyl group, a 5- or 6- membered heterocyclic group having one or two hetero- atoms selected from nitrogen atom, oxygen atom and sulfur atom, or a group represented by the formula:
  • R and R independently stand for a lower alkyl group or R and R are combined with each other directly or through a hetero-ato selected from nitrogen atom, oxygen atom and sulfur atom to optionally form a 5- or 6-membered ring, taken together with the nitrogen atom adjacent to R and R ;
  • R stands for a bond or a lower alkylene group
  • L 1 and L2 independently stand for, when R1 is an alkyl group, a lower alkyl group, or they may optionally be combined with each other to form an alkylene group, and, when R is not an alkyl group, L and L may, besides the above definition, optionally be hydrogen atom; are described, and there is also disclosed that these compounds have an activity of lowering lipid in blood and sugar in blood.
  • R stands for an optionally substituted hydrocarbon residue, or heterocyclic group
  • Y stands for a group shown by -CO-, -CH(OH)- or NR 3- (wherein R3 stands for an optionally substituted alkyl group); m denotes 0 or 1; n denotes 0, 1 or 2; X stands for CH or N; A stands for a C,_ 7 divalent aliphatic hydrocarbon residue; R and R z independently stand for hydrogen atom or an alkyl group, or R and R combine with each other to form a 5- to 6-membered heterocyclic group, optionally containing nitrogen; L and M respectively stand for hydrogen atom, or L and M may optionally be combined with each other to form a bond; and their salts as well as their use as a therapeutic agent of diabetes mellitus are disclosed.
  • R stands for a C ⁇ g straight-chain or branched alkyl group
  • X stands for oxygen atom or sulfur atom
  • Y stands for hydrogen atom or a group: -A-COOH (A stands for a C . 6 straight chain or branched alkylene group)
  • Ar stands for a C 6 .
  • substituents (a) include halogen, haloalkyl having Cj. ⁇ straight-chain or branched alkyl, hydroxy, Cj_ A straight-chain or branched alkyl or C ⁇ straight-chain or branched alkoxy; are useful as prophylactic and/or therapeutic agents of, among others, hyperglycemia, hyperlipemia and obesity.
  • the object of this invention is to provide such a novel antitumor agent having less side-effects and based on a novel action mechanism.
  • D stands for hydrogen atom or an optionally substituted hydrocarbon group
  • X stands for CH or N
  • A stands for a divalent aliphatic hydrocarbon group
  • R stands for a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group, (2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) a hydroxyl group optionally substituted by a hydrocarbon group or an acyl group, (7) a thiol group optionally substituted by a hydrocarbon group or an acyl group, (8) an optionally esterified carboxyl group, (9) cyano group or (10) oxo group;
  • Q stands for -N(R )- (R stands for hydrogen atom or a lower alkyl group), oxygen atom or sulfur atom;
  • Z stands for oxygen atom or sulfur atom;
  • L and M independently stand for hydrogen atom, or they may optionally be combined with each other to form one bond; and ring E may optionally be further substituted, and the substituent may optionally be combined with
  • an antitumor agent comprising a compound of the formula:
  • D stands for hydrogen atom or an optionally substituted hydrocarbon group
  • X stands for CH or N
  • A stands for a bond or a divalent aliphatic hydrocarbon group
  • R stands for hydrogen atom or a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group, (2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) a hydroxyl group optionally substituted by a hydrocarbon group or an acyl group, (7) a thiol group optionally substituted by a hydrocarbon group or an acyl group, (8) an optionally esterified carboxyl group, (9) cyano group or (10) oxo group;
  • Q stands for -N(R°)- (R stands for hydrogen atom or a lower alkyl group) , oxygen atom or sulfur atom; Z stands for oxygen atom or sulfur atom; L and M independently stand for hydrogen atom, or they may optionally be combined with each other to form one bond; and ring E may optionally be further substituted, and the substituent may optionally be combined with D to form a ring; and when A stands for a bond, D stands for an optionally substituted hydrocarbon group; or a salt thereof;
  • D stands for hydrogen atom or an optionally substituted hydrocarbon group.
  • hydrocarbon group shown by D mention is made of, for example, aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, aromatic hydrocarbon groups, aromatic-aliphatic hydrocarbon groups and alicyclic-aliphatic hydrocarbon groups.
  • aliphatic hydrocarbon groups use is made of, for example, C J . J Q aliphatic hydrocarbon groups.
  • the aliphatic hydrocarbon groups include c ⁇ - ⁇ o f preferably Cj.g saturated aliphatic hydrocarbon groups (e.g.
  • alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.- butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl, isohexyl, heptyl, octyl, and decyl; and C 2 __. ⁇ 0r preferably C 2 _ 8 unsaturated aliphatic hydrocarbon groups (e.g.
  • alkenyl group, alkadienyl group, alkynyl group, alkadiynyl group) such as vinyl (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, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 1-hexynyl, 3-hexynyl, 2,4-he
  • alicyclic hydrocarbon groups use is made of, for example, C _ 7 alicyclic hydrocarbon groups.
  • the alicyclic hydrocarbon groups include C 3 _ 7 saturated alicyclic hydrocarbon groups (e.g. cycloalkyl group) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; and C 5 . 7 unsaturated alicyclic hydrocarbon groups (e.g.
  • cycloalkenyl group such as 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1- cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, and 2,4-cycloheptadienyl .
  • aromatic hydrocarbon groups mention is made of, for example, C 6 . 14 aromatic hydrocarbon groups.
  • the aromatic hydrocarbon groups include C 6 _ aryl groups such as phenyl and naphthyl ( ⁇ -naphthyl, ⁇ -naphthyl) .
  • aromatic-aliphatic hydrocarbon groups mention is made of, for example, C 7 _ 20 aromatic- aliphatic hydrocarbon groups .
  • aromatic-aliphatic hydrocarbon groups include C 7 . aralkyl groups (e.g. benzyl, 2-phenylethyl) and Cg. ⁇ aryl-C 2 _ 6 alkenyl groups (e.g. styryl(2-phenylethenyl) , 2-(2-naphthyl)vinyl, 4-phenyl-l,3-butadienyl) .
  • alicyclic-aliphatic hydrocarbon groups mention is made of, among those formed by combination of the above-mentioned alicyclic hydrocarbon groups with aliphatic hydrocarbon groups, d,.-, ones.
  • examples of the alicyclic-aliphatic hydrocarbon groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3- cyclop tenylmethyl, cyclohexylmethyl, 2- cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, and cycloheptylethyl.
  • the hydrocarbon group shown by D is preferably an aliphatic hydrocarbon group, more preferably a C j . 6 aliphatic hydrocarbon group.
  • the hydrocarbon group shown by D may optionally have, at any possible position, 1 to 4 substituents selected from, for example, "an optionally substituted heterocyclic group", “an aliphatic chain hydrocarbon group”, “an alicyclic hydrocarbon group”, “an optionally substituted aromatic hydrocarbon group”, “an aromatic-aliphatic hydrocarbon group”, “a halogen atom”, “nitro group”, “an optionally substituted amino group”, “an optionally substituted acyl group”, “an optionally substituted hydroxyl group”, “an optionally substituted thiol group”, “an optionally esterified carboxyl group”, “cyano group” and “oxo group”.
  • the heterocyclic group in "the optionally substituted heterocyclic group” as the substituent of the hydrocarbon group shown by D includes, for example, 5- to 7-membered heterocyclic groups containing in addition to carbon atom, as a ring component atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and condensed ring groups.
  • the 5- to 7-membered heterocyclic groups include a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, a 5- to 6- membered heterocyclic group containing two to four nitrogen atoms and a 5- to 6-membered heterocyclic group containing one or two nitrogen atoms and one sulfur atom or oxygen atom.
  • condensed ring groups include, for example, those formed by condensation of the above- mentioned 5- to 7-membered heterocyclic groups with a 6-membered ring containing two or less nitrogen atom, benzene ring or a 5-membered ring containing one sulfur atom.
  • heterocyclic groups include pyran, dihydropyran, tetrahydropyran, chroman, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3- pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3- pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4- oxazolyl, 5-oxazolyl, 1,2,4-triazol-3-yl, 1,3,4- triazol-2-yl, l,2,3-triazol-4-yl, tetrazol-5-
  • the aliphatic chain hydrocarbon group as the substituent of the hydrocarbon group shown by D include C x . 15 straight-chain or branched aliphatic hydrocarbon groups as exemplified by alkyl groups, alkenyl groups, and alkynyl groups .
  • alkyl groups include C J .
  • JO alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, 1- ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbuty1, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl .
  • alkenyl groups include C 2 - ⁇ o alkenyl groups such as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl- 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl .
  • alkynyl groups include C 2 .
  • alkynyl groups such as 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 and 5-hexynyl,
  • the alicyclic hydrocarbon group as the substituent of the hydrocarbon group shown by D include C 3 . 12 saturated or unsaturated alicyclic hydrocarbon groups, for example, cycloalkyl groups, cycloalkenyl groups and cycloalkadienyl groups.
  • cycloalkyl groups include C 3 . 12 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2. l]heptyl, bicyclo[2.2.2 Joctyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3. l]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl .
  • cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2. l]heptyl, bicyclo[2.2.2 Joctyl, bicyclo[3.2.1]octyl,
  • cycloalkenyl groups include C 5 _ 12 cycloalkenyl groups such as 2-cyclopenten- 1-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl and 3- cyclohexen-1-yl .
  • cycloalkadienyl groups include C 5 . 12 cycloalkadienyl groups such as 2,4- cyclopentadien-1-yl, 2,4-cyclohexadien-l-yl and 2,5- cyclohexadien-1-yl .
  • the aromatic hydrocarbon group in "the optionally substituted aromatic hydrocarbon group” as the substituent of the hydrocarbon group shown by D means monocyclic or condensed polycyclic aromatic hydrocarbon group.
  • the aromatic hydrocarbon group include C 6 . ltl aromatic hydrocarbon groups such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and 3,4-dihydro-2-naphthyl .
  • substituents in "the optionally substituted aromatic hydrocarbon group” as the substituent of the hydrocarbon group shown by D include halogen (e.g.
  • a lower alkyl group e.g. Cj.g alkyl groups such as methyl, ethyl, propyl and butyl
  • a lower alkoxy group e.g. Ci. 6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentyloxy
  • hydroxyl group nitro group
  • cyano group an acyl group (e.g. Cj.g alkanoyl groups such as formyl, acetyl, propionyl and butyryl), amino group, thiol group and trifluoromethyl group.
  • the number of substituents is, for example, one to five.
  • the aromatic-aliphatic hydrocarbon group as the substituent of the hydrocarbon group shown by D include C 7 . 20 aromatic-aliphatic hydrocarbon groups.
  • the aromatic-aliphatic hydrocarbon groups include C 7 . 14 aralkyl groups (e.g. benzyl, 2- phenylethyl) , C 6 . 1
  • the halogen atom as the substituent of the hydrocarbon group shown by D include fluorine, chlorine, bromine and iodine, and, among them, fluorine and chlorine are especially preferable.
  • the optionally substituted amino group as the substituent of the hydrocarbon group shown by D include, amino group which is mono- or di- substituted by C J . J Q alkyl, C 2 _ 10 alkenyl, C,. 10 acyl or aromatic group (e.g. methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino and N-methyl-N-phenylamino) and a 4- to 6-membered cyclic amino group (e.g.
  • the 4- to 6-membered cyclic amino group may optionally be further substituted by 1) C j .g alkyl groups, 2) C 6 _ 1 aryl groups optionally substituted by halogen, C ⁇ g alkoxy groups or trifluoromethyl, 3) 5- or 6-membered heterocyclic groups containing in addition to carbon atom, as a ring component atom, 1 or 2 nitrogen atoms (e.g. 2-pyridyl, pyrimidinyl) , or 4) 6-membered cyclic amino group (e.g. piperidino, 1-piperadinyl) .
  • acyl group in "the optionally substituted acyl group" as the substituent of the hydrocarbon group shown by D mention is made of, besides formyl, for example, groups formed by combination of C ⁇ K , alkyl, C 2 _ 10 alkenyl or C 6 . 12 aromatic group with carbonyl group (e.g.
  • substituents in “the optionally substituted acyl group” mention is made of, for example, Cj_ 3 alkyl groups, C j . 3 alkoxy groups, halogen (e.g. chlorine, fluorine or bromine), nitro group, hydroxyl group and amino group.
  • the number of substituents is, for example, 1 to 3.
  • the substituted hydroxyl group in "the optionally substituted hydroxyl group" as the substituent of the hydrocarbon group shown by D mention is made of, for example, hydroxyl group which is substituted by hydrocarbon groups or acyl groups, such as alkoxy groups , alkenyloxy groups, aralkyloxy groups, aryloxy groups and acyloxy groups.
  • alkoxy groups include C ⁇ .
  • alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy.
  • alkenyloxy groups include C 2 . 10 alkenyloxy groups such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2- cyclopentenylmethoxy and 2-cyclohexenylmethoxy.
  • aralkyloxy groups include phenyl-Cj. ⁇ alkyloxy groups (e.g. benzyloxy, phenethyloxy) .
  • aryloxy groups include C 6 _ 1A aryloxy groups such as phenoxy and 4- chlorophenoxy.
  • acyloxy groups include C 2 - A acyloxy groups such as C 2 .
  • a alkanoyloxy groups e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy.
  • substituted thiol group in "the optionally substituted thiol group" as the substituent of the hydrocarbon group shown by D mention is made of, thiol group which is substituted by hydrocarbon groups or acyl groups, such as alkylthio groups, alkenylthio groups, aralkylthio groups, arylthio groups and acylthio groups.
  • alkylthio groups include C ⁇ _ 10 alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec .-butylthio, tert.- butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio and cyclohexylthio.
  • C ⁇ _ 10 alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec .-butylthio, tert.- butylthio, pentylthio, isopentylthio, neopentyl
  • alkenylthio groups include C z _ ⁇ o alkenylthio groups such as allylthio, crotylthio, 2- pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio and 2-cyclohexenylmethylthio.
  • aralkylthio groups include Cy. ⁇ aralkylthio groups such as phenyl-Ci. 4 alkylthio (e.g. benzylthio, phenethylthio) .
  • arylthio groups include C 6 . 1A arylthio groups such as phenylthio and 4-chlorophenylthio.
  • acylthio groups include C 2 . « acylthio groups such as C . 4 alkanoylthio groups (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio) .
  • esterified carboxyl group in "the optionally esterified carboxyl group” as the substituent of the hydrocarbon group shown by D mention is made of, for example, alkoxycarbonyl groups, aralkyloxycarbonyl groups and aryloxycarbonyl groups .
  • alkoxycarbonyl groups include C 2 - 5 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl.
  • aralkyloxycarbonyl groups include C 8 . 15 aralkyloxycarbonyl groups such as benzyloxycarbonyl .
  • aryloxycarbonyl groups include C 7 . 15 aryloxycarbonyl groups such as phenoxycarbonyl and p-tolyloxycarbonyl .
  • the heterocyclic groups as the substituent of the hydrocarbon group shown by D may optionally have at any possible position, one to three substituents, respectively.
  • substituents mention is made of "aliphatic chain hydrocarbon groups", “alicyclic hydrocarbon groups”, “optionally substituted aromatic hydrocarbon groups”, “aromatic-aliphatic hydrocarbon groups”, “aromatic heterocyclic groups”, “non-aromatic heterocyclic groups”, “halogen atoms”, “nitro group”, “optionally substituted amino groups”, “optionally substituted acyl groups”, “optionally substituted hydroxyl groups”, “optionally substituted thiol groups”, “optionally esterified carboxyl groups” and “aromatic heterocyclic-aliphatic hydrocarbon groups”.
  • the aromatic heterocyclic groups as substituents of the heterocyclic groups include aromatic monocyclic heterocyclic groups 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-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; and aromatic condensed heterocyclic groups such as benzofuranyl, isobenzofuranyl, benzofb]thienyl,
  • the non-aromatic heterocyclic groups as substituents of the heterocyclic groups include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl.
  • the aromatic heterocyclic- aliphatic hydrocarbon groups as substituents of the heterocyclic groups include alkyl groups (e.g. (2-furyl)methyl) , 2-furyl-C 2 . 6 alkenyl groups (e.g. (2-furyl)vinyl) , thienyl-C ⁇ alkyl groups (e.g. thienylmethyl) , thienyl-C 2 _ 6 alkenyl groups (e.g. 2- thienylvinyl) .
  • alkyl groups e.g. (2-furyl)methyl
  • 2-furyl-C 2 . 6 alkenyl groups e.g. (2-furyl)vinyl
  • thienyl-C ⁇ alkyl groups e.g. thienylmethyl
  • thienyl-C 2 _ 6 alkenyl groups e.g. 2- thienylvinyl
  • D is preferably a hydrocarbon group which is substituted by an optionally substituted heterocyclic group, more preferably a hydrocarbon group which is substituted by oxazolyl or thiazolyl group optionally having one or two substituents selected from Cj.g alkyl groups, C 2 - 8 alkenyl groups, C 3 _ 8 cycloalkyl groups, C 6 .
  • aryl groups C 7 _ 14 aralkyl groups, C 6 . ltl aryl-C 2 . 6 alkenyl groups, aromatic heterocyclic groups, aromatic heterocyclic-C j . 6 alkyl groups and aromatic heterocyclic-C 2 _ 6 alkenyl groups.
  • hydrocarbon group shown by R or R include similar hydrocarbon group to those set forth as D .
  • substituent of the hydrocarbon group shown by R or R mention is made of, for example, (1) “an optionally substituted heterocyclic group", (2) “a halogen atom", (3) “nitro group”, (4) “an optionally substituted amino group”, (5) “an optionally substituted acyl group”, (6) “hydroxyl group optionally substituted by a hydrocarbon group or an acyl group", (7) “thiol group optionally substituted by a hydrocarbon group or an acyl group”, (8) “an optionally esterified carboxyl group", (9) “cyano group” and (10) "oxo group”.
  • the number of substituents is, for example, one to four. Examples of these substituents include similar ones to those set forth as the substituent of the hydrocarbon group shown by D.
  • the substituent of the optionally substituted hydrocarbon group shown by R or R is preferably "an optionally substituted heterocyclic group", "a halogen atom”, “nitro group”, “an optionally substituted amino group”, “an optionally substituted acyl group”, “an optionally esterified carboxyl group”, “cyano group” or “oxo group”, more preferably "an optionally substituted heterocyclic group” or “an optionally substituted amino group”.
  • the heterocyclic group in “the optionally substituted heterocyclic group” oxazolyl or thiazolyl is preferable.
  • substituents in “the optionally substituted heterocyclic group” include Ci.g alkyl groups (e.g.
  • styryl(2-phenylethenyl) 2-(2- naphthyl)vinyl, 4-phenyl-l,3-butadienyl)
  • aromatic heterocyclic groups e.g. furyl,thienyl
  • aromatic heterocyclic-Cj. 6 alkyl groups e.g. (2-furyl)methyl
  • aromatic heterocyclic-C 2 _ 6 alkenyl groups e.g. 2-(2- furyl)vinyl
  • substituted amino groups in "the optionally substituted amino group” include C ⁇ K , acylamino groups (e.g. C ⁇ o alkanoylamino such as acetylamino and propionylamino) ; mono- or di- C J .
  • acylamino groups e.g. C ⁇ o alkanoylamino such as acetylamino and propionylamino
  • mono- or di- C J e.g.
  • cyclic amino groups optionally substituted by 1) C ⁇ alkyl groups, 2) C 6 _ 1A aryl groups optionally substituted by halogen, C j _ 6 alkoxy groups or trifluoromethyl, 3) 5- or 6-membered heterocyclic groups containing in addition to carbon atoms, as a ring component atom, 1 or 2 nitrogen atoms (e.g. 2- pyridyl, pyrimidinyl) or 4) 6-membered cyclic amino groups (e.g. piperidino, 1-piperadinyl) , (e.g.
  • the optionally substituted amino group is preferably a 4- to 6- membered cyclic amino group optionally substituted by 1) Cj.g alkyl groups, 2) C 6 . 14 aryl groups optionally substituted by halogen, C l . 6 alkoxy groups or trifluoromethyl, 3) 5- or 6-membered heterocyclic groups containing in addition to carbon atoms, as a ring component atom, 1 or 2 nitrogen atoms or 4) 6- membered cyclic amino groups.
  • R stands for hydrogen atom or a hydrocarbon group optionally having substituents selected from (1) “an optionally substituted heterocyclic group", (2) “a halogen atom", (3) “nitro group”, (4) “an optionally substituted amino group”, (5) “an optionally substituted acyl group”, (6) “hydroxyl group optionally substituted by a hydrocarbon group or an acyl group", (7) “thiol group optionally substituted by a hydrocarbon group or an acyl group”, (8) “an optionally esterified carboxyl group", (9) “cyano group” and (10) "oxo group”.
  • R preferably stands for a hydrocarbon group optionally having substituents selected from (1) to (10) .
  • R and R are preferably hydrocarbon groups substituted by 1) an optionally substituted heterocyclic group or 2) an optionally substituted amino group.
  • R and R are more preferably hydrocarbon groups substituted by (a) oxazolyl or thiazolyl group optionally having 1 or 2 substituents selected from Cj.g alkyl groups, C 2 _ 8 alkenyl groups, C 3 _ 8 cycloalkyl groups, C 6 _ 14 aryl groups, C 7 _ 14 aralkyl groups, C 6 . 14 aryl-C 2 _ 6 alkenyl groups, aromatic heterocyclic groups, aromatic heterocyclic-Ci.g alkyl groups, and aromatic heterocyclic-C 2 _ 6 alkenyl groups; or (b) 4- to 6- membered cyclic amino groups optionally substituted by 1) Ci.e alkyl groups, 2) C 6 .
  • aryl groups optionally substituted by halogen, Cj.g alkoxy groups or trifluoromethyl, 3) 5- or 6-membered heterocyclic groups containing in addition to carbon atoms, as a ring component atom, 1 or 2 nitrogen atoms or 4) 6- membered cyclic amino groups.
  • divalent aliphatic hydrocarbon group shown by A or A 1 one having 1 to 7 carbon atoms is preferable, which may be straight-chain or branched, and may be saturated or unsaturated.
  • a or A 1 is more preferably a C ⁇ divalent aliphatic hydrocarbon group, with prefence given to saturated one.
  • a or A is especially preferably -CH 2 - or -(CH 2 ) 2 -.
  • X stands for CH or N, preferably CH.
  • Q stands for -N(R )- (R stands for hydrogen atom or a lower alkyl group) , oxygen atom or sulfur atom, preferably oxygen atom.
  • R stands for hydrogen atom or a lower alkyl group
  • oxygen atom or sulfur atom preferably oxygen atom.
  • Examples of the lower alkyl group shown by R include Cj__.
  • Z stands for oxygen atom or sulfur atom, preferably oxygen atom.
  • L and M are preferably hydrogen.
  • [ £_1J preferably represents D includes groups shown by, for example, R-(Y) m - (CH 2 ) n -CH(D 1 ) wherein R stands for an optionally substituted hydrocarbon group; m is 0 or 1; n is 0, 1 or 2 ; Y stands for -CO-, -CH(OH)- or -N(R 4 ) (R 4 stands for an optionally substituted alkyl group); D stands for hydrogen atom or a lower alkyl group.
  • R stands for an optionally substituted hydrocarbon group
  • m is 0 or 1
  • n is 0, 1 or 2
  • Y stands for -CO-, -CH(OH)- or -N(R 4 ) (R 4 stands for an optionally substituted alkyl group)
  • D stands for hydrogen atom or a lower alkyl group.
  • n denotes 0, 1 or 2, preferably 0 or 1, most preferably 0.
  • Y stands for -CO-, -CH(OH)- or -N(R*)-, preferably -CH(OH)- or -N(R A )-.
  • the alkyl group in “the optionally substituted alkyl group” shown by R 4 mention is made of Ci_ 4 one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl and tert.-butyl.
  • substituents in “the optionally substituted alkyl group” include halogen (e.g. fluorine, chlorine, bromine, iodine), C ⁇ alkoxy groups (e.g.
  • Ring E may optionally have, besides
  • a lower (C ⁇ ) alkyl group e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec .-butyl and tert.-butyl
  • a lower (Ci.i) alkoxy group e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec . -butoxy and tert. - butoxy
  • halogen e.g. fluorine, chlorine, bromine and iodine
  • amino group e.g. fluorine, chlorine, bromine and iodine
  • R and R independently stand for hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or hydroxyl group, or, R and D may optionally be combined with each other to form a 5- or 6-membered heterocyclic ring optionally containing nitrogen atom or oxygen atom, and other symbols are of the same meaning as defined above, or their salts.
  • C ⁇ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl and tert.-butyl .
  • R and R As the lower alkoxy group shown by R and R , mention is made of a C ⁇ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.- butoxy and tert.-butoxy.
  • halogen atom shown by R and R mention is made of fluorine, chloride, bromine and iodine, preferably fluorine or chlorine.
  • the compounds represented by the formula (I-a) include those represented by the following formulae.
  • the compound represented by the formula (I-b-2) is preferable.
  • the compounds wherein substituents in ring E (R ) are combined with D to form a ring include the compounds represented by the following formulae. (1) D and R are combined with each other to form a 5- membered heterocyclic ring.
  • D stands for hydrogen atom or a lower alkyl group, and other symbols are of the same meaning as defined above.
  • the lower alkyl group shown by D is exemplified by C j.4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec .-butyl and tert.-butyl.
  • compounds represented by the formulae (I-c-1) to (I-c-8) are preferable.
  • compounds represented by the formulae (I-c-2), (I-c-3) and (I-c-6) are preferable.
  • Preferable examples of the compound represented by the formula (I) or (II) include compounds wherein D is C ⁇ . 6 aliphatic hydrocarbon groups substituted by oxazolyl or thiazolyl group optionally having one or two substituents selected from Cj.g alkyl groups, C 2 . 8 alkenyl groups, C 3 . 8 cycloalkyl groups, C 6 _ 14 aryl groups, C 7 . l ⁇ aralkyl groups, C 6 _ u aryl-C 2 . 6 alkenyl groups, aromatic heterocyclic groups, aromatic heterocyclic-Cj.g alkyl groups, and aromatic heterocyclic-C 2 _ 6 alkenyl groups;
  • X is CH;
  • a or A is a Cj_ A divalent aliphatic hydrocarbon group
  • R or R is a 6 aliphatic hydrocarbon group substituted by (a) oxazolyl or thiazolyl group optionally having 1 or 2 substituents selected from C ⁇ alkyl groups, C 2 . 8 alkenyl groups, C 3 _ 8 cycloalkyl groups, C 6 _ 1 aryl groups, C 7 _ 14 aralkyl groups, C 6 . 14 aryl-C 2 - 6 alkenyl groups, aromatic heterocyclic groups, aromatic heterocyclic-Ci. 6 alkyl groups, and aromatic heterocyclic-C 2 .
  • Preferable examples of the compound represented by the formula (I) or (II) include 5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-oxazolidinedione; 5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[(E)-2- phenylethenyl]-4-thiazolylmethyl]-2,4-oxazolidinedione; 5-[3-[4-[2-[(E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[ (E)-2- phenylethenyl]-4
  • salts of the object compounds (I) and (II) of this invention pharmaceutically acceptable ones are preferable, as exemplified by salts with an inorganic base, salts with an organic base, salts with an inorganic acid, salts with an organic acid and salts with a basic or acidic amino acid.
  • salts with an inorganic base include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts, ammonium salts or the like.
  • salts with an organic base include those with, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,N'- dibenzylethylenediamine.
  • salts with an inorganic acid include those with, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid.
  • salts with an organic acid include those with, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p- toluenesulfonic acid.
  • Preferable examples of salts with a basic amino acid include those with, for example, arginine, lysine or ornithine, and, preferable examples of salts with an acidic amino acid include those with, for example, aspartic acid or glutamic acid.
  • the object compounds (I) and (II) or their salts can be used as hydrate.
  • the object compounds (I) and (II) or their pharmaceutically acceptable salts of the present invention are low in toxicity and can be used as a medicine as such or as a pharmaceutical composition, for mammals including man (e.g. horse, bovine, dog, cat, rat, mouse, rabbit, swine, monkey), prepared by mixing with a per se known pharmaceutically acceptable carrier, excipient and filler.
  • man e.g. horse, bovine, dog, cat, rat, mouse, rabbit, swine, monkey
  • the compounds (I) and (II) or their salts of this invention possess an activity of inhibiting the tumor cell growth or an activity of inhibiting tyrosine kinase, thus being useful as anticancer agents. More specifically, these compounds exert excellent effects as antitumor agents on inhibiting principally the growth of malignant tumors occurring on breast, remote metastatic breast cancer onto organs including e.g. lymph node, bone, brain and liver, and primary and nodal breast cancer aggravated and recurred after treatment, by inhibiting growth of, among human tumor cells, especially human breast cancer cell strains selectively.
  • the compounds (I) and (II) or their salts of this invention are useful also as therapeutic agents of diabetes, based on an action of enhancing insulin- sensitivity.
  • the compounds (I) and (II) or their salts of this invention are low in toxicity and can be administered safely.
  • oral administration of the compound of Working Example 36 at a dose of 10 mg/kg/day for 14 days to mice killed no test animals, causing no change in body weight.
  • a compound (I), (II) or a salt thereof as a medicine to mammals including man is usually performed orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules) , powdery preparations and granular preparations, and, depending on cases, non-orally in the form of, for example, injections, suppositories and pellets.
  • the dosage of a compound (I), (II) or a salt thereof varies depending on the administration route, the condition of a patient and the like, in the case of oral administration to a patient (40 to 80 kg body weight) having a malignant tumor, it ranges from 0.05 to 200 mg/kg, preferably from 0.1 to 100 mg/kg, especially from 5 to 50 mg/kg per day, desirably dividing this amount into once to three times a day.
  • the object compounds (I) and (II) or their salts of this invention, mixed with pharmaceutically acceptable carriers, can be administered orally or non- orally in the form of solid preparations such as tablets, capsules, granules and powdery preparations; or in the form of liquid preparations such as syrups and injections.
  • the pharmaceutically acceptable carriers use is made of conventional organic or inorganic carriers for pharmaceutical preparations, more specifically, for example, excipients, lubricants, binders and disintegrators for solid preparations; and solvents, solubilizers, suspending agents, isotonizers, buffering agents and local anesthetic agents for liquid preparations. And, upon necessity, such additives as antiseptics, antioxidants, colorants and sweetners are further used.
  • excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose and light silicon dioxide.
  • lubricants include magnesium stearate, calcium stearate, talc and colloid silica.
  • binders include crystalline cellulose, sugar, D- mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinyl pyrrolidine.
  • disintegrators include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, crosscarmellose sodium and carboxymethyl starch sodium.
  • solvents include distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil.
  • solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-amino methane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.
  • suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.
  • isotonizers include sodium chloride, glycerin and D-mannitol.
  • buffering agents include buffer solutions of phosphates, acetates, carbonates and citrates.
  • Preferable examples of local anesthetic agents include benzyl alcohol.
  • Preferable examples of antiseptics include para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • Preferable examples of antioxidants include sulfites and ascorbic acid.
  • the pharmaceutical preparation of this invention can be formulated in accordance with a conventional method, by allowing the object compound (I), (II) or a salt thereof to be contained in an amount of 0.1 to 90% (w/w) relative to the total weight of the preparation.
  • the compound (II) or a salt thereof of this invention (hereinafter containing the compound (I) or a salt thereof) can be produced by, for example, the following methods. Additionally stating, in the following production methods, excepting the compound of the formula (VI), not only the compounds shown by the respective formulae but also their salts may optionally be used. Examples of these salts include those set forth as the salts of the compounds (I) and (II). And, in each production method, when the product is obtained as a free form, it can be converted to the corresponding salt, and, when the product is obtained as a salt, it can be converted to the free compound in accordance with a conventional method.
  • halogen atoms e.g. chlorine, bromine, fluorine
  • methanesulfonyloxy benzonesulfonyloxy and p-toluenesulfonyloxy.
  • the compound (I) is produced by subjecting the compound (II-l) to condensation with the compound (III). This reaction is conducted, in accordance with a conventional method, in an adequate solvent in the presence of a base.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dioxane, tetrahydrofuran and dimethoxyethane
  • ketones such as acetone and 2- butanone
  • N,N-dimethylformamide dimethyl sulfoxide
  • halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2- tetrachloroethane; and a mixed solvent of them.
  • alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate
  • amines such as pyridine, triethylamine and N,N-dimethyl aniline
  • metal hydrides such as sodium hydride and potassium hydride
  • sodium ethoxide sodium methoxide and potassium tert.- butoxide.
  • the amount of these bases to be employed ranges, preferably, from 1 to 5 molar equivalents relative to the compound (II-l).
  • the reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C.
  • the reaction time ranges from 0.5 to 50 hours.
  • the compound (I) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
  • R stands for hydrogen atom or a lower alkyl group, and other symbols are of the same meaning as defined above.
  • alkyl group shown by R mention is made of C j . ⁇ one such as methyl, ethyl, propyl, isopropyl, butyl and tert.-butyl.
  • the compound (II-2) is condensed with the compound (IV) to produce the compound (II-3).
  • This reaction is conducted in a solvent similar to that in Method A and in the presence of a base similar to that in Method A.
  • the amount of the base to be used ranges, preferably, from 2 to 5 molar equivalents relative to the compound (II-2).
  • the amount of the compound (IV) to be used ranges, preferably, from 0.8 to 1.2 molar equivalents relative to the compound (II- 2 ) .
  • the reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C.
  • the reaction time ranges from 0.5 to 50 hours.
  • the compound (II-3) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
  • the compound (II-2) is condensed with the compound (III) to produce the compound (I-l), then the compound (I-l) is condensed with the compound
  • the compounds (I-l) and (1-2) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography .
  • the compound (II-2) is condensed with the compound (III) to produce the compound (1-3).
  • This reaction is conducted in a solvent similar to that in Method A and in the presence of a base similar to that in Method A.
  • the amount of the base to be used ranges preferably form 2 to 5 molar equivalents relative to the compound (II-2).
  • the amount of the compound (III) to be used ranges preferably from 2 to 5 molar equivalents relative to the compound (II-2).
  • the reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C.
  • the reaction time ranges from 0.5 to 50 hours.
  • the compound (1-3) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
  • Method E The compound (II-l) to be employed in Method A can be produced, in accordance with Method E, from the compound (V) .
  • T stands for CHO or -CH(J) 2 ' (J stands for a lower alkoxy, a lower alkylthio or a lower acylthio), and other symbols are of the same meaning as defined above.
  • Examples of the lower alkoxy include C j .z, ones such as methoxy, ethoxy, propoxy, isopropoxy and butoxy.
  • Examples of the lower alkylthio include C ⁇ ones such as methylthio, ethylthio, propylthio, isopropylthio and butylthio.
  • Examples of the lower acyloxy include C j . ⁇ ones such as acetyloxy and propionyloxy.
  • -CH(J) 2 two J's may optionally be combined with each other to form ethylenedioxy, propylenedioxy and dithiotrimethylene, for example.
  • - CH(J) 2 means a protected aldehyde group.
  • the compound (V) is condensed with the compound (VI) to produce the compound (II-4).
  • This condensation reaction is conducted in a solvent in the presence of a base.
  • the solvent examples include alcohols such as methanol, ethanol, propanol, isopropanol and 2- methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; N,N- dimethylformamide; dimethyl sulfoxide and acetic acid.
  • alcohols such as methanol, ethanol, propanol, isopropanol and 2- methoxyethanol
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran
  • N,N- dimethylformamide dimethyl sulfoxide and acetic acid.
  • sodium alkoxide e.g.
  • the amount of the compound (VI) to be used ranges from 1 to 10 molar equivalents, preferably from 1 to 5 molar equivalents relative to the compound (V) .
  • the amount of the base to be employed ranges from 0.01 to 5 molar equivalents, preferably from 0.05 to 2 molar equivalents, relative to the compound (V) .
  • the reaction temperature ranges from about 0 to
  • reaction time ranges from 0.5 to 30 hours.
  • the compound (II-4) thus produced is obtained, in some instances, as a mixture of (E) compound and (Z) compound relative to the double bond at the 5-position of the azolidine ring.
  • the compound (II-4) is subjected to reduction to produce the compound (II-5).
  • This reduction reaction is conducted, in accordance with a conventional method, in a solvent in the presence of a catalyst under hydrogen atmosphere of 1 to 150 atmospheric pressure.
  • the solvent examples include alcohols such as methanol, ethanol, propanol, isopropanol and 2- methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1, 1,2,2-tetrachloroethane; ethyl acetate; acetic acid and a mixture solvent of them.
  • alcohols such as methanol, ethanol, propanol, isopropanol and 2- methoxyethanol
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran
  • halogenated hydrocarbons such as chloroform, dichloromethan
  • the reaction is conducted more advantageously by employing, as the catalyst, a metal such as a nickel compound and a zinc compound; or a transition metal such as palladium, platinum and rhodium.
  • a metal such as a nickel compound and a zinc compound; or a transition metal such as palladium, platinum and rhodium.
  • the reaction temperature ranges from 0 to 150°C, preferably from 10 to 120°C.
  • the reaction time ranges from 0.5 to 100 hours.
  • the compounds (II-4) and (II-5) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
  • the compound (V) to be employed in Method E can be produced in accordance with, for example the method described in JPA H7 ( 1995)-101945.
  • JPA H7(1995)- 101945 the method of producing the compound (VII) shown by the following formula is described.
  • R 8 stands for isopropyl or benzyl group
  • R 7 stands for a lower alkyl group
  • G stands for a halogen atom
  • q denotes 1,3,4,5 or 6
  • R 9 and R10 independently stand for a lower alkyl group or an aralkyl group, and other symbols are of the same meaning as defined above.
  • C ⁇ alkyl e.g. methyl, ethyl, propyl, isopropyl, butyl and isobutyl
  • C tt alkyl e.g.
  • the aralkyl group shown by R means alkyl groups having an aryl group as the substituent (i.e. an arylalkyl group).
  • aryl group mention is made of, for example, phenyl and naphthyl, and these groups may optionally have, as the substituents, for example, the above-mentioned lower alkyl groups (C ⁇ ones), halogen atoms (fluorine, chlorine, bromine and iodine), hydroxyl group, and nitro group.
  • alkyl group in the arylalkyl group mention is made of C ⁇ z , ones such as methyl, ethyl and propyl .
  • Preferable examples of the aralkyl group include benzyl, phenethyl, 3-phenylpropyl, (1- naphthyl)methyl and (2-naphthyl)methyl, and, among them, benzyl and phenethyl are preferable.
  • R As the lower alkyl group or aralkyl group shown by R , mention is made of similar ones to those shown by R 9 .
  • halogen atom shown by G mention is made of chlorine, bromine and iodine.
  • the carboxylic acid derivative (X) is produced by allowing the carbonyl derivative (VIII) to react with the phosphonium salt (IX)-
  • the reaction between the compound (VIII) and the compound (IX) is conducted in dimethyl sulfoxide in the presence of sodium hydride.
  • the amount of sodium hydride to be employed ranges from about 2 to 5 molar equivalents relative to the compound (VIII).
  • the amount of the compound (IX) to be used preferably ranges from about 1 to 3 molar equivalents relative to the compound (VIII).
  • the reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C.
  • the reaction time ranges from 0.5 to 50 hours.
  • the carboxylic acid derivative (X) is subjected to esterification to produce the compound (XI).
  • This esterification reaction can be conducted by a per se known method. Examples of such method include a method in which the compound (X) is esterified directly with alcohol (R OH) in the presence of an acid; a method in which a reactive derivative of the compound (X) such as acid anhydride, acid halide (acid chloride, acid bromide), imidazolide and a mixed acid anhydride (e.g.
  • the compound (XI) is subjected to catalytic reduction to produce the compound (XII).
  • This catalytic reduction can be conducted in substantially the same manner as in the reduction of the compound (II-4) in Method E.
  • the compound (XII) is allowed to react with oxalic acid ester (COOR ) 2 in the presence of a base.
  • the reaction of the compound (XII) with oxalic acid ester (COOR ) 2 is conducted, by a conventional method in a suitable solvent in the presence of a base.
  • the solvent examples include alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxy ethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; and halogenated hydrocarbons such as chloroform, dichloromethane and 1, 1,2,2-tetrachloroethane.
  • alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxy ethanol
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran
  • halogenated hydrocarbons such as chloroform, dichloromethane and 1, 1,2,2-tetrachloroethane.
  • the base mention is made of sodium ethoxide, sodium methoxide and potassium tert. -butoxide.
  • the amount of these bases to be employed preferably ranges from about 1 to 5 molar equivalents relative to the compound (XII), and the amount of the oxalic acid ester (COOR ) 2 to be employed ranges preferably from about 1 to 5 molar equivalents relative to the compound (XII).
  • the reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C.
  • the reaction time ranges from 0.5 to 50 hours.
  • the condensed product (XIII) thus obtained is subjected to decarboxylation reaction to produce -keto ester (XIV) .
  • This decarboxylation reaction is conducted under heating in hydrous dimethyl sulfoxide in the presence of sodium chloride or lithium chloride.
  • the amount of sodium chloride or lithium chloride to be used ranges from 1 to 5 molar equivalents .
  • the reaction temperature ranges from 50°C to 150°C, preferably from about 80°C to 120°C.
  • the reaction time ranges from 0.5 to 50 hours.
  • the ⁇ -keto ester (XIV) is subjected to reduction to produce the compound (XV) .
  • This reduction reaction can be conducted by a per se known method, for example, reduction with a metal hydride, reduction with a metal hydride complex, reduction with diborane and a substituted borane, or catalytic hydrogenati ⁇ n.
  • this reaction can be conducted by treating the compound (XIV) with a reducing agent.
  • the reducing agent include alkali metal borohydride (e.g.
  • metal hydride complex such as lithium aluminum hydride; metal hydride such as sodium hydride; an organotin compound (e.g. triphenyltin hydride), metals and metal salts such as a nickel compound and a zinc compound; a catalytic reduction agent using a transition metal catalyst such as palladium, platinum, rhodium and the like together with hydrogen; and diborane.
  • alkali metal borohydride e.g. sodium borohydride, lithium borohydride
  • This reaction is conducted in an organic solvent which does not interfere with the reaction.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxy ethanol; amides such as N,N-dimethylformamide; and a mixture of them, and, from among these solvents, a suitable one is selectively employed depending on kinds of the reducing agent.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachlor
  • the reaction temperature ranges from -20°C to 150°C, especially preferably from 0°C to 100°C.
  • the reaction time ranges from about 1 to 24 hours.
  • the cyclization reaction is conducted by a per se known method such as a method in which the compound (XV) is reacted with alkali metal cyanate; and a method in which the compound (XV) is reacted with urea in the presence of a base.
  • alkali metal cyanate potassium cyanate or sodium cyanate
  • the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxy ethanol and butanol; N,N-dimethylformamide (DMF); dimethyl sulfoxide; acetonitrile; and a mixture of them.
  • the amount of alkali metal cyanate ranges, relative to the compound (XV) , from 1 to 10 molar equivalents, preferably from 1 to 5 molar equivalents.
  • the reaction temperature ranges from 0 to 180°C, preferably from 30 to 150°C.
  • the reaction time ranges from 0.5 to 100 hours.
  • the alkali metal salt of the compound (II-6) thus obtained is processed with an acid by a conventional method to produce the compound (II-6) as a free form. This process with an acid is conducted in the presence or absence of a suitable solvent.
  • the solvent examples include alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxy ethanol and butanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachloroethane; ethyl acetate; acetonitrile; and a mixture of them.
  • alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxy ethanol and butanol
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran
  • excess amount of an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and hydrobro ic acid is preferably employed, while an organic acid such as acetic acid, citric acid and tartaric acid may also employed.
  • the compound (II-6) is subjected to the reaction with titanium tetrachloride to produce the compound (II-7).
  • the reaction of the compound (II-6) with titanium tetrachloride is conducted in an suitable organic solvent.
  • the solvent use is made of, suitably selectively, for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; or a mixture of them.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachloroethane
  • ethers such as diethyl ether, tetrahydrofuran and dioxane; or a mixture of them.
  • the amount of titanium tetrachloride to be used ranges from 1 to 10 molar equivalents, preferably from 1 to 5 molar equivalents, relative to the compound (
  • the reaction temperature ranges from -50°C to 100°C, and especially preferably from -20°C to 80°C.
  • the reaction time ranges from about 1 to 24 hours.
  • the 2,4-oxazolidinedione derivatives (II-6) and (II-7) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
  • the starting compound (IX) in Method F is produced by the method described in Journal of Medicinal Chemistry, 2_8, p.287, (1985).
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; N,N-dimethylformamide; dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2- tetrachloroethane; and a suitable mixture of them.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dioxane, tetrahydrofuran and dimethoxyethane
  • alcohols such as methanol, ethanol and propanol
  • N,N-dimethylformamide dimethyl sulfoxide
  • halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloro
  • Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate; amines such as pyridine, triethylamine and N,N-dimethyl aniline; metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide, sodium methoxide and potassium ter .- butoxide.
  • the amount of these bases to be employed ranges, preferably, from about 1 to 5 molar equivalents relative to the compound (VIII).
  • the amount of the compound (XVI) to be employed ranges from 1 to 5 molar equivalents, preferably from about 1 to 3 molar equivalents, relative to the compound (VIII).
  • the reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C.
  • the reaction time ranges from 0.5 to 30 hours.
  • the compound (XVII) is subjected to substantially the same catalytic reduction of the compound (II-4) in Method E to produce the compound (XVIII). Further, the compound (XVIII) is subjected to substantially the same reduction of the compound (XIV) in Method F to produce the alcohol derivative (XIX) •
  • the alcohol derivative (XIX) can be led, by a per se known method, for example, chlorination by using thionyl chloride, bromination by using phosphorus tribromide or mesylation by using methanesulfonyl chloride, to the compounds represented by the formula (XX) wherein W is Cl, Br or OS0 2 CH 3 , respectively.
  • the compound (XX) is allowed to react with potassium cyanide or sodium cyanide in a suitable solvent to produce the compound (XXI).
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol, and propanol; N,N-dimethylformamide; dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2- tetrachloroethane; ketones such as acetone and 2- butanone; and a mixture of them.
  • the amount of potassium cyanide or sodium cyanide to be used ranges preferably from about 1 to 5 molar equivalents relative to the compound (XX) .
  • the reaction temperature ranges usually from 0°C to 150°C, preferably from about 20°C to 100°C.
  • the reaction time ranges from 0.5 to 30 hours.
  • the compound (XXI) is subjected to hydrolysis to produce the carboxylic acid derivative (XXII).
  • This hydrolysis is conducted, preferably, in an aqueous solvent in the presence of potassium hydroxide or sodium hydroxide.
  • the compound (XXIII) is produced by subjecting the carboxylic acid derivative (XXII) to substantially the same esterification of the compound (X) in Method F.
  • ester derivative (XXIII) thus obtained can be isolated and purified by a conventional isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
  • 2,4-oxazolidinedione derivatives (II-6) and (II-7) wherein q is 2 can be produced by substantially the same procedure as in the production of 2,4- oxazolidinedione derivatives (II-6) and (II-7) from the compound (XII) in Method F.
  • the 2, -oxazolidinedione derivative wherein A is a bond, and, Q and Z are oxygen atoms can be produced in accordance with the methods described in, for example, JPA H3(1991)-170478, Journal of Medicinal Chemistry, 3_4, p.1538 (1991), Japanese Patent Application under PCT laid-open under Kohyo No.H5(1994)-506456, WO92/02520 and the like, or the methods analogus thereto.
  • the reaction from the compound (XXIV) to the compound (XXV) is conducted in substantially the same manner as in the reaction from the compound (XIX) to the compound (XX) in Method G. Then, the compound (XXV) is subjected to a reaction with thiourea to produce the 2-iminothiazolidin-4-one derivative (XXVI). The reaction of the compound (XXV) with thiourea is conducted in a suitable solvent.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol, propanol and 2-methoxyethanol; N,N-dimethylformamide; dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane; sulfolan; and a mixture of them.
  • This reaction may optionally be conducted in the presence of a deoxidizing agent (e.g. sodium acetate, potassium acetate)
  • the amount of thiourea to be employed ranges preferably from 1 to 5 molar equivalents relative to the compound (XXV) .
  • the reaction temperature ranges usually from 0°C to 150°C, preferably from about 50°C to 120°C.
  • the reaction time ranges from 0.5 to 30 hours.
  • the compound (XXVI) is subjected, after isolation or without isolation, to acid hydrolysis to produce the 2,4-thiazolidinedione derivative (II-8).
  • This hydrolysis is conducted in a suitable aqueous solvent.
  • the solvent include ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol, propanol and 2- methoxyethanol; N,N-dimethylformamide; dimethyl sulfoxide; sulfolan; ketones such as acetone and 2- butanone; and a mixture of them.
  • the amount of the acid e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid
  • the reaction temperature ranges usually from 0°C to 150°C, preferably from about 50°C to 120°C.
  • the reaction time ranges from 0.5 to 30 hours.
  • the compound (II-8) thus obtained can be derived to the compound (II-9) in substantially the same manner as in the reaction from the compound (II-6) to the compound (II-7) in Method F.
  • the 2,4-oxazolidinedione derivative wherein A is a bond, Q is sulfur atom and Z is oxygen atom can be produced in accordance with the methods described in, for example, WO94/25026, WO94/05659, JPA under PCT laid-open under Kohyo No.H6( 1994)-502146, JPA HI(1989)- 131169, JPA S64(1989)-13088, JPA S64 ( 1989)-13076, JPA under PCT laid-open under Kohyo No.
  • R stands for a lower alkyl group or a substituted phenyl group, and other symbols are of the same meaning as defined above.
  • the lower alkyl group shown by R mention is made of C ⁇ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl).
  • the substituent in the substituted phenyl group shown by R mention is made of, for example, the above-mentioned lower alkyl groups (Cj. 4 ones), halogen atoms (fluorine, chlorine, bromine, iodine), hydroxyl group and nitro group.
  • This method provide a method of producing the 2,4- oxazolidinedione derivative (11-10) starting from ⁇ - hydroxyester represented by the formula (XXIV) containing the compound (XV) produced by Method F and the compound which is produced by subjecting the compound (XXIII) produced by Method G to the method of producing the compound (XV) from the compound (XII) in Method F.
  • the compound (XXIV) is subjected to hydrolysis to produce the ⁇ - hydroxycarboxylic acid derivative (XXVII).
  • the hydrolysis is conducted, in accordance with a per se known method, in an aqueous solvent in the presence of an acid or a base.
  • the solvent alcohols such as methanol and ethanol are preferable.
  • the amount of the base to be employed ranges from about 1 to 5 molar equivalents, and the amount of the acid to be employed is usually a large excess.
  • the compound (XXVII) is allowed to react with chlorocarbonic acid ester (C1COOR ), followed by allowing the reaction product to further react with ammonia to produce the compound (XXVIII).
  • the reaction of the compound (XXVII) with chlorocarbonic acid ester (C1COOR ) is conducted, in accordance with a conventional method, in a suitable solvent in the presence of a base.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dioxane, tetrahydrofuran and dimethoxyethane
  • halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachloroethane
  • alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate
  • amines such as pyridine, triethylamine and N,N-dimethyl aniline.
  • the amount of these bases to be employed is preferably about 2 to 5 molar equivalents relative to the compound (XXVII).
  • the amount of chlorocarbonic acid ester (ClCOOR ) to be employed is 2 to 5 molar equivalents, preferably about 2 to 3 molar equivalents, relative to the compound (XXVII) .
  • This reaction temperature ranges usually from -
  • reaction time ranges from 0.5 to 30 hours.
  • reaction temperature ranges from -30°C to 50°C, preferably from about -20°C to 30°C.
  • the reaction time ranges from 0.5 to 30 hours.
  • the compound (XXVIII) is led to the 2,4- oxazolidinedione derivative (11-10), in accordance with a conventional method, by processing the compound (XXVIII) with a base in a suitable solvent.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dioxane, tetrahydrofuran and dimethoxyethane
  • halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachloroethane
  • acetonitrile and a mixture solvent of these solvents .
  • alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate
  • amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8- diazabicyclo[5.4.0]undecen-7-ene (DBU) and 1,5- diazabicyclo[4.3.0]non-5-ene (DBN); sodium ethoxide, sodium methoxide and potassium tert.-butoxide.
  • the amount of these bases to be employed is preferably about 1 to 5 molar equivalents relative to the compound (XXVIII).
  • the reaction temperature ranges usually from -80°C to 50°C, preferably from about -50°C to 30°C.
  • the reaction time ranges form 0.5 to 30 hours.
  • the 2,4-oxazolidinedione derivative (11-10) thus obtained can be isolated and purified by a conventional isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
  • This reaction is conducted in a solvent, preferably, in the presence of triphenylphosphine and diethyl ester of azodicarboxylic acid.
  • a solvent preferably, in the presence of triphenylphosphine and diethyl ester of azodicarboxylic acid.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran
  • halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2- tetrachloroethane; and a mixture of them.
  • the respective amounts of triphenylphosphine and diethyl ester of azodicarboxylic acid to be used are, preferably, about 1 to 5 molar equivalents relative to the compound (XXX), and the amount of the compound (XXXI) to be used is preferably about 1 to 2 molar equivalents relative to the compound (XXX) .
  • the reaction temperature ranges usually from - 50°C to 100°C, preferably from about -30°C to 80°C.
  • the reaction time ranges from 0.5 to 50 hours.
  • the compound (XXIX) thus obtained can be isolated and purified by a conventional isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
  • Method K In this method, when the compounds produced in accordance with Method A, Method B, Method C, Method D, Method E, Method H or Method I contain methoxy group as a substituent on the ring E, these compounds are subjected to demethylation reaction to produce the corresponding phenol derivative.
  • This reaction is conducted by the reaction with alkyl mercaptan (e.g. ethyl mercaptan, dodecamercaptan) in a solvent in the presence of aluminum chloride.
  • alkyl mercaptan e.g. ethyl mercaptan, dodecamercaptan
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran
  • halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2- tetrachloroethane
  • the amount of aluminum chloride to be used ranges preferably from about 5 to 20 molar equivalents relative to the methoxy derivative
  • titanium tetrachloride to be used ranges preferably from about 5 to 20 molar equivalents relative to the methoxy derivative.
  • the reaction temperature ranges usually from -80°C to 100°C, preferably from about -50°C to 50°C.
  • the reaction time ranges from 0.5 to 50 hours.
  • the phenol derivatives thus obtained can be isolated and purified by a conventional isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
  • Test Example 1 Cell growth-inhibiting action in vitro A 100 ⁇ l (2,000 cells) each suspension of human breast cancer cells MDA-MB-453 or human pancreatic carcinoma cells AsPC-1 and, as human normal cells, fibroblast cells MRC5 derived from fetal lung was plated in 96-well microplates and incubated at 37°C in a 5% carbon dioxide incubator. On the following day, a 100 ⁇ l each solution of the respective test compounds in serial two-folds dilution was added, followed by incubation for 3 days .
  • the culture medium containing the test compounds was removed, and the cells were washed, to which was added a 0.4% (w/v) solution (dissolved in 1% acetic acid) of the dye SRB (sulforhodamine B) to fix and stain the cell protein.
  • SRB dye forhodamine B
  • the unbound dye was removed and the plates were washed, to which was then added 200 ⁇ l of an extracting solution (10 mM Tris buffer solution) to extract the dye.
  • the absorbance at 540 run of the absorption wave ⁇ length was measured and the cell amount was determined as the amount of protein.
  • the ratio of the remaining amount of protein in each test group assuming the amount of protein in the control group to which a solution of the test compound was not added as 100%, was determined to calculate the concentration, IC 50 value, of the compound required for suppressing the remaining cell amount to 50% of that of the control group.
  • the unbound dye was removed and the plates were washed, to which was then added 200 ⁇ l of an extracting solution (10 mM Tris buffer solution) to extract the dye.
  • the absorbance at 540 nm of the absorption wave-length was measured and the cell amount was determined as the amount of protein.
  • the ratio of the remaining amount of protein in each test group assuming the amount of protein in the control group to which a solution of the test compound was not added as 100%, was determined to calculate the concentration, IC 50 value, of the compound required for suppressing the remaining cell amount to 50% of that of the control group.
  • the precipitate was fractionated by protein electrophoresis, then, the protein in the electrophoresis gel was transferred to a nylon filter. This filter was allowed to react with a phosphorylated tyrosine specific antibody.
  • the reaction product was fluorescent-labeld and allowed to react with a sensitive film. The amount of light in the sensitive film was quantitatively determined by means of an image-analyzing device. Assuming the amount of phosphorylation of EGF-receptor tyrosine of cells in the group to which the epidermal growth factor EGF was added as 100%, the ratios of the amount of phosphorylation in the groups to which solutions of compounds of various concentrations were added were determined.
  • halegrin was added to extract protein in the same manner, to which was added an antibody against human EGF receptor type oncogene HER3 to allow the EGF receptor type oncogene HER3 protein to precipitate by immunoprecipitation.
  • This precipitate was subjected, in the same manner, to electrophoresis to thereby transfer the protein in the electrophoresis gel into nylon filter.
  • this filter was allowed to react with a phosphorylated tyrosine specific antibody.
  • the reaction product was fluorescent-labeled and allowed to react with a sensitive film. The amount of light in the sensitive film was quantitatively determined by means of an image analyzing device.
  • the compounds of this invention are found to exhibit an action of inhibiting the activation of receptor tyrosine kinase due to the stimulation of growth factor, and to inhibit the growth of tumor cells, especially to inhibit the growth of breast cancer cells selectively, while showing no cytotoxicity to the growth of normal cells.
  • NMR spectra show proton NMR and were measured using tetramethylsilane as an internal or external standard with VARIAN Gemini 200 (200 MH Z type spectrometer) . All 6 values were expressed in ppm. And, the abbreviations used in Working Examples have the following meanings . srsinglet, brrbroad, drdoublet, trtriplet, q:guartet, dd:double doublet, td:triple doublet, ddd:doublet doublet doublet, mtmultiplet, J:coupling constant, Hz:Hertz.
  • Reference Example 1
  • the concentrate was dissolved in dimethyl sulfoxide (DMSO) (60 ml) - water (6 m). To the solution was added sodium chloride (2.6 g) , and the mixture was stirred for 3 hours at 125°C. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ⁇ ,), and then concentrated. The concentrate was dissolved in ethanol (100 ml), to which was added dropwise, at 0°C, a solution of sodium borohydride (NaBH ⁇ ) (0.52 g) in ethanol (20 ml).
  • NaBH ⁇ sodium borohydride
  • the mixture was stirred for 30 minutes at 0°C, to which was added acetic acid (1.6 ml).
  • acetic acid 1.6 ml
  • the reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate.
  • the ethyl acetate layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, successively, which was dried (MgSO ⁇ ,) and then concentrated.
  • the concentrate was subjected to a silica gel column chromatography.
  • the mixture was stirred for 30 minutes at 85°C.
  • the mixture was cooled to room temperature, to which was added, in limited amounts at 25-30°C, (5-carboxypentyl)triphenylphosphonium bromide [(C 6 H 5 ) 3 P " (CH 2 ) 5 COOH.Br + ] (75.5 g).
  • the mixture was stirred for 15 minutes at room temperature, to which was then added, in limited amounts under ice-cooling, 4-benzyloxybenzaldehyde (31.8 g) .
  • the reaction mixture was stirred for 30 minutes at room temperature, which was poured into ice-water and acidified, followed by extraction with ethyl acetate.
  • Triethylamine (20.7 g) was added dropwise, at - 30°C, to a solution of 4-(4-benzyloxyphenyl)-2- hydroxybutanoic acid (28.0 g) in tetrahydrofuran (THF) (400 ml).
  • THF tetrahydrofuran
  • ethyl chlorocarbonate 22.3 g
  • the reaction mixture was stirred for 2.5 hours at temperatures ranging from -25 to -10°C.
  • the reaction mixture was then added dropwise at 0°C to a cone, aqueous ammonia (25%, 100 ml).
  • the mixture was stirred for 40 minutes at 0°C, which was then poured into water.
  • Reference Example 25 A mixture of 3-[3-methoxy-4-(5-methyl-2-phenyl-4- oxazolylmethoxy)phenyl]propionaldehyde (1.79 g) , sodium cyanide (0.3 g), acetic anhydride (0.62 g) , benzyltributylammonium chloride (0.79 g), water (12 ml) and dichloromethane (35 ml) was stirred for 15 hours at room temperature. The organic layer was separated, washed with water and dried (MgSO,) . The solvent was distilled off. The residual oily substance was subjected to a silica gel column chromatography.
  • Example 10 ethyl 4-benzyloxy-3-ethoxycinnamate was subjected to catalytic reduction to give ethyl 3-(3- ethoxy-4-hydroxyphenyl)propionate.
  • Example 38 ethyl 3-(3-ethoxy-4- hydroxyphenyl) ropionate was allowed to react with benzyl bromide to give ethyl 3-(4-benzyloxy-3- ethoxyphenyl)propionate.
  • Example 12 starting from ethyl 3-(4-benzyloxy-3- ethoxyphenyl)propionate, 4-(4-benzyloxy-3- ethoxyphenyl)-2-hydroxybutanoate was obtained.
  • Example 6 3-benzyloxy-4-methoxybenzaldehyde was allowed to react with triethyl phosphonoacetate to give ethyl 3-benzyloxy-4-methoxycinnamate.
  • Example 10 ethyl 3-benzyloxy-4-methoxycinnamate was subjected to catalytic reduction to give ethyl 3-(3- hydroxy-4-methoxyphenyl)propionate.
  • Example 34 ethyl 3-(3-hydroxy-4- methoxyphenyl)propionate was allowed to react with benzyl bromide to give ethyl 3-(3-benzyloxy-4- methoxyphenyl)propionate. Recrystallization from hexane gave colorless needles, m.p. 49.5-50.5°C
  • Example 34 syringaldehyde was allowed to react with benzyl bromide to give 4-benzyloxy-3,5- dimethoxybenzaldehyde. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 65-66°C.
  • Example 6 4-benzyloxy-3,5-dimethoxybenzaldehyde was allowed to react with triethyl phosphonoacetate to give ethyl 4-benzyloxy-3,5-dimethoxycinnamate.
  • the ethyl acetate layer was washed with water and dried (MgS0 4 ) , and, then, the solvent was distilled off to give an oily substance.
  • the oily substance was dissolved in hydrochloric acid - ethanol (5%, 80 ml), which was stirred for 30 minutes at 80°C.
  • the reaction mixture was poured into water, which was subjected to extraction with ethyl acetate.
  • the ethyl acetate layer was washed with water and dried (MgSO ) , and, then, the solvent was distilled off. The residue was subjected to a silica gel column chromatography.
  • the ethyl acetate layer was washed with water and a saturated aqueous saline solution, successively, which was dried (MgSO A ), then the solvent was distilled off.
  • the residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:4, v/v), an oily product (14.5 g) was obtained. This oily product was dissolved in ethanol (250 ml), to which was added palladium-carbon (5%, 50% wet, 5.0 g) .
  • the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated.
  • Methanesulfonyl chloride (8.4 g) was added dropwise to an ice-cooled mixture of 7-(4- benzyloxyphenyl)heptanol (8.4 g) , triethylamine (2.8 g) and ethyl acetate (100 ml), followed by stirring for 30 minutes at the same temperature.
  • the reaction mixture was washed with water, dried (MgS0 A ) and, then, concentrated to give 7-(4-benzyloxyphenyl)heptyl methanesulfonate (9.9 g, 94%).
  • Example 10 ethyl (E,E)-5-(4-benzyloxy-3-ethoxyphenyl)- 2,4-pentadienoate was subjected to catalytic reduction to give ethyl 5-(3-ethoxy-4-hydroxyphenyl)pentanoate.
  • Example 34 ethyl 5-(3-hydroxy-4- methoxyphenyl)pentanoate was allowed to react with benzyl bromide to give ethyl 5-(3-benzyloxy-4- methoxyphenyl)pentanoate.
  • TiCl A titanium tetrachloride
  • dichloromethane 10 ml
  • 5-[3-(4-isopropoxy-3- methoxyphenyl)propyl]-2,4-oxazolidinedione 4.3 g
  • the mixture was stirred for one hour at 0°C, which was poured into 2N HCl.
  • the mixture was stirred for 15 minutes at room temperature.
  • the organic layer was separated, and the aqueous layer was subjected to extraction with chloroform.
  • the concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (2:3, v/v), 5-[3-(4- hydroxyphenyl)propyl]-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethyl]-2,4-oxazolidinedione (0.28 g, 52%) was obtained as an oily product.
  • the mixture was subjected to catalytic reduction at room temperature under hydrogen pressure of 3.8 kgf/cm .
  • the catalyst was filtered off, and the filtrate was concentrated under reduced pressure.
  • the concentrate was subjected to a silica gel column chromatography. From the fraction eluted with chloroform - ethyl acetate (9:1, v/v), 5-[3-(4- isopropoxyphenyl)propyl]-2,4-thiazolidinedione (3.61 g, 39%) was obtained as an oily product.
  • Example 6 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-5-methyl-2-[ (E)-2-phenylethenyl]thiazole to give 5-[4-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- thiazolylmethoxy]phenyl]butyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 167-168°C Working Example 50
  • Example 3 4-benzyloxy-3,5-dimethoxycinnamaldehyde was subjected to condensation with 2, 4-oxazolidinedione to give 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave yellow prisms, m.p. 181-182°C.
  • 1-Dodecanethiol (2.37 g) was added, at 0 °C, to a suspension of aluminum chloride (1.56 g) in dichloromethane (30 ml). The mixture was stirred for 10 minutes, to which was then added dropwise, at the same temperature, a solution of 5-[3-[4-[2-(2-furyl)-5- methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4- oxazolidinedione (0.5 g) in dichloromethane (10 ml) . The reaction mixture was stirred for 2 hours at room temperature, which was then poured into ice-water, followed by extraction with dichloromethane.
  • Example 15 5-(4-hydroxybenzyl)-2,4-thiazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenyl]oxazole to give 5-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]benzyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-thiazolidinedione, Recrystallization from acetone-ethanol gave colorless prisms, m.p. 165-166 °C.
  • Example 4 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)- 2,4-thiazolidinedione was subjected to catalytic reduction to give 5-[3-(4-benzyloxy-3,5- dimethoxyphenyl)propylJ-2,4-thiazolidinedione.
  • 2,4-thiazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [3-[3,5-dimethoxy-4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJpropylJ-2,4-thiazolidinedione.
  • Example 1 5-[ 3-[3,5-dimethoxy-4-[2-[ (E)-2- phenylethenylj-4-oxazolylmethoxyJphenylJpropylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [3-[3,5-dimethoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJpropyl]-3-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethyl]-2,4-oxazolidinedione as an oily product.
  • the aqueous layer was basified with an aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with ethyl acetate.
  • the ethyl acetate layer was washed with water and dried (MgS0 ) . Then, the solvent was distilled off, and the residual oily substance was dissolved in ethyl acetate (5 ml). To this solution was added hydrochloric acid - ethanol (10%, 0.8 ml), which was concentrated under reduced pressure.
  • Example 47 ethyl 6-(3-benzyloxy-4-methoxyphenyl)-2- hydroxyhexanoate was allowed to react with potassium cyanate (KCNO) to give 5-[4-(3-benzyloxy-4- methoxyphenyl)butylJ-2,4-oxazolidinedione as an oily product.
  • KCNO potassium cyanate
  • 2,4-oxazolidinedione was subjected to catalytic reduction to give 5-[4-(3-hydroxy-4- methoxyphenyl)butylJ-2,4-oxazolidinedione, m.p. 90- 91°C.
  • Example 6 5-(4-hydroxybenzyl)-2,4-thiazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenylJoxazole to give 5-[4-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJbenzyl]-2,4- thiazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 182-183°C
  • Example 6 5-[4-(3-hydroxy-4-methoxyphenyl)butylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [4-[4-methoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJbutylJ-2,4-oxazolidinedione. Recrystalization from ethyl acetate gave colorless needles, m.p. 159-160°C.
  • Working Example 136 5-[4-(3-hydroxy-4-methoxyphenyl)butylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [4-[4-methoxy-3-[2-[ (E)-2-phenylethenyl]
  • Example 119 3-(3-chloropropyl)-5-[2-[4-methoxy-3-[2- [(E)-2-phenylethenylJ-4-oxazolylmethoxyJphenylJethylJ- 2,4-oxazolidinedione was allowed to react with l-(4- trifluoromethylphenyl)piperazine to give 5-[2-[4- methoxy-3-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJethyl]-3-[3-[4-(4- trifluoromethylphenyl)piperazin-1-ylJpropylJ-2,4- oxazolidinedione as an oily product.
  • This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
  • Example 1 5-[2-[3-[3-[4-(3-chlorophenyl)piperazin-l- ylJpropoxyJ-4-methoxyphenylJethyl]-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenylJoxazole to give 5-[2-[3-[3-[4-(3- chlorophenyl)piperazin-1-yl)propoxy]-4- methoxyphenyl]ethylJ-3-[2-[(E)-2-phenylethenylJ-4- oxazolylmethylJ-2,4-oxazolidinedione as an oily product.
  • This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
  • Example 3 4-benzyloxycinnamaldehyde was subjected to condensation with 1-methylhydantoin to give 5-(4- benzyloxycinnamylidene)-l-methylhydantoin, which was subjected to catalytic reduction in substantially the same manner as in Working Example 4 to give 5-[3-(4- hydroxyphenyl)propylJ-1-methylhydantoin. Recrystalization from N,N-dimethylformamide (DMF) - water gave colorless prisms, m.p. 179-180°C.
  • DMF N,N-dimethylformamide
  • Example 15 5-[3-(4-hydroxyphenyl)propylJ-l- methylhydantoin was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 1- methyl-5-[3-[4-[2-[(E)-2- phenylethenyl]oxazolylmethoxy]phenyl]propyl]-3-[2-[(E)-
  • Example 107 5-[2-(3-benzyloxy-4-methoxyphenyl)ethylJ- 2,4-oxazolidinedione was allowed to react with l-(3- chloropropyl)-4-phenylpiperazine to give 5-[2-(3- benzyloxy-4-methoxyphenyl)ethyl ]-3-[3-(4- phenylpiperazin-1-yl)propylJ-2,4-oxazolidinedione as an oily product.
  • a mixture of 10.0 mg of the compound of Working Example 36, 60.0 mg of lactose and 35.0 mg of corn starch was granulated, by using 0.03 ml of a 10 weight % aqueous solution of gelatin (3.0 mg in terms of gelatin), through a sieve of 1 mm mesh.
  • the granules were dried at 40 °C, which were again subjected to sieving.
  • the resulting granules were mixed with 2.0 mg of magnesium stearate, which was compressed.
  • Thus- obtained core tablets was sugar-coated with a suspension consisting of sucrose, titanium dioxide, talc and gum arabic, followed by polishing with bee wax.
  • a mixture of 10.0 mg of the compound of Working Example 36 and 3.0 mg of magnesium stearate was granulated by using 0.07 ml of an aqueous solution of soluble starch (7.0 mg in terms of soluble starch) and dried, which was mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture was compressed to give a tablet.

Abstract

A heterocyclic compound represented by formula (I), wherein D stands for H or an optionally substituted hydrocarbon group; X stands for CH or N; A stands for a divalent aliphatic hydrocarbon group; R stands for an optionally substituted hydrocarbon group; Q stands for -N(R0)- (R0 stands for hydrogen atom or a lower alkyl), O or S; Z stands for O or S; L and M independently stand for H, or they may optionally be combined with each other to form a bond; ring E may optionally be further substituted, and the substituent may optionally be combined with D to form a ring; or a salt thereof; which is useful as an antitumor agent.

Description

DESCRIPTION HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND USE
TECHNICAL FIELD This invention relates to a novel heterocyclic compound useful as a medicine especially an antitumor agent, a method of producing it and a preparation comprising it.
BACKGROUND ART
In JPA S55(1980)-22636 (EP-A 8203), thiazolidine derivatives represented by the formula:
Figure imgf000003_0001
wherein R stands for an alkyl group, a cycloalkyl group, a phenylalkyl group, phenyl group, a 5- or 6- membered heterocyclic group having one or two hetero- atoms selected from nitrogen atom, oxygen atom and sulfur atom, or a group represented by the formula:
: - wherein R and R independently stand for a lower alkyl group or R and R are combined with each other directly or through a hetero-ato selected from nitrogen atom, oxygen atom and sulfur atom to optionally form a 5- or 6-membered ring, taken together with the nitrogen atom adjacent to R and R ;
2
R stands for a bond or a lower alkylene group;
L 1 and L2 independently stand for, when R1 is an alkyl group, a lower alkyl group, or they may optionally be combined with each other to form an alkylene group, and, when R is not an alkyl group, L and L may, besides the above definition, optionally be hydrogen atom; are described, and there is also disclosed that these compounds have an activity of lowering lipid in blood and sugar in blood.
In JPA H7(1995)-165735 (EP-A 612743), 2,4- oxazolidine derivatives represented by the formula:
Figure imgf000004_0001
wherein R stands for an optionally substituted hydrocarbon residue, or heterocyclic group; Y stands for a group shown by -CO-, -CH(OH)- or NR 3- (wherein R3 stands for an optionally substituted alkyl group); m denotes 0 or 1; n denotes 0, 1 or 2; X stands for CH or N; A stands for a C,_7 divalent aliphatic hydrocarbon residue; R and Rz independently stand for hydrogen atom or an alkyl group, or R and R combine with each other to form a 5- to 6-membered heterocyclic group, optionally containing nitrogen; L and M respectively stand for hydrogen atom, or L and M may optionally be combined with each other to form a bond; and their salts as well as their use as a therapeutic agent of diabetes mellitus are disclosed.
In JPA H6(1994)-157522 (EP-A 590793), there is disclosed that thiazolidine derivatives represented by the formula:
Figure imgf000004_0002
wherein R stands for a C^g straight-chain or branched alkyl group; X stands for oxygen atom or sulfur atom; Y stands for hydrogen atom or a group: -A-COOH (A stands for a C .6 straight chain or branched alkylene group) ; Ar stands for a C6.10 aryl group optionally having the same or different one to five substituents (a), and the said substituents (a) include halogen, haloalkyl having Cj.ή straight-chain or branched alkyl, hydroxy, Cj_A straight-chain or branched alkyl or C^ straight-chain or branched alkoxy; are useful as prophylactic and/or therapeutic agents of, among others, hyperglycemia, hyperlipemia and obesity.
However, use of these azolidine compounds as antitumor agent has not been known.
So far, the study of antitumor agents has been conducted broadly, and antitumor agents having less side-effects and being of a high practical value are desired. For example, even in the case of early breast cancer in which no metastatis is observed, in spite of ardent study on adjuvant chemotherapy by combination of known antitumor agents, the therapeutic effects are only temporary and no radical cure of the patient has been observed while involving a risk of side-effects and secondary carcinogenesis caused by a drug. Further, it is considered that adjuvant therapy is not applicable to patients with invasive progressive breast cancer [c.f.: e.g. "Adjuvant Therapy for Node-Negative Breast Cancer", Section 11 of "Important Advances in Oncology 1990" Edited by DeVita, Hellman and Rosenberg, Published by J. B. Lippincott Company (Philadelphia) 1990, p.183]. Therefore, development of antitumor agents which suppress cancer cells selectively and are based on a novel action mechanism is awaited.
The object of this invention is to provide such a novel antitumor agent having less side-effects and based on a novel action mechanism.
DISCLOSURE OF INVENTION As a result of various studies for accomplishing the above-mentioned object, the present inventors succeeded in synthesizing, for the first time, a heterocyclic compound [hereinafter simply called "compound (I)"], whose characteristic feature on the chemical structure lies in that the 3-position of the azolidine is substituted and the 5-position is substituted with a side chain via two or more carbon atoms, which is represented by the formula (I):
Figure imgf000006_0001
wherein D stands for hydrogen atom or an optionally substituted hydrocarbon group; X stands for CH or N;
A stands for a divalent aliphatic hydrocarbon group; R stands for a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group, (2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) a hydroxyl group optionally substituted by a hydrocarbon group or an acyl group, (7) a thiol group optionally substituted by a hydrocarbon group or an acyl group, (8) an optionally esterified carboxyl group, (9) cyano group or (10) oxo group; Q stands for -N(R )- (R stands for hydrogen atom or a lower alkyl group), oxygen atom or sulfur atom; Z stands for oxygen atom or sulfur atom; L and M independently stand for hydrogen atom, or they may optionally be combined with each other to form one bond; and ring E may optionally be further substituted, and the substituent may optionally be combined with D to form a ring; or a salt thereof, and found that this compound (I) has, unexpectedly, an excellent suppressing action of tyrosine kinase based on the specific chemical structure and can be safely used as an antitumor agent, Based on these finding, the present invention has been accomplished. More specifically, the present invention relates to: (1) the compound (I) or a salt thereof;
(2) a pharmaceutical composition comprising the compound (I) or a salt thereof;
(3) an antitumor agent comprising a compound of the formula:
Figure imgf000007_0001
wherein D stands for hydrogen atom or an optionally substituted hydrocarbon group; X stands for CH or N; A stands for a bond or a divalent aliphatic hydrocarbon group;
R stands for hydrogen atom or a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group, (2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) a hydroxyl group optionally substituted by a hydrocarbon group or an acyl group, (7) a thiol group optionally substituted by a hydrocarbon group or an acyl group, (8) an optionally esterified carboxyl group, (9) cyano group or (10) oxo group;
Q stands for -N(R°)- (R stands for hydrogen atom or a lower alkyl group) , oxygen atom or sulfur atom; Z stands for oxygen atom or sulfur atom; L and M independently stand for hydrogen atom, or they may optionally be combined with each other to form one bond; and ring E may optionally be further substituted, and the substituent may optionally be combined with D to form a ring; and when A stands for a bond, D stands for an optionally substituted hydrocarbon group; or a salt thereof;
(4) a tyrosine kinase inhibitor which comprises the compound (II) or a salt thereof;
(5) a method of producing a compound represented by the formula:
Figure imgf000008_0001
wherein symbols are of the same meaning as defined above, or a salt thereof, which is characterized by allowing a compound represented by the formula:
Figure imgf000008_0002
wherein symbols are of the same meaning as defined above, or a salt thereof to react with a compound represented by the formula: R- wherein stands for a leaving group and R is of the same meaning as defined above, or a salt thereof; and (6) a method of producing a compound represented by the formula:
Figure imgf000008_0003
wherein symbols are of the same meaning as defined above, or a salt thereof, which is characterized by allowing a compound represented by the formula:
Figure imgf000009_0001
wherein symbols are of the same meaning as defined above, or a salt thereof to react with a compound represented by the formula: R- wherein W stands for a leaving group and R is of the same meaning as defined above, or a salt thereof.
In the above formulae, D stands for hydrogen atom or an optionally substituted hydrocarbon group. As the hydrocarbon group shown by D, mention is made of, for example, aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, aromatic hydrocarbon groups, aromatic-aliphatic hydrocarbon groups and alicyclic-aliphatic hydrocarbon groups. As the aliphatic hydrocarbon groups, use is made of, for example, CJ.JQ aliphatic hydrocarbon groups. Examples of the aliphatic hydrocarbon groups include cι-ιof preferably Cj.g saturated aliphatic hydrocarbon groups (e.g. alkyl group) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.- butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl, isohexyl, heptyl, octyl, and decyl; and C2__.ι0r preferably C2_8 unsaturated aliphatic hydrocarbon groups (e.g. alkenyl group, alkadienyl group, alkynyl group, alkadiynyl group) such as vinyl (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, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5- hexynyl, 1-heptynyl, 1-octynyl and geranyl.
As the alicyclic hydrocarbon groups, use is made of, for example, C _7 alicyclic hydrocarbon groups. Examples of the alicyclic hydrocarbon groups include C3_7 saturated alicyclic hydrocarbon groups (e.g. cycloalkyl group) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; and C5.7 unsaturated alicyclic hydrocarbon groups (e.g. cycloalkenyl group, cycloalkadienyl group) such as 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1- cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, and 2,4-cycloheptadienyl . As the aromatic hydrocarbon groups, mention is made of, for example, C6.14 aromatic hydrocarbon groups. Examples of the aromatic hydrocarbon groups include C6_ aryl groups such as phenyl and naphthyl (α-naphthyl, β-naphthyl) . As the aromatic-aliphatic hydrocarbon groups, mention is made of, for example, C7_20 aromatic- aliphatic hydrocarbon groups . Examples of the aromatic-aliphatic hydrocarbon groups include C7. aralkyl groups (e.g. benzyl, 2-phenylethyl) and Cg.^ aryl-C2_6 alkenyl groups (e.g. styryl(2-phenylethenyl) , 2-(2-naphthyl)vinyl, 4-phenyl-l,3-butadienyl) .
As the alicyclic-aliphatic hydrocarbon groups, mention is made of, among those formed by combination of the above-mentioned alicyclic hydrocarbon groups with aliphatic hydrocarbon groups, d,.-, ones. Examples of the alicyclic-aliphatic hydrocarbon groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3- cyclop tenylmethyl, cyclohexylmethyl, 2- cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, and cycloheptylethyl.
The hydrocarbon group shown by D is preferably an aliphatic hydrocarbon group, more preferably a Cj.6 aliphatic hydrocarbon group. The hydrocarbon group shown by D may optionally have, at any possible position, 1 to 4 substituents selected from, for example, "an optionally substituted heterocyclic group", "an aliphatic chain hydrocarbon group", "an alicyclic hydrocarbon group", "an optionally substituted aromatic hydrocarbon group", "an aromatic-aliphatic hydrocarbon group", "a halogen atom", "nitro group", "an optionally substituted amino group", "an optionally substituted acyl group", "an optionally substituted hydroxyl group", "an optionally substituted thiol group", "an optionally esterified carboxyl group", "cyano group" and "oxo group". The heterocyclic group in "the optionally substituted heterocyclic group" as the substituent of the hydrocarbon group shown by D includes, for example, 5- to 7-membered heterocyclic groups containing in addition to carbon atom, as a ring component atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and condensed ring groups. Examples of the 5- to 7-membered heterocyclic groups include a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, a 5- to 6- membered heterocyclic group containing two to four nitrogen atoms and a 5- to 6-membered heterocyclic group containing one or two nitrogen atoms and one sulfur atom or oxygen atom.
Examples of the condensed ring groups include, for example, those formed by condensation of the above- mentioned 5- to 7-membered heterocyclic groups with a 6-membered ring containing two or less nitrogen atom, benzene ring or a 5-membered ring containing one sulfur atom. Specific examples of these heterocyclic groups include pyran, dihydropyran, tetrahydropyran, chroman, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3- pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3- pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4- oxazolyl, 5-oxazolyl, 1,2,4-triazol-3-yl, 1,3,4- triazol-2-yl, l,2,3-triazol-4-yl, tetrazol-5-yl, benzimidazol-2-yl, indol-3-yl, benzpyrazol-3-yl, 1H- pyrrolo[2,3-b]pyrazin-2-yl, lH-pyrrolo[2,3-b]pyridin-6- yl, lH-imidazo[4,5-b]pyridin-2-yl, lH-imidazo[4,5- c]pyridin-2-yl, lH-imidazo[4,5-b]pyrazin-2-yl, furyl, thienyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, triazinyl, benzofuranyl, isobenzofuranyl, benzofb]thienyl, isoindolyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H- benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α- carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl, indolidinyl, pyrrolo[ l,2-b]pyridazinyl, pyrazolof1,5-aJpyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and l,2,4-triazolo[4,3-b]pyridazinyl . Among these, oxazolyl, thiazolyl and triazolyl are preferable, and oxazolyl or thiazolyl is more preferable.
Examples of "the aliphatic chain hydrocarbon group" as the substituent of the hydrocarbon group shown by D include Cx.15 straight-chain or branched aliphatic hydrocarbon groups as exemplified by alkyl groups, alkenyl groups, and alkynyl groups .
Preferable examples of the alkyl groups include CJ.JO alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, 1- ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbuty1, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl . Preferable examples of the alkenyl groups include C2-ιo alkenyl groups such as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl- 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl . Preferable examples of the alkynyl groups include C2.10 alkynyl groups such as 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 and 5-hexynyl,
Examples of "the alicyclic hydrocarbon group" as the substituent of the hydrocarbon group shown by D include C3.12 saturated or unsaturated alicyclic hydrocarbon groups, for example, cycloalkyl groups, cycloalkenyl groups and cycloalkadienyl groups.
Preferable examples of the cycloalkyl groups include C3.12 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2. l]heptyl, bicyclo[2.2.2 Joctyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3. l]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl .
Preferable examples of the cycloalkenyl groups include C5_12 cycloalkenyl groups such as 2-cyclopenten- 1-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl and 3- cyclohexen-1-yl .
Preferable examples of the cycloalkadienyl groups include C5.12 cycloalkadienyl groups such as 2,4- cyclopentadien-1-yl, 2,4-cyclohexadien-l-yl and 2,5- cyclohexadien-1-yl .
The aromatic hydrocarbon group in "the optionally substituted aromatic hydrocarbon group" as the substituent of the hydrocarbon group shown by D means monocyclic or condensed polycyclic aromatic hydrocarbon group. Preferable examples of the aromatic hydrocarbon group include C6.ltl aromatic hydrocarbon groups such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and 3,4-dihydro-2-naphthyl . Among them, phenyl, 1- naphthyl and 2-naphthyl are preferable. Examples of substituents in "the optionally substituted aromatic hydrocarbon group" as the substituent of the hydrocarbon group shown by D include halogen (e.g. fluorine, chlorine, bromine and iodine), a lower alkyl group (e.g. Cj.g alkyl groups such as methyl, ethyl, propyl and butyl), a lower alkoxy group (e.g. Ci.6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentyloxy) , hydroxyl group, nitro group, cyano group, an acyl group (e.g. Cj.g alkanoyl groups such as formyl, acetyl, propionyl and butyryl), amino group, thiol group and trifluoromethyl group. The number of substituents is, for example, one to five.
Examples of "the aromatic-aliphatic hydrocarbon group" as the substituent of the hydrocarbon group shown by D include C7.20 aromatic-aliphatic hydrocarbon groups. Examples of the aromatic-aliphatic hydrocarbon groups include C7.14 aralkyl groups (e.g. benzyl, 2- phenylethyl) , C6.1| aryl-C2-6 alkenyl groups (e.g. styryl(2-phenylethenyl) , 2-(2-naphthyl)vinyl, 4-phenyl- 1,3-butadienyl) .
Examples of "the halogen atom" as the substituent of the hydrocarbon group shown by D include fluorine, chlorine, bromine and iodine, and, among them, fluorine and chlorine are especially preferable.
Examples of "the optionally substituted amino group" as the substituent of the hydrocarbon group shown by D include, amino group which is mono- or di- substituted by CJ.JQ alkyl, C2_10 alkenyl, C,.10 acyl or aromatic group (e.g. methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino and N-methyl-N-phenylamino) and a 4- to 6-membered cyclic amino group (e.g. 1- azetidinyl, 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl) . The 4- to 6-membered cyclic amino group may optionally be further substituted by 1) Cj.g alkyl groups, 2) C6_1 aryl groups optionally substituted by halogen, C^g alkoxy groups or trifluoromethyl, 3) 5- or 6-membered heterocyclic groups containing in addition to carbon atom, as a ring component atom, 1 or 2 nitrogen atoms (e.g. 2-pyridyl, pyrimidinyl) , or 4) 6-membered cyclic amino group (e.g. piperidino, 1-piperadinyl) .
As the acyl group in "the optionally substituted acyl group" as the substituent of the hydrocarbon group shown by D, mention is made of, besides formyl, for example, groups formed by combination of C^K, alkyl, C2_ 10 alkenyl or C6.12 aromatic group with carbonyl group (e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2- cyclohexenecarbonyl, benzoyl and nicotinoyl).
As substituents in "the optionally substituted acyl group", mention is made of, for example, Cj_3 alkyl groups, Cj.3 alkoxy groups, halogen (e.g. chlorine, fluorine or bromine), nitro group, hydroxyl group and amino group. The number of substituents is, for example, 1 to 3.
As the substituted hydroxyl group in "the optionally substituted hydroxyl group" as the substituent of the hydrocarbon group shown by D , mention is made of, for example, hydroxyl group which is substituted by hydrocarbon groups or acyl groups, such as alkoxy groups , alkenyloxy groups, aralkyloxy groups, aryloxy groups and acyloxy groups. Preferable examples of the alkoxy groups include Cι.ϊ0 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy. Preferable examples of the alkenyloxy groups include C2.10 alkenyloxy groups such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2- cyclopentenylmethoxy and 2-cyclohexenylmethoxy. Preferable examples of the aralkyloxy groups include phenyl-Cj.ή alkyloxy groups (e.g. benzyloxy, phenethyloxy) .
Preferable examples of the aryloxy groups include C6_1A aryloxy groups such as phenoxy and 4- chlorophenoxy. Preferable examples of the acyloxy groups include C2-A acyloxy groups such as C2.A alkanoyloxy groups (e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy) .
As the substituted thiol group in "the optionally substituted thiol group" as the substituent of the hydrocarbon group shown by D, mention is made of, thiol group which is substituted by hydrocarbon groups or acyl groups, such as alkylthio groups, alkenylthio groups, aralkylthio groups, arylthio groups and acylthio groups. Preferable examples of the alkylthio groups include Cι_10 alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec .-butylthio, tert.- butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio and cyclohexylthio. Preferable examples of the alkenylthio groups include Cz_ιo alkenylthio groups such as allylthio, crotylthio, 2- pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio and 2-cyclohexenylmethylthio. Preferable examples of the aralkylthio groups include Cy.^ aralkylthio groups such as phenyl-Ci.4 alkylthio (e.g. benzylthio, phenethylthio) . Preferable examples of the arylthio groups include C6.1A arylthio groups such as phenylthio and 4-chlorophenylthio. Preferable examples of the acylthio groups include C2.« acylthio groups such as C . 4 alkanoylthio groups (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio) .
As the esterified carboxyl group in "the optionally esterified carboxyl group" as the substituent of the hydrocarbon group shown by D, mention is made of, for example, alkoxycarbonyl groups, aralkyloxycarbonyl groups and aryloxycarbonyl groups . Preferable examples of the alkoxycarbonyl groups include C2-5 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl. Preferable examples of the aralkyloxycarbonyl groups include C8.15 aralkyloxycarbonyl groups such as benzyloxycarbonyl . Preferable examples of the aryloxycarbonyl groups include C7.15 aryloxycarbonyl groups such as phenoxycarbonyl and p-tolyloxycarbonyl .
The heterocyclic groups as the substituent of the hydrocarbon group shown by D may optionally have at any possible position, one to three substituents, respectively. As these substituents, mention is made of "aliphatic chain hydrocarbon groups", "alicyclic hydrocarbon groups", "optionally substituted aromatic hydrocarbon groups", "aromatic-aliphatic hydrocarbon groups", "aromatic heterocyclic groups", "non-aromatic heterocyclic groups", "halogen atoms", "nitro group", "optionally substituted amino groups", "optionally substituted acyl groups", "optionally substituted hydroxyl groups", "optionally substituted thiol groups", "optionally esterified carboxyl groups" and "aromatic heterocyclic-aliphatic hydrocarbon groups". As these "aliphatic chain hydrocarbon groups", "alicyclic hydrocarbon groups", "aromatic hydrocarbon groups", "aromatic-aliphatic hydrocarbon groups", "halogen atoms", "optionally substituted amino groups", "optionally substituted acyl groups", "optionally substituted hydroxyl groups", "optionally substituted thiol groups" and "optionally esterified carboxyl groups", mention is made of similar ones to substituents of the hydrocarbon group shown by D. Preferable examples of "the aromatic heterocyclic groups" as substituents of the heterocyclic groups include aromatic monocyclic heterocyclic groups 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-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; and aromatic condensed heterocyclic groups such as benzofuranyl, isobenzofuranyl, benzofb]thienyl, indolyl, isoindolyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, 1,2- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, α- carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl, indolizinyl, pyrrolo[ 1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[ 1,2-b]pyridazinyl, imidazo[l,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and l,2,4-triazolo[4,3-b]pyridazinyl.
Preferable examples of "the non-aromatic heterocyclic groups" as substituents of the heterocyclic groups include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl.
Preferable examples of "the aromatic heterocyclic- aliphatic hydrocarbon groups" as substituents of the heterocyclic groups include
Figure imgf000019_0001
alkyl groups (e.g. (2-furyl)methyl) , 2-furyl-C2.6 alkenyl groups (e.g. (2-furyl)vinyl) , thienyl-C^ alkyl groups (e.g. thienylmethyl) , thienyl-C2_6 alkenyl groups (e.g. 2- thienylvinyl) . Among the above-mentioned substituents, especially preferable ones on the heterocyclic groups as the substituent of the hydrocarbon group shown by D include styryl, phenyl, naphthyl, furyl, thienyl, C2._, alkenyl groups and Cj.g alkyl groups . D is preferably a hydrocarbon group which is substituted by an optionally substituted heterocyclic group, more preferably a hydrocarbon group which is substituted by oxazolyl or thiazolyl group optionally having one or two substituents selected from Cj.g alkyl groups, C2-8 alkenyl groups, C3_8 cycloalkyl groups, C6.1A aryl groups, C7_14 aralkyl groups, C6.ltl aryl-C2.6 alkenyl groups, aromatic heterocyclic groups, aromatic heterocyclic-Cj.6 alkyl groups and aromatic heterocyclic-C2_6 alkenyl groups. Examples of the hydrocarbon group shown by R or R include similar hydrocarbon group to those set forth as D .
As the substituent of the hydrocarbon group shown by R or R , mention is made of, for example, (1) "an optionally substituted heterocyclic group", (2) "a halogen atom", (3) "nitro group", (4) "an optionally substituted amino group", (5) "an optionally substituted acyl group", (6) "hydroxyl group optionally substituted by a hydrocarbon group or an acyl group", (7) "thiol group optionally substituted by a hydrocarbon group or an acyl group", (8) "an optionally esterified carboxyl group", (9) "cyano group" and (10) "oxo group". The number of substituents is, for example, one to four. Examples of these substituents include similar ones to those set forth as the substituent of the hydrocarbon group shown by D. The substituent of the optionally substituted hydrocarbon group shown by R or R is preferably "an optionally substituted heterocyclic group", "a halogen atom", "nitro group", "an optionally substituted amino group", "an optionally substituted acyl group", "an optionally esterified carboxyl group", "cyano group" or "oxo group", more preferably "an optionally substituted heterocyclic group" or "an optionally substituted amino group". As the heterocyclic group in "the optionally substituted heterocyclic group", oxazolyl or thiazolyl is preferable. Preferable examples of substituents in "the optionally substituted heterocyclic group" include Ci.g alkyl groups (e.g. methyl, ethyl, propyl) , C2.8 alkenyl groups (e.g. ethenyl, 1-propenyl, 2-propenyl, 1-butenyl), C3.8 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C6_u aryl groups (e.g. phenyl, naphthyl, anthryl), C7.14 aralkyl groups (e.g. benzyl, 2-phenylethyl) , C5.1A aryl-C2.6 alkenyl groups (e.g. styryl(2-phenylethenyl) , 2-(2- naphthyl)vinyl, 4-phenyl-l,3-butadienyl) , aromatic heterocyclic groups (e.g. furyl,thienyl) , aromatic heterocyclic-Cj.6 alkyl groups (e.g. (2-furyl)methyl) , aromatic heterocyclic-C2_6 alkenyl groups (e.g. 2-(2- furyl)vinyl) .
Preferable examples of the substituted amino groups in "the optionally substituted amino group" include C^K, acylamino groups (e.g. C^o alkanoylamino such as acetylamino and propionylamino) ; mono- or di- CJ.JO alkylamino groups (e.g. methylamino, ethylamino, dimethylamino, diethylamino) ; and 4- to 6-membered cyclic amino groups optionally substituted by 1) C^ alkyl groups, 2) C6_1A aryl groups optionally substituted by halogen, Cj_6 alkoxy groups or trifluoromethyl, 3) 5- or 6-membered heterocyclic groups containing in addition to carbon atoms, as a ring component atom, 1 or 2 nitrogen atoms (e.g. 2- pyridyl, pyrimidinyl) or 4) 6-membered cyclic amino groups (e.g. piperidino, 1-piperadinyl) , (e.g. 1- azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1- piperazinyl, 4-piperidino-l-piperidinyl, 4-(3- chlorophenyl)piperadinyl, 4-methylpiperadinyl, 4- phenylpiperadinyl, 4-(4-fluorophenyl)piperadinyl, 4-(4- methoxyphenyl)piperadinyl, 4-(2-pyridyl)piperadinyl, 4- (pyrimidinyl)piperadinyl, 4-(4- trifluoromethylphenyl)piperadinyl. "The optionally substituted amino group" is preferably a 4- to 6- membered cyclic amino group optionally substituted by 1) Cj.g alkyl groups, 2) C6.14 aryl groups optionally substituted by halogen, Cl.6 alkoxy groups or trifluoromethyl, 3) 5- or 6-membered heterocyclic groups containing in addition to carbon atoms, as a ring component atom, 1 or 2 nitrogen atoms or 4) 6- membered cyclic amino groups.
R stands for hydrogen atom or a hydrocarbon group optionally having substituents selected from (1) "an optionally substituted heterocyclic group", (2) "a halogen atom", (3) "nitro group", (4) "an optionally substituted amino group", (5) "an optionally substituted acyl group", (6) "hydroxyl group optionally substituted by a hydrocarbon group or an acyl group", (7) "thiol group optionally substituted by a hydrocarbon group or an acyl group", (8) "an optionally esterified carboxyl group", (9) "cyano group" and (10) "oxo group". R preferably stands for a hydrocarbon group optionally having substituents selected from (1) to (10) . R and R are preferably hydrocarbon groups substituted by 1) an optionally substituted heterocyclic group or 2) an optionally substituted amino group.
R and R are more preferably hydrocarbon groups substituted by (a) oxazolyl or thiazolyl group optionally having 1 or 2 substituents selected from Cj.g alkyl groups, C2_8 alkenyl groups, C3_8 cycloalkyl groups, C6_14 aryl groups, C7_14 aralkyl groups, C6.14 aryl-C2_6 alkenyl groups, aromatic heterocyclic groups, aromatic heterocyclic-Ci.g alkyl groups, and aromatic heterocyclic-C2_6 alkenyl groups; or (b) 4- to 6- membered cyclic amino groups optionally substituted by 1) Ci.e alkyl groups, 2) C6.1A aryl groups optionally substituted by halogen, Cj.g alkoxy groups or trifluoromethyl, 3) 5- or 6-membered heterocyclic groups containing in addition to carbon atoms, as a ring component atom, 1 or 2 nitrogen atoms or 4) 6- membered cyclic amino groups.
As the divalent aliphatic hydrocarbon group shown by A or A1, one having 1 to 7 carbon atoms is preferable, which may be straight-chain or branched, and may be saturated or unsaturated. Examples of the divalent aliphatic hydrocarbon group include saturated one such as -CH2-, -CH(CH3)-, -(CH2)2-, -CH(C2H5)-, - (CH2)3-, -(CH2)4-, .-(CH2)5-, -(CH2)6- and -(CH2)7-, and, unsaturated one such as -CH=CH-,
-C(CH3)=CH-, -CH=CH-CH2-, -C(C2H5)=CH-, -CH2-CH=CH-CH2- , -CH2-CH2-CH=CH-CH2-, -CH=CH-CH=CH-CH2-, and -CH=CH- CH=CH-CH=CH-CH2-. A or A1 is more preferably a C^ divalent aliphatic hydrocarbon group, with prefence given to saturated one. A or A is especially preferably -CH2- or -(CH2)2-.
X stands for CH or N, preferably CH. Q stands for -N(R )- (R stands for hydrogen atom or a lower alkyl group) , oxygen atom or sulfur atom, preferably oxygen atom. Examples of the lower alkyl group shown by R include Cj__.A one such as methyl, ethyl, propyl and butyl.
Z stands for oxygen atom or sulfur atom, preferably oxygen atom.
L and M are preferably hydrogen.
In the compounds of this invention, when L and M are combined with each other to form one bond, there exist (E) and (Z) isomers relative to the double bond at the 5-position of azolidine ring.
When L and M respectively stand for hydrogen atom, there exist optical isomers of (R) and (S) isomers due to the asymmetric carbon at the 5-position of azolidine ring. In the compounds of this invention, the partial formula:
[ £_1J preferably represents
Figure imgf000023_0001
D includes groups shown by, for example, R-(Y)m- (CH2)n-CH(D1) wherein R stands for an optionally substituted hydrocarbon group; m is 0 or 1; n is 0, 1 or 2 ; Y stands for -CO-, -CH(OH)- or -N(R4) (R4 stands for an optionally substituted alkyl group); D stands for hydrogen atom or a lower alkyl group. As the optionally substituted hydrocarbon groups shown by R , mention is made of ones similar to hydrocarbon groups set forth as D.
The symbol m denotes 0 or 1, preferably 0. The symbol n denotes 0, 1 or 2, preferably 0 or 1, most preferably 0.
Y stands for -CO-, -CH(OH)- or -N(R*)-, preferably -CH(OH)- or -N(RA)-.
As the alkyl group in "the optionally substituted alkyl group" shown by R4, mention is made of Ci_4 one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl and tert.-butyl. Eamples of substituents in "the optionally substituted alkyl group" include halogen (e.g. fluorine, chlorine, bromine, iodine), C^ alkoxy groups (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec .- butoxy and tert.-butoxy) , hydroxyl group, nitro group and Cj.ή acyl groups (e.g. alkanoyl groups such as formyl, acetyl and propionyl) . Ring E may optionally have, besides
L H D\θ- and -A-CH—C~ 0 Y\
, one to four substituents selected from a lower (C^) alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec .-butyl and tert.-butyl) , a lower (Ci.i) alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec . -butoxy and tert. - butoxy), halogen (e.g. fluorine, chlorine, bromine and iodine), amino group, nitro group and hydroxyl group. Especially, as examples of compounds in which ring E is further substituted, mention is made of compounds represented by the formula:
Figure imgf000025_0001
wherein R and R independently stand for hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or hydroxyl group, or, R and D may optionally be combined with each other to form a 5- or 6-membered heterocyclic ring optionally containing nitrogen atom or oxygen atom, and other symbols are of the same meaning as defined above, or their salts.
As the lower alkyl group shown by R 2 and R5, mention is made of C^ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl and tert.-butyl .
As the lower alkoxy group shown by R and R , mention is made of a C^ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.- butoxy and tert.-butoxy.
As the halogen atom shown by R and R , mention is made of fluorine, chloride, bromine and iodine, preferably fluorine or chlorine.
Especially, the compounds represented by the formula (I-a) include those represented by the following formulae.
Figure imgf000026_0001
wherein each symbol is of the same meaning as defined above.
When medicinal effects and toxicity are taken into consideration, among compounds represented by the formulae (I-a-1), (I-a-2) and (I-a-3), those represented by (I-a-1) and (I-a-2) are preferable, and, those represented by (I-a-1) are most preferable.
The compounds wherein L and M are combined with each other to form one bond in the formula (I-a), are represented by the formula:
Figure imgf000026_0002
wherein each symbol is of the same meaning as defined above, and, the compounds wherein L and M respectively stand for hydrogen atom are represented by the formula:
Figure imgf000027_0001
wherein each symbol is of the same meaning as defined above.
Among compounds represented by the formulae (I-b- 1) and (I-b-2), the compound represented by the formula (I-b-2) is preferable. Examples of the compounds wherein substituents in ring E (R ) are combined with D to form a ring (e.g. a 5- or 6-membered heterocyclic ring optionally containing nitrogen atom) in the formula (I), include the compounds represented by the following formulae. (1) D and R are combined with each other to form a 5- membered heterocyclic ring.
(i-c-1)
Figure imgf000027_0002
(2) D and R are combined with each other to form a 6- membered heterocyclic ring.
Figure imgf000028_0001
t
R3-(Y)π-(CH2 fr -C-r
(I-c-5)
(3) D and R are combined with each other to form a 5- membered heterocyclic ring containing a nitrogen atom.
Figure imgf000028_0002
(4) D and R are combined with each other to form a 6- membered heterocyclic ring containing a nitrogen atom.
Figure imgf000028_0003
wherein D stands for hydrogen atom or a lower alkyl group, and other symbols are of the same meaning as defined above. The lower alkyl group shown by D is exemplified by Cj.4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec .-butyl and tert.-butyl.
Among the compounds represented by the formulae (I-c-1) to (I-c-8), compounds represented by the formulae (I-c-2), (I-c-3) and (I-c-6) are preferable. Preferable examples of the compound represented by the formula (I) or (II) include compounds wherein D is Cχ.6 aliphatic hydrocarbon groups substituted by oxazolyl or thiazolyl group optionally having one or two substituents selected from Cj.g alkyl groups, C2.8 alkenyl groups, C3.8 cycloalkyl groups, C6_14 aryl groups, C7.lή aralkyl groups, C6_u aryl-C2.6 alkenyl groups, aromatic heterocyclic groups, aromatic heterocyclic-Cj.g alkyl groups, and aromatic heterocyclic-C2_6 alkenyl groups; X is CH;
A or A is a Cj_A divalent aliphatic hydrocarbon group; R or R is a 6 aliphatic hydrocarbon group substituted by (a) oxazolyl or thiazolyl group optionally having 1 or 2 substituents selected from C^ alkyl groups, C2.8 alkenyl groups, C3_8 cycloalkyl groups, C6_1 aryl groups, C7_14 aralkyl groups, C6.14 aryl-C2-6 alkenyl groups, aromatic heterocyclic groups, aromatic heterocyclic-Ci.6 alkyl groups, and aromatic heterocyclic-C2.6 alkenyl groups, or (b) 4- to 6- membered cyclic amino groups optionally substituted by 1) Cj.s alkyl groups, 2) C6. aryl groups optionally substituted by halogen, C^g alkoxy groups or trifluoromethyl, 3) 5- or 6-membered heterocyclic groups containing in addition to carbon atoms, as a ring component atom, 1 or 2 nitrogen atoms or 4) 6- membered cyclic amino groups . Q and Z are oxygen atom; L and M are hydrogen atom; ring E, namely the partial formula:
Figure imgf000030_0001
and R and R are independently hydrogen atom or C^ alkoxy groups .
Preferable examples of the compound represented by the formula (I) or (II) include 5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-oxazolidinedione; 5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[(E)-2- phenylethenyl]-4-thiazolylmethyl]-2,4-oxazolidinedione; 5-[3-[4-[2-[(E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-oxazolidinedione; 5-[3-[3,5-dimethoxy-4-[2-[ (E)-2-ρhenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[(E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-oxazolidinedione; 5-[2-[4-methoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethox ]phenyl]ethyl]-3-[3-[4-(4- methoxyphenyl)piperadin-1-yl]propyl]-2,4- oxazolidinedione; 5-[2-[4-methoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolyl ethoxy]phenyl]ethyl]-3-[3-(4-phenylpiperadin- 1-yl)propyl]-2,4-oxazolidinedione; and the like.
As salts of the object compounds (I) and (II) of this invention, pharmaceutically acceptable ones are preferable, as exemplified by salts with an inorganic base, salts with an organic base, salts with an inorganic acid, salts with an organic acid and salts with a basic or acidic amino acid.
Preferable examples of salts with an inorganic base include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts, ammonium salts or the like. Preferable examples of salts with an organic base include those with, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,N'- dibenzylethylenediamine. Preferable examples of salts with an inorganic acid include those with, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid. Preferable examples of salts with an organic acid include those with, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p- toluenesulfonic acid. Preferable examples of salts with a basic amino acid include those with, for example, arginine, lysine or ornithine, and, preferable examples of salts with an acidic amino acid include those with, for example, aspartic acid or glutamic acid. The object compounds (I) and (II) or their salts can be used as hydrate.
The object compounds (I) and (II) or their pharmaceutically acceptable salts of the present invention are low in toxicity and can be used as a medicine as such or as a pharmaceutical composition, for mammals including man (e.g. horse, bovine, dog, cat, rat, mouse, rabbit, swine, monkey), prepared by mixing with a per se known pharmaceutically acceptable carrier, excipient and filler.
The compounds (I) and (II) or their salts of this invention possess an activity of inhibiting the tumor cell growth or an activity of inhibiting tyrosine kinase, thus being useful as anticancer agents. More specifically, these compounds exert excellent effects as antitumor agents on inhibiting principally the growth of malignant tumors occurring on breast, remote metastatic breast cancer onto organs including e.g. lymph node, bone, brain and liver, and primary and nodal breast cancer aggravated and recurred after treatment, by inhibiting growth of, among human tumor cells, especially human breast cancer cell strains selectively.
And, the compounds (I) and (II) or their salts of this invention are useful also as therapeutic agents of diabetes, based on an action of enhancing insulin- sensitivity.
The compounds (I) and (II) or their salts of this invention are low in toxicity and can be administered safely. For example, oral administration of the compound of Working Example 36 at a dose of 10 mg/kg/day for 14 days to mice killed no test animals, causing no change in body weight.
The administration of a compound (I), (II) or a salt thereof as a medicine to mammals including man is usually performed orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules) , powdery preparations and granular preparations, and, depending on cases, non-orally in the form of, for example, injections, suppositories and pellets. The dosage of a compound (I), (II) or a salt thereof varies depending on the administration route, the condition of a patient and the like, in the case of oral administration to a patient (40 to 80 kg body weight) having a malignant tumor, it ranges from 0.05 to 200 mg/kg, preferably from 0.1 to 100 mg/kg, especially from 5 to 50 mg/kg per day, desirably dividing this amount into once to three times a day.
The object compounds (I) and (II) or their salts of this invention, mixed with pharmaceutically acceptable carriers, can be administered orally or non- orally in the form of solid preparations such as tablets, capsules, granules and powdery preparations; or in the form of liquid preparations such as syrups and injections.
As the pharmaceutically acceptable carriers, use is made of conventional organic or inorganic carriers for pharmaceutical preparations, more specifically, for example, excipients, lubricants, binders and disintegrators for solid preparations; and solvents, solubilizers, suspending agents, isotonizers, buffering agents and local anesthetic agents for liquid preparations. And, upon necessity, such additives as antiseptics, antioxidants, colorants and sweetners are further used.
Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose and light silicon dioxide. Preferable examples of lubricants include magnesium stearate, calcium stearate, talc and colloid silica. Preferable examples of binders include crystalline cellulose, sugar, D- mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinyl pyrrolidine. Preferable examples of disintegrators include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, crosscarmellose sodium and carboxymethyl starch sodium. Preferable examples of solvents include distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. Preferable examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-amino methane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Preferable examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Preferable examples of isotonizers include sodium chloride, glycerin and D-mannitol. Preferable examples of buffering agents include buffer solutions of phosphates, acetates, carbonates and citrates. Preferable examples of local anesthetic agents include benzyl alcohol. Preferable examples of antiseptics include para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid. Preferable examples of antioxidants include sulfites and ascorbic acid. The pharmaceutical preparation of this invention can be formulated in accordance with a conventional method, by allowing the object compound (I), (II) or a salt thereof to be contained in an amount of 0.1 to 90% (w/w) relative to the total weight of the preparation. The compound (II) or a salt thereof of this invention (hereinafter containing the compound (I) or a salt thereof) can be produced by, for example, the following methods. Additionally stating, in the following production methods, excepting the compound of the formula (VI), not only the compounds shown by the respective formulae but also their salts may optionally be used. Examples of these salts include those set forth as the salts of the compounds (I) and (II). And, in each production method, when the product is obtained as a free form, it can be converted to the corresponding salt, and, when the product is obtained as a salt, it can be converted to the free compound in accordance with a conventional method. In the following descriptions, when, for example, NH2, OH or COOH is included in the substituents, the compounds in which these groups are protected may optionally be employed as starting compounds, and, after completion of the reaction, the protecting group is removed to produce the object compound. Method A
Figure imgf000035_0001
wherein each symbol is of the same meaning as defined above.
As the leaving group shown by W, mention is made of, for example, halogen atoms (e.g. chlorine, bromine, fluorine), methanesulfonyloxy, benzonesulfonyloxy and p-toluenesulfonyloxy.
In this method, the compound (I) is produced by subjecting the compound (II-l) to condensation with the compound (III). This reaction is conducted, in accordance with a conventional method, in an adequate solvent in the presence of a base.
As the solvent, mention is made of aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; ketones such as acetone and 2- butanone; N,N-dimethylformamide; dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2- tetrachloroethane; and a mixed solvent of them.
As the base, use is made of, for example, alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate; amines such as pyridine, triethylamine and N,N-dimethyl aniline; metal hydrides such as sodium hydride and potassium hydride; and sodium ethoxide, sodium methoxide and potassium tert.- butoxide. The amount of these bases to be employed ranges, preferably, from 1 to 5 molar equivalents relative to the compound (II-l).
The reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C. The reaction time ranges from 0.5 to 50 hours.
The compound (I) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography. Method B
Figure imgf000036_0001
wherein R stands for hydrogen atom or a lower alkyl group, and other symbols are of the same meaning as defined above. As the alkyl group shown by R , mention is made of Cj.ή one such as methyl, ethyl, propyl, isopropyl, butyl and tert.-butyl.
In this method, the compound (II-2) is condensed with the compound (IV) to produce the compound (II-3). This reaction is conduced in a solvent similar to that in Method A and in the presence of a base similar to that in Method A. The amount of the base to be used ranges, preferably, from 2 to 5 molar equivalents relative to the compound (II-2). The amount of the compound (IV) to be used ranges, preferably, from 0.8 to 1.2 molar equivalents relative to the compound (II- 2 ) .
The reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C. The reaction time ranges from 0.5 to 50 hours. The compound (II-3) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography. Method C
Figure imgf000037_0001
wherein each symbol is of the same meaning as defined above.
In this method, the compound (II-2) is condensed with the compound (III) to produce the compound (I-l), then the compound (I-l) is condensed with the compound
(IV) to produce the compound (1-2). The reaction between the compound (II-2) and the compound (III) is conducted in a manner similar to that of Method B.
Then, the reaction between the compound (I-l) and the compound (IV) is conducted in a manner similar to that of Method A.
The compounds (I-l) and (1-2) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography . Method D
Figure imgf000038_0001
wherein each symbol is of the same meaning as defined above. In this method, the compound (II-2) is condensed with the compound (III) to produce the compound (1-3). This reaction is conducted in a solvent similar to that in Method A and in the presence of a base similar to that in Method A. The amount of the base to be used ranges preferably form 2 to 5 molar equivalents relative to the compound (II-2). The amount of the compound (III) to be used ranges preferably from 2 to 5 molar equivalents relative to the compound (II-2).
The reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C. The reaction time ranges from 0.5 to 50 hours.
The compound (1-3) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
The compound (II-l) to be employed in Method A can be produced, in accordance with Method E, from the compound (V) . Method E
Figure imgf000039_0001
wherein T stands for CHO or -CH(J)2 '(J stands for a lower alkoxy, a lower alkylthio or a lower acylthio), and other symbols are of the same meaning as defined above.
Examples of the lower alkoxy include Cj.z, ones such as methoxy, ethoxy, propoxy, isopropoxy and butoxy.
Examples of the lower alkylthio include C^ ones such as methylthio, ethylthio, propylthio, isopropylthio and butylthio. Examples of the lower acyloxy include Cj.^ ones such as acetyloxy and propionyloxy. In the group -CH(J)2, two J's may optionally be combined with each other to form ethylenedioxy, propylenedioxy and dithiotrimethylene, for example. In other words, - CH(J)2 means a protected aldehyde group.
In this method, the compound (V) is condensed with the compound (VI) to produce the compound (II-4). This condensation reaction is conducted in a solvent in the presence of a base.
Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol and 2- methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; N,N- dimethylformamide; dimethyl sulfoxide and acetic acid. As the base, use is made of sodium alkoxide (e.g. sodium methoxide, sodium ethoxide), potassium carbonate, sodium carbonate, sodium hydride, sodium acetate, or secondary amines such as piperidine, piperazine, pyrrolidine, morpholine, diethylamine and diisopropylamine. The amount of the compound (VI) to be used ranges from 1 to 10 molar equivalents, preferably from 1 to 5 molar equivalents relative to the compound (V) . The amount of the base to be employed ranges from 0.01 to 5 molar equivalents, preferably from 0.05 to 2 molar equivalents, relative to the compound (V) . The reaction temperature ranges from about 0 to
150°C, preferably from 20 to 100°C. The reaction time ranges from 0.5 to 30 hours.
The compound (II-4) thus produced is obtained, in some instances, as a mixture of (E) compound and (Z) compound relative to the double bond at the 5-position of the azolidine ring.
Then, the compound (II-4) is subjected to reduction to produce the compound (II-5). This reduction reaction is conducted, in accordance with a conventional method, in a solvent in the presence of a catalyst under hydrogen atmosphere of 1 to 150 atmospheric pressure.
Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol and 2- methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1, 1,2,2-tetrachloroethane; ethyl acetate; acetic acid and a mixture solvent of them. The reaction is conducted more advantageously by employing, as the catalyst, a metal such as a nickel compound and a zinc compound; or a transition metal such as palladium, platinum and rhodium. The reaction temperature ranges from 0 to 150°C, preferably from 10 to 120°C. The reaction time ranges from 0.5 to 100 hours.
The compounds (II-4) and (II-5) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
The compound (V) to be employed in Method E can be produced in accordance with, for example the method described in JPA H7 ( 1995)-101945. In the JPA H7(1995)- 101945, the method of producing the compound (VII) shown by the following formula is described.
Figure imgf000041_0001
wherein each symbol is the same meaning as defined above.
Among the compounds (II-2) to be employed in Method B, Method C and Method D, 2,4-oxazolidinedione derivatives, wherein Q and Z are oxygen atom, and, L and M are hydrogen atom, can be produced in accordance with Method F. Method F
Figure imgf000042_0001
(VIII) (X)
Figure imgf000042_0002
wherein R 8 stands for isopropyl or benzyl group, R 7 stands for a lower alkyl group, G stands for a halogen atom, q denotes 1,3,4,5 or 6, R 9 and R10 independently stand for a lower alkyl group or an aralkyl group, and other symbols are of the same meaning as defined above. In the above formulae, as the lower alkyl group shown by R , mention is made of C^ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl and isobutyl). As the lower alkyl group shown by R , mention is made of C tt alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl and tert.-butyl) . The aralkyl group shown by R means alkyl groups having an aryl group as the substituent (i.e. an arylalkyl group). As the aryl group, mention is made of, for example, phenyl and naphthyl, and these groups may optionally have, as the substituents, for example, the above-mentioned lower alkyl groups (C^ ones), halogen atoms (fluorine, chlorine, bromine and iodine), hydroxyl group, and nitro group. As the alkyl group in the arylalkyl group, mention is made of C^z, ones such as methyl, ethyl and propyl . Preferable examples of the aralkyl group include benzyl, phenethyl, 3-phenylpropyl, (1- naphthyl)methyl and (2-naphthyl)methyl, and, among them, benzyl and phenethyl are preferable. As the lower alkyl group or aralkyl group shown by R , mention is made of similar ones to those shown by R9. As the halogen atom shown by G, mention is made of chlorine, bromine and iodine.
In this method, firstly, the carboxylic acid derivative (X) is produced by allowing the carbonyl derivative (VIII) to react with the phosphonium salt (IX)- The reaction between the compound (VIII) and the compound (IX) is conducted in dimethyl sulfoxide in the presence of sodium hydride. The amount of sodium hydride to be employed ranges from about 2 to 5 molar equivalents relative to the compound (VIII). The amount of the compound (IX) to be used preferably ranges from about 1 to 3 molar equivalents relative to the compound (VIII).
The reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C. The reaction time ranges from 0.5 to 50 hours.
Then, the carboxylic acid derivative (X) is subjected to esterification to produce the compound (XI). This esterification reaction can be conducted by a per se known method. Examples of such method include a method in which the compound (X) is esterified directly with alcohol (R OH) in the presence of an acid; a method in which a reactive derivative of the compound (X) such as acid anhydride, acid halide (acid chloride, acid bromide), imidazolide and a mixed acid anhydride (e.g. anhydride with methyl carbonate, anhydride with ethyl carbonate or anhydride with isobutyl carbonate) to react with alcohol (ROH); and a method in which the compound (X) is reacted with R -G in the presence of a base.
Then, the compound (XI) is subjected to catalytic reduction to produce the compound (XII). This catalytic reduction can be conducted in substantially the same manner as in the reduction of the compound (II-4) in Method E.
Then, the compound (XII) is allowed to react with oxalic acid ester (COOR )2 in the presence of a base. The reaction of the compound (XII) with oxalic acid ester (COOR )2 is conducted, by a conventional method in a suitable solvent in the presence of a base.
Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxy ethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; and halogenated hydrocarbons such as chloroform, dichloromethane and 1, 1,2,2-tetrachloroethane.
As the base, mention is made of sodium ethoxide, sodium methoxide and potassium tert. -butoxide. The amount of these bases to be employed preferably ranges from about 1 to 5 molar equivalents relative to the compound (XII), and the amount of the oxalic acid ester (COOR )2 to be employed ranges preferably from about 1 to 5 molar equivalents relative to the compound (XII).
The reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C. The reaction time ranges from 0.5 to 50 hours.
The condensed product (XIII) thus obtained is subjected to decarboxylation reaction to produce -keto ester (XIV) . This decarboxylation reaction is conducted under heating in hydrous dimethyl sulfoxide in the presence of sodium chloride or lithium chloride. The amount of sodium chloride or lithium chloride to be used ranges from 1 to 5 molar equivalents .
The reaction temperature ranges from 50°C to 150°C, preferably from about 80°C to 120°C. The reaction time ranges from 0.5 to 50 hours. Then, the α-keto ester (XIV) is subjected to reduction to produce the compound (XV) . This reduction reaction can be conducted by a per se known method, for example, reduction with a metal hydride, reduction with a metal hydride complex, reduction with diborane and a substituted borane, or catalytic hydrogenatiσn. In other words, this reaction can be conducted by treating the compound (XIV) with a reducing agent. Examples of the reducing agent include alkali metal borohydride (e.g. sodium borohydride and lithium borohydride); metal hydride complex such as lithium aluminum hydride; metal hydride such as sodium hydride; an organotin compound (e.g. triphenyltin hydride), metals and metal salts such as a nickel compound and a zinc compound; a catalytic reduction agent using a transition metal catalyst such as palladium, platinum, rhodium and the like together with hydrogen; and diborane. Above all, use of alkali metal borohydride (e.g. sodium borohydride, lithium borohydride) serves to conduct the the reaction advantageously. This reaction is conducted in an organic solvent which does not interfere with the reaction.
Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxy ethanol; amides such as N,N-dimethylformamide; and a mixture of them, and, from among these solvents, a suitable one is selectively employed depending on kinds of the reducing agent.
The reaction temperature ranges from -20°C to 150°C, especially preferably from 0°C to 100°C. The reaction time ranges from about 1 to 24 hours. Then, the compound (XV) is subjected to cyclization reaction to produce 2,4-oxazolidinedione derivative (II-6). The cyclization reaction is conducted by a per se known method such as a method in which the compound (XV) is reacted with alkali metal cyanate; and a method in which the compound (XV) is reacted with urea in the presence of a base.
The reaction between the compound (XV) and alkali metal cyanate (potassium cyanate or sodium cyanate) for example is conducted in a suitable solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxy ethanol and butanol; N,N-dimethylformamide (DMF); dimethyl sulfoxide; acetonitrile; and a mixture of them. The amount of alkali metal cyanate ranges, relative to the compound (XV) , from 1 to 10 molar equivalents, preferably from 1 to 5 molar equivalents.
The reaction temperature ranges from 0 to 180°C, preferably from 30 to 150°C. The reaction time ranges from 0.5 to 100 hours. The alkali metal salt of the compound (II-6) thus obtained is processed with an acid by a conventional method to produce the compound (II-6) as a free form. This process with an acid is conducted in the presence or absence of a suitable solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxy ethanol and butanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachloroethane; ethyl acetate; acetonitrile; and a mixture of them.
As the acid, excess amount of an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and hydrobro ic acid is preferably employed, while an organic acid such as acetic acid, citric acid and tartaric acid may also employed. α
Then, by removing R of the compound (II-6), the compound (II-7) is produced.
When R is a benzyl group, the compound (II-6) is subjected to substantially the same catalytic reduction of the compound (II-4) in Method E to produce the compound (II-7) . o
When R is an isopropyl group, the compound (II-6) is subjected to the reaction with titanium tetrachloride to produce the compound (II-7). The reaction of the compound (II-6) with titanium tetrachloride is conducted in an suitable organic solvent.
As the solvent, use is made of, suitably selectively, for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; or a mixture of them. The amount of titanium tetrachloride to be used ranges from 1 to 10 molar equivalents, preferably from 1 to 5 molar equivalents, relative to the compound (II- 6).
The reaction temperature ranges from -50°C to 100°C, and especially preferably from -20°C to 80°C. The reaction time ranges from about 1 to 24 hours. The 2,4-oxazolidinedione derivatives (II-6) and (II-7) thus obtained can be isolated and purified by a known isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
The starting compound (IX) in Method F is produced by the method described in Journal of Medicinal Chemistry, 2_8, p.287, (1985).
Among the 2,4-oxazolidinedione derivatives represented by the formulae (II-6) and (II-7) set forth in Method F, compounds wherein q is 2 can be derived from the ester derivative (XXIII) produced in accordance with Method G. Method G
Figure imgf000048_0001
wherein each symbol is of the same meaning as defined above. In this method, firstly, the carbonyl derivative (VII) is allowed to react with the phosphonoacetic acid derivative (XVI) to produce the unsaturated ester derivative (XVII). The reaction of the compound (VIII) with the compound (XVI) is conducted, in accordance with a conventional method, in an adequate solvent in the presence of a base.
Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; N,N-dimethylformamide; dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2- tetrachloroethane; and a suitable mixture of them.
Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate; amines such as pyridine, triethylamine and N,N-dimethyl aniline; metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide, sodium methoxide and potassium ter .- butoxide. The amount of these bases to be employed ranges, preferably, from about 1 to 5 molar equivalents relative to the compound (VIII). The amount of the compound (XVI) to be employed ranges from 1 to 5 molar equivalents, preferably from about 1 to 3 molar equivalents, relative to the compound (VIII).
The reaction temperature ranges usually from -50°C to 150°C, preferably from about -10°C to 100°C. The reaction time ranges from 0.5 to 30 hours.
Then, the compound (XVII) is subjected to substantially the same catalytic reduction of the compound (II-4) in Method E to produce the compound (XVIII). Further, the compound (XVIII) is subjected to substantially the same reduction of the compound (XIV) in Method F to produce the alcohol derivative (XIX) • The alcohol derivative (XIX) can be led, by a per se known method, for example, chlorination by using thionyl chloride, bromination by using phosphorus tribromide or mesylation by using methanesulfonyl chloride, to the compounds represented by the formula (XX) wherein W is Cl, Br or OS02CH3, respectively.
The compound (XX) is allowed to react with potassium cyanide or sodium cyanide in a suitable solvent to produce the compound (XXI).
Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol, and propanol; N,N-dimethylformamide; dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2- tetrachloroethane; ketones such as acetone and 2- butanone; and a mixture of them. The amount of potassium cyanide or sodium cyanide to be used ranges preferably from about 1 to 5 molar equivalents relative to the compound (XX) .
The reaction temperature ranges usually from 0°C to 150°C, preferably from about 20°C to 100°C. The reaction time ranges from 0.5 to 30 hours.
Then, the compound (XXI) is subjected to hydrolysis to produce the carboxylic acid derivative (XXII). This hydrolysis is conducted, preferably, in an aqueous solvent in the presence of potassium hydroxide or sodium hydroxide. The compound (XXIII) is produced by subjecting the carboxylic acid derivative (XXII) to substantially the same esterification of the compound (X) in Method F.
The ester derivative (XXIII) thus obtained can be isolated and purified by a conventional isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
And 2,4-oxazolidinedione derivatives (II-6) and (II-7) wherein q is 2 can be produced by substantially the same procedure as in the production of 2,4- oxazolidinedione derivatives (II-6) and (II-7) from the compound (XII) in Method F.
Among the compounds (II-l) and (II-2) to be employed in Method A, Method B, Method C and Method D, the 2, -oxazolidinedione derivative wherein A is a bond, and, Q and Z are oxygen atoms can be produced in accordance with the methods described in, for example, JPA H3(1991)-170478, Journal of Medicinal Chemistry, 3_4, p.1538 (1991), Japanese Patent Application under PCT laid-open under Kohyo No.H5(1994)-506456, WO92/02520 and the like, or the methods analogus thereto.
Among the compounds (II-l) and (II-2) to be employed in Method A, Method B, Method C and Method D, the 2,4-thiazolidinedione derivative, wherein Q is sulfur atom, Z is oxygen atom and, L and M are hydrogen atoms, can be produced by, for example, Method H. Method H
Figure imgf000052_0001
(XXIV)
Figure imgf000052_0002
(XXV)
Figure imgf000052_0003
wherein 1 denotes an integer of 1 to 6, and other symbols are of the same meaning as defined above. In this method, starting from the hydroxyester derivative represented by the formula (XXIV) produced by subjecting the compound (XV) produced by Method F and the compound (XXIII) produced by Method G to condensation with oxalic acid ester, decarboxylation and reduction, in substantially the same manner as in Method F,the 2,4-thiazolidinedione derivatives (II-8) and (II-9) are produced.
The reaction from the compound (XXIV) to the compound (XXV) is conducted in substantially the same manner as in the reaction from the compound (XIX) to the compound (XX) in Method G. Then, the compound (XXV) is subjected to a reaction with thiourea to produce the 2-iminothiazolidin-4-one derivative (XXVI). The reaction of the compound (XXV) with thiourea is conducted in a suitable solvent.
Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol, propanol and 2-methoxyethanol; N,N-dimethylformamide; dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane; sulfolan; and a mixture of them. This reaction may optionally be conducted in the presence of a deoxidizing agent (e.g. sodium acetate, potassium acetate) The amount of thiourea to be employed ranges preferably from 1 to 5 molar equivalents relative to the compound (XXV) .
The reaction temperature ranges usually from 0°C to 150°C, preferably from about 50°C to 120°C. The reaction time ranges from 0.5 to 30 hours.
The compound (XXVI) is subjected, after isolation or without isolation, to acid hydrolysis to produce the 2,4-thiazolidinedione derivative (II-8). This hydrolysis is conducted in a suitable aqueous solvent. Examples of the solvent include ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol, propanol and 2- methoxyethanol; N,N-dimethylformamide; dimethyl sulfoxide; sulfolan; ketones such as acetone and 2- butanone; and a mixture of them. While the amount of the acid (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid) to be employed is usually a large excess relative to the compound (XXVI), it ranges preferably from about 10 to 50 molar equivalents.
The reaction temperature ranges usually from 0°C to 150°C, preferably from about 50°C to 120°C. The reaction time ranges from 0.5 to 30 hours.
The compound (II-8) thus obtained can be derived to the compound (II-9) in substantially the same manner as in the reaction from the compound (II-6) to the compound (II-7) in Method F.
Among the compounds (II-l) and (II-2) to be employed in Method A, Method B, Method C and Method D, the 2,4-oxazolidinedione derivative wherein A is a bond, Q is sulfur atom and Z is oxygen atom can be produced in accordance with the methods described in, for example, WO94/25026, WO94/05659, JPA under PCT laid-open under Kohyo No.H6( 1994)-502146, JPA HI(1989)- 131169, JPA S64(1989)-13088, JPA S64 ( 1989)-13076, JPA under PCT laid-open under Kohyo No. H6( 1994)-503353, Chemical and Pharmaceutical Bulletin, .30., p.3563 (1982), USP 4,340,605, USP 4,703,052, USP 4,725,610, EP-299,620A, JPA under PCT laid-open under Kohyo No. H5(1993)-506456, JPB H4 ( 1992)-60584, JPB H4(1992)- 60583, JPA S61( 1986)-271287, JPA H6( 1994)-157522, EP- 549366-A1, EP-549365A1, JPB H5( 1993)-57988, JPA H4(1992)-159282, JPA H4( 1992)-225978, JPA H4(1992)- 210977, JPB H2(1990)-31079, JPA S64 ( 1989)-38090, JPA S62(1987)-123186, JPA S62( 1987)-5981, JPA S62(1987)- 5980, W094/22857, JPA H6( 1994)-80677, WO94/01433, JPA H6(1994)-9629, W093/22445, EP-508740-A1, WO9218501-A1, JPA S63(1988)-139182, JPA S61( 1986)-267580, JPA S61(1986)-85372, JPA H5( 1993)-194222, JPA H5(1993)- 194221, JPB H5(1993)-39928, JPB H5( 1993J-39927, JPA H2(1990)-167224, JPA H2 ( 1990)-167225, JPA H2(1990)- 167226, JPA S63( 1988)-230689, Journal of Medicinal Chemistry, 32, p.3977 (1994), Journal of Medicinal Chemistry, .32., p.421 (1989), Journal of Medicinal Chemistry, 3_4, p.319 (1991), Journal of Medicinal Chemistry, 3_4, p.1538 (1991), Arzneimittel-
Forschung/Drug Research), 4J), p.37 (1990), Journal of Medicinal Chemistry, 3_5, p.2617 (1992), Chemical and Pharmaceutical Bulletin, .39., p.1440 (1991) and Chemical and Pharmaceutical Bulletin, .30., p.3580 (1982), or the methods analogus thereto.
2,4-Oxazolidinedione derivatives can be produced in accordance with Method I also, Method I
Figure imgf000055_0001
(XXIV)
Figure imgf000055_0002
(XXVII)
Figure imgf000055_0003
(XXVIII)
Figure imgf000055_0004
wherein R stands for a lower alkyl group or a substituted phenyl group, and other symbols are of the same meaning as defined above. As the lower alkyl group shown by R , mention is made of C^ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl). As the substituent in the substituted phenyl group shown by R , mention is made of, for example, the above-mentioned lower alkyl groups (Cj.4 ones), halogen atoms (fluorine, chlorine, bromine, iodine), hydroxyl group and nitro group.
This method provide a method of producing the 2,4- oxazolidinedione derivative (11-10) starting from α- hydroxyester represented by the formula (XXIV) containing the compound (XV) produced by Method F and the compound which is produced by subjecting the compound (XXIII) produced by Method G to the method of producing the compound (XV) from the compound (XII) in Method F.
In this method, firstly, the compound (XXIV) is subjected to hydrolysis to produce the α- hydroxycarboxylic acid derivative (XXVII). The hydrolysis is conducted, in accordance with a per se known method, in an aqueous solvent in the presence of an acid or a base. As the solvent, alcohols such as methanol and ethanol are preferable. The amount of the base to be employed ranges from about 1 to 5 molar equivalents, and the amount of the acid to be employed is usually a large excess. Then, the compound (XXVII) is allowed to react with chlorocarbonic acid ester (C1COOR ), followed by allowing the reaction product to further react with ammonia to produce the compound (XXVIII). The reaction of the compound (XXVII) with chlorocarbonic acid ester (C1COOR ) is conducted, in accordance with a conventional method, in a suitable solvent in the presence of a base.
As the solvent, mention is made of, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachloroethane; and a mixture of these solvents . As the base, mention is made of alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate; and amines such as pyridine, triethylamine and N,N-dimethyl aniline. The amount of these bases to be employed is preferably about 2 to 5 molar equivalents relative to the compound (XXVII). The amount of chlorocarbonic acid ester (ClCOOR ) to be employed is 2 to 5 molar equivalents, preferably about 2 to 3 molar equivalents, relative to the compound (XXVII) . This reaction temperature ranges usually from -
80°C to 50°C, preferably from about -50°C to 30°C. The reaction time ranges from 0.5 to 30 hours.
Subsequently, the product is subjected to reaction with ammonia to produce the compound (XXVIII). This reaction is conducted, usually, by using aqueous ammonia. The reaction temperature ranges from -30°C to 50°C, preferably from about -20°C to 30°C.
The reaction time ranges from 0.5 to 30 hours. The compound (XXVIII) is led to the 2,4- oxazolidinedione derivative (11-10), in accordance with a conventional method, by processing the compound (XXVIII) with a base in a suitable solvent.
As the solvent, mention is made of, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1, 1,2,2-tetrachloroethane; acetonitrile; and a mixture solvent of these solvents . As the base, mention is made of, alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate; amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8- diazabicyclo[5.4.0]undecen-7-ene (DBU) and 1,5- diazabicyclo[4.3.0]non-5-ene (DBN); sodium ethoxide, sodium methoxide and potassium tert.-butoxide. The amount of these bases to be employed is preferably about 1 to 5 molar equivalents relative to the compound (XXVIII). The reaction temperature ranges usually from -80°C to 50°C, preferably from about -50°C to 30°C. The reaction time ranges form 0.5 to 30 hours. The 2,4-oxazolidinedione derivative (11-10) thus obtained can be isolated and purified by a conventional isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
Among the starting compounds (V) in Method E and the starting compounds (VIII) in Method F, the compounds represented by the formula (XXIX) can be produced also by Method J. Method J
Figure imgf000058_0001
R3-α) m- (CH2)n-cn-oH αxxn
(XXX)
Figure imgf000058_0002
(XXIX) wherein G stands for -A-T, -C(R7)=0; A, T R7 and other symbols are of the same meaning as defined above.
In this reaction, the compound (XXX) is allowed to react with the compound (XXXI) to produce the compound (XXIX) . This reaction is conducted in accordance with a per se known Mitsunobu reaction.
This reaction is conducted in a solvent, preferably, in the presence of triphenylphosphine and diethyl ester of azodicarboxylic acid. As the solvent, mention is made of, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2- tetrachloroethane; and a mixture of them. The respective amounts of triphenylphosphine and diethyl ester of azodicarboxylic acid to be used are, preferably, about 1 to 5 molar equivalents relative to the compound (XXX), and the amount of the compound (XXXI) to be used is preferably about 1 to 2 molar equivalents relative to the compound (XXX) .
The reaction temperature ranges usually from - 50°C to 100°C, preferably from about -30°C to 80°C. The reaction time ranges from 0.5 to 50 hours.
The compound (XXIX) thus obtained can be isolated and purified by a conventional isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography. Method K In this method, when the compounds produced in accordance with Method A, Method B, Method C, Method D, Method E, Method H or Method I contain methoxy group as a substituent on the ring E, these compounds are subjected to demethylation reaction to produce the corresponding phenol derivative.
This reaction is conducted by the reaction with alkyl mercaptan (e.g. ethyl mercaptan, dodecamercaptan) in a solvent in the presence of aluminum chloride.
As the solvent, mention is made of, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2- tetrachloroethane; and a mixture of them. The amount of aluminum chloride to be used ranges preferably from about 5 to 20 molar equivalents relative to the methoxy derivative, and the amount of titanium tetrachloride to be used ranges preferably from about 5 to 20 molar equivalents relative to the methoxy derivative.
The reaction temperature ranges usually from -80°C to 100°C, preferably from about -50°C to 50°C. The reaction time ranges from 0.5 to 50 hours.
The phenol derivatives thus obtained can be isolated and purified by a conventional isolating and purifying means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.
BEST MODE FOR CARRYING OUT THE INVENTION
The actions of the compounds of this invention are described by means of the following Test Examples. Test Example 1 Cell growth-inhibiting action in vitro A 100 μl (2,000 cells) each suspension of human breast cancer cells MDA-MB-453 or human pancreatic carcinoma cells AsPC-1 and, as human normal cells, fibroblast cells MRC5 derived from fetal lung was plated in 96-well microplates and incubated at 37°C in a 5% carbon dioxide incubator. On the following day, a 100 μl each solution of the respective test compounds in serial two-folds dilution was added, followed by incubation for 3 days . The culture medium containing the test compounds was removed, and the cells were washed, to which was added a 0.4% (w/v) solution (dissolved in 1% acetic acid) of the dye SRB (sulforhodamine B) to fix and stain the cell protein. The unbound dye was removed and the plates were washed, to which was then added 200 μl of an extracting solution (10 mM Tris buffer solution) to extract the dye. The absorbance at 540 run of the absorption wave¬ length was measured and the cell amount was determined as the amount of protein. The ratio of the remaining amount of protein in each test group, assuming the amount of protein in the control group to which a solution of the test compound was not added as 100%, was determined to calculate the concentration, IC50 value, of the compound required for suppressing the remaining cell amount to 50% of that of the control group.
The results were as shown in [Table 1]. All of the test compounds suppressed the cell-growth of the breast cancer cells MDA-MB-453 at a by far lower concentration than that suppressing the growth of normal cells MRC5. Incidentally, in the following, the test compounds were shown by Working Example Number, for example, the compound of Working Example 36 was shown as "compound 36". [Table 1]
Cell-growth inhibition test
Figure imgf000061_0001
Test Example 2
Breast cancer cell growth-inhibiting action in vitro A 100 μl (2,000 cells) each suspension of the human cancer cells shown in [Table 2] was plated in 96- well microplates and incubated at 37°C in a 5% carbon dioxide incubator. On the following day, a 100 μl each solution of the respective test compounds in serial two-folds dilution was added, followed by incubation for 3 days . The culture medium containing the test compounds was removed, and the cells were washed, to which was added a 0.4% (w/v) solution (dissolved in 1% acetic acid) of the dye SRB to fix and stain the cell protein. The unbound dye was removed and the plates were washed, to which was then added 200 μl of an extracting solution (10 mM Tris buffer solution) to extract the dye. The absorbance at 540 nm of the absorption wave-length was measured and the cell amount was determined as the amount of protein. The ratio of the remaining amount of protein in each test group, assuming the amount of protein in the control group to which a solution of the test compound was not added as 100%, was determined to calculate the concentration, IC50 value, of the compound required for suppressing the remaining cell amount to 50% of that of the control group.
The results were as shown in [Table 2], The compounds of Working Example 36 and Working Example 7 of this invention were shown to suppress selectively the growth of human breast cancer strains . [Table 2]
Cell-growth inhibiting test
Figure imgf000062_0001
Test Example 3
Inhibition of phosphorylation of growth factor receptor tyrosine of human breast cancer
1000 μl (500,000 cells) of a cell suspension of human breast cancer T-47D was plated in 6-well culture plates and incubated at 37°C in a 5% carbon dioxide incubator. On the following day, added was 1000 μl of a solution of the test compound in 10 times stepwise dilution by means of a culture medium containing a 0.1% bovine fetal albumin in place of blood serum. One hour later, 10 ng/ml of epidermal growth factor (EGF) was added. Five minutes later, the extraction solution was added to suspend the reaction and, at the same time, the protein was extracted. To the extract solution was added antibody against the epidermal growth factor EGF receptor. Then, the epidermal growth factor EGF receptor protein was allowed to precipitate by immunoprecipitation. The precipitate was fractionated by protein electrophoresis, then, the protein in the electrophoresis gel was transferred to a nylon filter. This filter was allowed to react with a phosphorylated tyrosine specific antibody. The reaction product was fluorescent-labeld and allowed to react with a sensitive film. The amount of light in the sensitive film was quantitatively determined by means of an image-analyzing device. Assuming the amount of phosphorylation of EGF-receptor tyrosine of cells in the group to which the epidermal growth factor EGF was added as 100%, the ratios of the amount of phosphorylation in the groups to which solutions of compounds of various concentrations were added were determined.
And, to the human breast cancer cell T-47D, 2 ug/ml of hereglin was added to extract protein in the same manner, to which was added an antibody against human EGF receptor type oncogene HER2 to allow the human EGF receptor type oncogene HER2 protein to precipitate by immunoprecipitation. This precipitate was subjected, in the same manner, to electrophoresis to thereby transfer the protein in the electrophoresis gel into nylon filter. In the same manner, this filter was allowed to react with a phosphorylated tyrosine specific antibody. The reaction product was fluorescent-labeled and allowed to react with a sensitive film. The amount of light in the sensitive film was quantitatively determined by means of an image analyzing device. Assuming the amount of phosphorylation of HER2 tyrosine of cells in the group to which hereglin was added as 100%, the ratios of the amount of phosphorylation of HER2 tyrosine of cells in the groups, to which solutions of various concentrations were added, were determined.
And, to the human breast cancer cell T-47D, 2 ug/ml of halegrin was added to extract protein in the same manner, to which was added an antibody against human EGF receptor type oncogene HER3 to allow the EGF receptor type oncogene HER3 protein to precipitate by immunoprecipitation. This precipitate was subjected, in the same manner, to electrophoresis to thereby transfer the protein in the electrophoresis gel into nylon filter. In the same manner, this filter was allowed to react with a phosphorylated tyrosine specific antibody. The reaction product was fluorescent-labeled and allowed to react with a sensitive film. The amount of light in the sensitive film was quantitatively determined by means of an image analyzing device. Assuming the amount of phosphorylation of HER3 tyrosine of cells in the group to which hereglin was added as 100%, the ratios of the amount of phosphorylation of HER3 tyrosine of cells in the groups, to which solutions of various concentrations were added, were determined.
The results were as shown in [Table 3]. The compound of Working Example 36 of this invention was shown to inhibit concentration-dependently phosphorylation reaction of the tyrosine residue of the receptor protein, the phosphorylation reaction being caused by activation of the receptor tyrosine kinase due to stimulation of growth factor, when human breast cancer cells were subjected to stimulation with the growth factor EGF and hereglin. [Table 3]
Inhibition of phosphorylation of receptor tyrosine residue
Figure imgf000065_0001
From [Table 1], [Table 2] and [Table 3], the compounds of this invention are found to exhibit an action of inhibiting the activation of receptor tyrosine kinase due to the stimulation of growth factor, and to inhibit the growth of tumor cells, especially to inhibit the growth of breast cancer cells selectively, while showing no cytotoxicity to the growth of normal cells.
The present invention will be illustrated in further detail in the following Reference Examples, Working Examples and Formulation Examples, which are not intended to limit this invention within the scope of these Examples .
Elution in the column chromatography conducted in Reference Examples and Working Examples was carried out while monitoring with TLC (Thin Layer Chromatography) . In the TLC monitoring, as the TLC plate, use was made of kieselguhr 60F254 (70 to 230 mesh) manufactured by Merck & Co. , Inc., as the developing solvent, use was made of the same solvent as employed for eluting in the column chromatography, and the detection was conducted with a UV detector. The silica gel for the column was Kieselguhr 60 (70 to 230 mesh) manufactured by Merck & Co. Inc.. NMR spectra show proton NMR and were measured using tetramethylsilane as an internal or external standard with VARIAN Gemini 200 (200 MHZ type spectrometer) . All 6 values were expressed in ppm. And, the abbreviations used in Working Examples have the following meanings . srsinglet, brrbroad, drdoublet, trtriplet, q:guartet, dd:double doublet, td:triple doublet, ddd:doublet doublet doublet, mtmultiplet, J:coupling constant, Hz:Hertz. Reference Example 1
A mixture of cinnamamide (25.3 g) and 1,3- dichloroacetone (20.9 g) was heated at 130 °C for one hour. To the reaction mixture was poured water, which was neutralized with potassium carbonate, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSOή), and concentrated. The concentrate was purified by means of a silica gel column chromatography. From the fraction eluted with ether-hexane (1:5, v/v), 4-chloromethyl-2-[ (E)-2- phenylethenyl]oxazole (16.9 g, 47%) was obtained. Recrystallization from ether-hexane gave colorless needles, m.p. 72-73°C. Reference Example 2
A mixture of thiocinnamamide (11.7 g) , 1,3- dichloroacetone (9.1 g) and ethanol (145 ml) was stirred for one hour under reflux. The reaction mixture was poured into ice-water, which was neutralized with potassium carbonate, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ) and concentrated. The concentrate was purified by means of a silica gel column chromatography. From the fraction eluted with ether-hexane (1:6, v/v), 4-chloromethyl-2-[ (E)-2- phenylethenyl]thiazole (9.4 g, 56%) was obtained. Recrystallization from ether-hexane gave colorless plates, m.p. 88-89°C. Reference Example 3
In substantially the same manner as in Reference Example 1, (E)-3-(2-furyl) acrylic acid amide was allowed to react with 1,3-dichloroacetone to give 4- chloromethyl-2-[ (E)-2-(2-furyl)ethenyl]oxazole. Recrystallization from hexane gave pale yellow plates, m.p. 84-85°C Reference Example 4 In substantially the same manner as in Reference Example 1, (E,E)-5-phenyl-2,4-pentadienamide was allowed to react with 1, 3-dichloroacetone to give 4- chloromethyl-2-[ (E,E)-4-phenyl-l, 3-butadienyl]oxazole. Recrystallization from hexane gave pale yellow needles, m.p. 95-96°C.
Reference Example 5
A mixture of vanillin (50.0 g) , isopropyl iodide (82.3 g) , potassium carbonate (68.1 g) and N,N- dimethylformamide (DMF) (400 ml) was stirred for 15 hours at 80°C. The mixture was then poured into ice- water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO/,) and concentrated under reduced pressure. The concentrate was subjected to distillation under reduced pressure to give 4- isopropoxy-3-methoxybenzaldehyde (61.2 g, 96%), m.p. 122-124°C/0.25 mmHg. Reference Example 6
Sodium hydride (60% oil, 12.9 g) was added, in limited amounts at 0°C, to a solution of triethyl phosphonoacetate (72.1 g) and 4-isopropoxy-3- methoxybenzaldehyde (61.2 g) in N,N-dimethylformamide (DMF) (700 ml). The mixture was stirred for one hour at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS04) and concentrated to give ethyl 4- isopropoxy-3-methoxycinnamate (75.9 g, 91%). Recrystallization from ethyl acetate-hexane gave colorless needles, m.p. 103-104°C. Reference Example 7
A solution of aluminum chloride (A1C13) (6.1 g) in ether (70 ml) was added dropwise, at 0°C, to a suspension of lithium aluminum hydride (LiAlH ) (6.4 g) in ether (270 ml). The mixture was stirred for 10 minutes at room temperature, to which was then added dropwise, at room temperature, a solution of ethyl 4- isopropoxy-3-methoxycinnamate (35.4 g) in ether- tetrahydrofuran (THF) (3:1, 220 ml) . The mixture was stirred for 2 hours at room temperature, to which were added dropwise, under ice-cooling, water (170 ml) and 6N H2S0A (230 ml). The organic layer was separated, and the aqueous layer was subjected to extraction with ether. The organic layers were combined, washed with water, dried (MgS04) and concentrated. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:2, v/v) , was obtained (E)-3-(4-isopropoxy-3- methoxyphenyl)-2-propen-l-ol (27.0 g, 91%). NMR(δ ppm in CDC13) : 1.37 (6H,d,J=6Hz) , 1.52(lH,s), 3.87(3H,s), 4.30(2H,dd,J=6&lHz) , 4.52(lH,m), 6.24(lH,dt,J=16&6Hz) , 6.55(lH,d,J=16Hz) , 6.83(lH,d,J=8Hz) , 6.90( lH,dd,J=8&2Hz) , 6.94(lH,d,J=2Hz) . Reference Example 8
Activated manganese dioxide (84.5 g) was added to a solution of (E)-3-(4-isopropoxy-3-methoxyphenyl)-2- propen-1-ol (27.0 g) in chloroform (750 ml). The mixture was stirred for 15 hours at room temperature, which was subjected to filtration through a celite layer. The filtrate was concentrated to give 4- isoproρoxy-3-methoxycinnamaldehyde (24.2 g, 90%). Recrystallization from ethyl acetate - hexane gave colorless plates, m.p. 93-94°C. Reference Example 9
Sodium hydride (60% oil, 4.8 g) was added, in limited amounts at 0°C, to a solution of triethyl 4- phosphonocrotonate (30.3 g) and 4-benzyloxybenzaldehyde (23.4 g) in N,N-dimethylformamide (DMF) (110 ml). The mixture was stirred for 15 hours at room temperature. The reaction mixture was poured into IN HC1 (600 ml), which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO^) and concentrated to give ethyl (E,E)-5-(4- benzyloxyphenyl)-2,4-pentadienoate (23.8 g, 70%). Recrystallization from ethyl acetate-hexane gave pale yellow prisms, m.p. 109-110°C Reference Example 10
A mixture of ethyl (E,E)-5-(4-benzyloxyphenyl)- 2,4-pentadienoate (23.2 g) , palladium-carbon (5%, 10.0 g) and tetrahydrofuran (THF) (250 ml) was subjected to catalytic reduction under atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:3, v/v) , ethyl 5-(4- hydroxyphenyl)pentanoate (12.5 g, 75%) was obtained as an oily product.
NMR(δ ppm in CDC13) : 1.25(3H,t,J=7Hz) , 1.60-1.68(4H,m) , 2.32(2H,t,J=7Hz) , 2.55(2H,t,J=7Hz) , 4.13(2H,q,J=7Hz) , 4.97(lH,s), 6.75(2H,d,J=8Hz) , 7.03(2H,d,J=9Hz) . Reference Example 11
A mixture of ethyl 5-(4-hydroxyphenyl)pentanoate (12.5 g), benzyl bromide (10.6 g) , potassium carbonate (11.7 g) and N,N-dimethylformamide (DMF) (70 ml) was stirred for 3 hours at 100°C The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS04) and then concentrated. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:9, v/v), ethyl 5- (4-benzyloxyphenyl)pentanoate (14.1 g, 80%) was obtained as an oily product.
NMR ( δ ppm in CDC13 ) : 1 . 25 ( 3H , t , J=7Hz ) , 1 . 57 - 1 . 67 ( 4H ,m ) , 2 . 31 ( 2H, t , J=7Hz ) , 2 . 57 ( 2H , t , J=7Hz ) , 4 . 12 ( 2H , q , J=7Hz ) , 5.04(2H,s), 6.90(2H,d,J=9Hz) , 7.09(2H,d,J=9Hz) , 7.31- 7.46(5H,m) . Reference Example 12
A solution of ethyl 5-(4- benzyloxyphenyl)pentanoate (14.1 g) and diethyl oxalate (13.2 g) in ethanol (10 ml) was added to an ethanol solution of sodium ethoxide [prepared from sodium (1.35 g) and ethanol (40 ml)]. The mixture was heated for 30 minutes under reflux. The reaction mixture was heated for 30 minutes at 70°C, while distilling off ethanol under reduced pressure. The residue was partitioned between 2N HC1 (150 ml) and ethyl acetate (300 ml). The ethyl acetate layer was washed with water, dried (MgSOή) and then concentrated. The concentrate was dissolved in dimethyl sulfoxide (DMSO) (60 ml) - water (6 m). To the solution was added sodium chloride (2.6 g) , and the mixture was stirred for 3 hours at 125°C. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO^,), and then concentrated. The concentrate was dissolved in ethanol (100 ml), to which was added dropwise, at 0°C, a solution of sodium borohydride (NaBH^) (0.52 g) in ethanol (20 ml). The mixture was stirred for 30 minutes at 0°C, to which was added acetic acid (1.6 ml). The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, successively, which was dried (MgSO^,) and then concentrated. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:5, v/v), ethyl 6-(4-benzyloxyphenyl)-2- hydroxyhexanoate (9.5 g, 62%) was obtained as an oily product. NMR(δ ppm in CDC13) : 1.28(3H,t,J=7Hz) , 1.40-1.83(6H,m) , 2.56(2H,t,J=8Hz) , 2.74( lH,d,J=6Hz) , 4.12-4.28( lH,m) , 4.23(2H,q,J=7Hz) , 5.04(2H,s), 6.89(2H,d,J=9Hz) , 7.09(2H,d,J=9Hz) , 7.31-7.46(5H,m) . Reference Example 13 Sodium hydride (60% oil, 14.4 g) was added to dimethyl sulfoxide (300 ml). The mixture was stirred for 30 minutes at 85°C. The mixture was cooled to room temperature, to which was added, in limited amounts at 25-30°C, (5-carboxypentyl)triphenylphosphonium bromide [(C6H5)3P"(CH2)5COOH.Br+] (75.5 g). The mixture was stirred for 15 minutes at room temperature, to which was then added, in limited amounts under ice-cooling, 4-benzyloxybenzaldehyde (31.8 g) . The reaction mixture was stirred for 30 minutes at room temperature, which was poured into ice-water and acidified, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS04) and then concentrated. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:2, v/v), 7-(4- benzyloxyphenyl)-6-heptenoic acid (31.0 g, 67%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 94-95°C Reference Example 14
To a mixture of 7-(4-benzyloxyphenyl)-6-heptenoic acid (29.0 g) and ethanol (500 ml) was added concentrated sulfuric acid (0.5 ml). The mixture was heated for 8 hours under reflux. The reaction mixture was concentrated under reduced pressure, which was poured into ice-water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSOή) and then concentrated to give ethyl 7-(4-benzyloxyphenyl)-6-heptenoate (31.6 g) . NMR(δ ppm in CDC13) : 1.24(3H,t,J=7Hz) , 1.40-1.60(2H,m) , 1.60-1.80(2H,m) , 2.15-2.45(4H,m) , 4.11(2H,q,J=7Hz) , 5.05&5.06(2H,each s) , 5.54(0.6H,double t,J=ll .6&7.2Hz) , 6.05(0.4H,double t,J=15.8&7.2Hz) ,
6.33(0.4H,d,J=15.8Hz) , 6.35(0.6H,d,J=ll .6Hz) , 6.85- 7.0(2H,m), 7.15-7.50(5H,m) . Reference Example 15 A mixture of ethyl 7-(4-benzyloxyphenyl)-6- heptenoate (31.5 g), platinum dioxide (Pt02) (0.8 g) and ethanol (300 ml) was subjected to catalytic reduction at room temperature under hydrogen pressure of 4 kgf/cm2. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:1, v/v), ethyl 7-(4- benzyloxyphenyl)heptanoate (30.1 g, 95%) was obtained as an oily product. NMR(δ ppm in CDC13) : 1.25(3H,t,J=7Hz) , 1.25-1.40(4H,m) , 1.50-1.70(4H,m) , 2.28(2H,t,J=7.3Hz) ,
2.54(2H,t,J=7.3Hz) , 4.12 (2H,q,J=7.2Hz) , 5.04(2H,s), 6.89(2H,d,J=8.6Hz) , 7.08(2H,d,J=8.6Hz) , 7.3-7.5(5H,m) . Reference Example 16 Ethyl 7-(4-benzyloxyphenyl)heptanoate was subjected to substantially the same reaction as in Reference Example 12 to give ethyl 8-(4- benzyloxyphenyl)-2-hydroxyoctanoate. Recrystallization from ether-hexane gave colorless needles, m.p. 52-53°C Reference Example 17
Ethyl 3-(4-benzyloxyphenyl)propionate was subjected to substantially the same reaction as in Reference Example 12 to give ethyl 4-(4- benzyloxyphenyl)-2-hydroxybutanoate. Recrystallization from hexane gave colorless crystals, m.p. 51-52°C. Reference Example 18
To a mixture of ethyl 4-(4-benzyloxyphenyl)-2- hydroxybutanoate (35.2 g) and ethanol (200 ml) was added IN NaOH (240 ml). The mixture was stirred for one hour (0-25°C), then for 40 minutes at 60-70°C. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The aqueous layer was acidified and subjected to extraction with ethyl acetate. This ethyl acetate layer was washed with water, dried (MgSO_,) and, then, concentrated to give 4-(4-benzyloxyphenyl)-2- hydroxybutanoate (28.8 g, 84%). Recrystallization from ethyl acetate - hexane gave colorless crystals, m.p. 157-158°C. Reference Example 18
Triethylamine (20.7 g) was added dropwise, at - 30°C, to a solution of 4-(4-benzyloxyphenyl)-2- hydroxybutanoic acid (28.0 g) in tetrahydrofuran (THF) (400 ml). To the mixture was, then, added dropwise ethyl chlorocarbonate (22.3 g) at the same temperature. The reaction mixture was stirred for 2.5 hours at temperatures ranging from -25 to -10°C. The reaction mixture was then added dropwise at 0°C to a cone, aqueous ammonia (25%, 100 ml). The mixture was stirred for 40 minutes at 0°C, which was then poured into water. Resulting crystalline precipitate was collected by filtration to give 4-(4-benzyloxyphenyl)-2- ethoxycarbonyloxybutanamide (30.9 g, 88%). Recrystallization from acetone-hexane gave yellow prisms, m.p. 160-161°C. Reference Example 20
In substantially the same manner as in Reference Example 6, 4-isopropoxybenzaldehyde was allowed to react with triethyl phosphonoacetate to give ethyl 4- isopropoxycinnamate as an oily product. NMR( δ ppm in CDC13 ) : 1 . 33 ( 3H , t , J=7Hz ) ,
1.35(6H,d,J=6Hz) , 4.25(2H,q,J=7Hz) , 4.5-4.7 ( lH,m) , 6.30(lH,d,J=16Hz) , 6.87(2H,d,J=9Hz) , 7.46(2H,d,J=9Hz) , 7.63(lH,d,J=16Hz) . Reference Example 21 Ethyl 4-isopropoxycinnamate was subjected to reduction with diisobutyl aluminum hydride to give (E)- 3-(4-isopropoxyphenyl)-2-propen-l-ol as an oily product. NMR(δ ppm in CDC13) : 1.33(6H,d,J=6Hz) , 1.38(lH,t,J=6Hz) , 4.30(2H,dt,J=6&1.5Hz) , 4.45-
4.65(lH,m), 6.23( lH,dt,J=16&6Hz) , 6.56( lH,d,J=16Hz) , 6.84(2H,d,J=8.5Hz), 7.31(2H,d,J=8.5Hz) . Reference Example 22
In substantially the same manner as in Reference Example 8, (E)-3-(4-isopropoxyphenyl)-2-propen-l-ol was subjected to oxidation with manganese dioxide to give 4-isopropoxycinnamaldehyde as an oily product. NMR(δ ppm in CDC13) : 1.37 (6H,t,J=6Hz) , 4.5-4.7 ( lH,m) , 6.61(lH,dd,J=16&8Hz) , 6.92(2H,d,J=9Hz) ,
7.42(lH,d,J=16Hz) , 7.51(2H,d,J=9Hz) , 9.65( lH,d,J=8Hz) . Reference Example 23
A hexane solution of n-butyl lithium (1.6M, 15.6 ml) was added dropwise at -15°C to a mixture of (1,3- dioxolan-2-ylmethyl)triphenylphosphonium bromide (10.74 g) and tetrahydrofuran (110 ml). This mixture was stirred for one hour at the same temperature, to which was then added 3-methoxy-4-(5-methyl-2-phenyl-4- oxazolylmethoxy)benzaldehyde (6.74 g) . The mixture was stirred for 4 hours at 50°C. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with 0. IN HCl, water and a saturated aqueous saline solution, successively, followed by drying (MgSO ) . The solvent was then distilled off. The residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:2, v/v), 2-[2-[3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]vinyl]-l, 3- dioxolan (4.84 g) was obtained as an oily product. This oily product (4.84 g) was dissolved in tetrahydrofuran (90 ml), to which was added palladium- carbon (5%, 50% wet, 1.8 g) . The mixture was subjected to catalytic reduction under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated, which was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:3, v/v), 2-[2-[3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-l, 3- dioxolan (3.03 g, 37%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 90-91°C.
Reference Example 24 A mixture of 2-[2-[3-methoxy-4-(5-methyl-2-phenyl- 4-oxazolylmethoxy)phenyl]ethyl]-l, 3-dioxolan (2.73 g) and aqueous solution of acetic acid (50%, 75 ml) was stirred for 3 hours at 80°C. The reaction mixture was concentrated under reduced pressure. The concentrate was poured into water, which was made basic with potassium carbonate, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and, then, dried (MgSOA) . The solvent was distilled off to give 3-[3-methoxy-4-(5-methyl-2-phenyl-4- oxazolylmethoxy)phenyl]propionaldehyde (2.09 g, 86%). Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 85-86°C. Reference Example 25 A mixture of 3-[3-methoxy-4-(5-methyl-2-phenyl-4- oxazolylmethoxy)phenyl]propionaldehyde (1.79 g) , sodium cyanide (0.3 g), acetic anhydride (0.62 g) , benzyltributylammonium chloride (0.79 g), water (12 ml) and dichloromethane (35 ml) was stirred for 15 hours at room temperature. The organic layer was separated, washed with water and dried (MgSO,) . The solvent was distilled off. The residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:3, v/v), 2-acetoxy-4-[3-methoxy-4-(5-methyl-2-phenyl-4- oxazolylmethoxy)phenyl]butyronitrile (2.0 g, 94%) was obtained.
NMR(δ ppm in CDC13) : 2.14(3H,s), 2.12-2.31(2H,m) , 2.41(3H,s), 2.78(2H,t,J=8Hz) , 3.87(3H,s), 5.04(2H,s), 5.27(lH,t,J=7Hz) , 6.70( lH,dd,J=8&2Hz) ,
6.71(lH,d,J=2Hz) , 7.00(lH,d,J=9Hz) , 7.42-7.47 (3H,m) , 7.99-8.04(2H,m) . Reference Example 26
A mixture of 2-acetoxy-4-[3-methoxy-4-(5-methyl-2- phenyl-4-oxazolylmethoxy)phenyl]butyror.^trile (2.0 g), 6N HCl (24 ml) and dioxane (12 ml) was stirred for 4 hours under reflux. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0A) . Then, the solvent was distilled off. To the residual oily substance was added ethanolic hydrochloride (10%, 24 ml). The mixture was stirred for 1.5 hour under reflux. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0A) .
Then, the solvent was distilled off. The residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:2, v/v), ethyl 2-hydroxy-4-(4- hydroxy-3-methoxyphenyl)butanoate (0.73 g, 60%) was obtained.
NMR(δ ppm in CDC13) : 1.29(3H,t,J=7Hz) , 1.81-2.17 (2H,m) , 2.70(2H,t,J=8Hz), 2.84(lH,d,J=5Hz) , 3.88(3H,s), 4.13- 4.19(lH,m), 4.22(2H,q,J=7Hz), 5.50(lH,s), 6.70(lH,dd,J=7δ.2Hz) , 6.72(lH,s), 6.84( lH,d,J=9Hz) . Reference Example 27
Sodium borohydride (1.41 g) was added, in limited amounts at 0°C, to a solution of 4-acetyl-5-methyl-2- phenyloxazole (15.0 g) in ethanol (100 ml). The mixture was stirred for one hour at the same temperature, and for one hour at room temperature. The reaction mixture was poured into water, which was neutralized with 2N HCl to give 1-(5-methyl-2-phenyl-4- oxazolyl)ethanol (13.0 g, 86%). Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 101- 102°C. Reference Example 28
To a mixture of l-(5-methyl-2-phenyl-4- oxazolyl)ethanol (5.0 g), vanillin (3.75 g) , triphenyl phosphine (Ph3P) (7.1 g) and tetrahydrofuran (THF) (80 ml) was added dropwise, under ice-cooling, diethyl azodicarboxylate (DEAD) (4.71 g) . The mixture was stirred for 8 hours at room temperature. Then, the reaction mixture was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:4, v/v), 3-methoxy-4-[1- (5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (4.48 g, 54%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 104- 105°C.
Reference Example 29
In substantially the same manner as in Reference Example 6, 3-methoxy-4-[1-(5-methyl-2-phenyl-4- oxazolyl)ethoxy]benzaldehyde was allowed to react with triethyl phosphonoacetate to give ethyl 3-methoxy-4-[ 1- (5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamate. Recrystallization from acetone-isopropyl ether gave colorless needles, m.p. 121-122°C. Reference Example 30 To a solution of ethyl 3-methoxy-4-[ l-(5-methyl-2- phenyl-4-oxazolyl)ethoxy]cinnamate (5.05 g) in dichloromethane (100 ml) was added dropwise at 0 °C a toluene solution (1M, 31.0 ml) of diisobutyl aluminum hydride. The mixture was stirred for one hour at room temperature. To the reaction mixture was added methanol (2.0 ml), which was poured into 2N hydrochloric acid, followed by extraction with chloroform. The chloroform layer was washed with water and dried (MgSOA) , then the solvent was distilled off to give (E)-3-[3-methoxy-4-[ 1-(5-methyl-2-phenyl-4- oxazolyl)ethoxy]phenyl]-2-propen-l-ol (4.50 g, 99%). NMR(δ ppm in CDC13) : 1.44(lH,br t,J=6.5Hz), 1.75(3H,d,J=6.5Hz), 2.28(3H,s), 3.88(3H,s), 4.25- 4.35(2H,m), 5.37 ( lH,q,J=6.5Hz) , 6.23( lH,dt,J=16&6Hz) , 6.52(lH,dt,J=16&1.5Hz), 6.8-6.95(3H,m) , 7.35-7.5(3H,m) , 7.95-8.05(2H,m) . Reference Example 31
In substantially the same manner as in Reference Example 8, (E)-3-[3-methoxy-4-[ l-(5-methyl-2-phenyl-4- oxazolyl)ethoxy]phenyl]-2-propen-l-ol was subjected to oxidation with activated manganese dioxide to give 3- methoxy-4-[l-(5-methyl-2-phenyl-4- oxazolyl)ethoxy]cinnamaldehyde. Recrystallization from acetone-isopropyl ether gave colorless needles, m.p. 152-153°C. Reference Example 32
Sodium hydride (60% oil, 8.43 g) was added, in limited amounts at 0°C, to a solution of 4-benzyloxy-3- methoxybenzaldehyde (46.4 g) and triethyl phosphonocrotonate (50.3 g) in N,N-dimethylformamide (DMF) (190 ml) . This mixture was stirred for 15 hours at room temperature, which was poured into IN HCl (1 L), followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ), then the solvent was distilled off. The residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:3, v/v), ethyl (E,E)-5-(4- benzyloxy-3-methoxyphenyl)-2,4-pentadienoate (38.3 g, 59%). Recrystallization from ethyl acetate - hexane gave pale yellow needles, m.p. 85-86°C. Reference Example 33
In substantially the same manner as in Reference Example 10, ethyl (E,E)-5-(4-benzyloxy-3- methoxyphenyl)-2,4-pentadienoate was subjected to catalytic reduction to give ethyl 5-(4-hydroxy-3- methoxyphenyl)pentanoate.
NMR(δ ppm in CDC13): 1.25(3H,t,J=7Hz) , 1.61-1.66(4H,m) , 2.32(2H,t,J=7Hz) , 2.56 (2H,t,J=7Hz) , 3.88(3H,s), 4.12(2H,q,J=7Hz) , 5.46(lH,s), 6.66(lH,dd,J=8&2Hz) , 6.83(lH,d,J=9Hz) .
Reference Example 34 A mixture of ethyl 5-(4-hydroxy-3- methoxyphenyl)pentanoate (27.92 g) , benzyl bromide (20.82 g) , potassium carbonate (22.9 g) and N,N- dimethylformamide (DMF) (140 ml) was stirred for 15 hours at 90°C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0A), then the solvent was distilled off. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:6, v/v), ethyl 5-(4-benzyloxy-3- methoxyphenyl)pentanoate (31.64 g, 84%) was obtained. NMR(δ ppm in CDC13) : 1.25(3H,t,J=7Hz) , 1.61-1.66(4H,m) , 2.32(2H,t,J=7Hz) , 2.56(2H,t,J=7Hz) , 3.88(3H,s), 4.12(2H,q,J=7Hz) , 5.12(2H,s), 6.64 ( lH,dd,J=8&2Hz) ,
6.72(lH,d,J=2Hz) , 6.80(lH,d,J=8Hz) , 7.28-7.47(5H,m) . Reference Example 35
In substantially the same manner as in Reference Example 12, ethyl 5-(4-benzyloxy-3- methoxyphenyl)pentanoate was condensed with diethyl oxalate, and the condensate was subjected to decarboxylation, followed by subjecting the reaction mixture to reduction with sodium borohydride to give ethyl 6-(4-benzyloxy-3-methoxyphenyl)-2- hydroxyhexanoate.
NMR(δ ppm in CDC13) : 1.27 (3H,t,J=7Hz) , 1.43-1.79(6H,m) , 2.55(2H,t,J=8H) , 2.73(lH,d,J=6Hz) , 3.88(3H,s), 4.12- 4.17(lH,m), 4.23(2H,q,J=7Hz) , 5.12(2H,s), 6.63(lH,dd,J=8&2Hz) , 6.72(lH,d,J=2Hz) , 6.79(lH,d,J=8Hz) , 7.26-7.46 (5H,m) . Reference Example 36
In substantially the same manner as in Reference Example 6, 4-benzyloxy-3-ethoxybenzaldehyde was allowed to react with triethyl phosphonoacetate to give ethyl 4-benzyloxy-3-ethoxycinnamate. Recrystallization from isopropyl ether - hexane gave colorless needles, m.p. 74 . 5-75 °C .
Reference Example 37
In substantially the same manner as in Reference
Example 10, ethyl 4-benzyloxy-3-ethoxycinnamate was subjected to catalytic reduction to give ethyl 3-(3- ethoxy-4-hydroxyphenyl)propionate.
NMR(δ ppm in CDC13): 1.24(3H,t,J=7Hz) ,
1.44(3H,t,J=7Hz) , 2.57(2H,t,J=7.7Hz) ,
2.87(2H,t,J=7.7Hz) , 4.09 (2H,q,J=7Hz) , 4.13(2H,q,J=7Hz) , 5.54(lH,s), 6.69(lH,d,J=8.4Hz), 6.70(lH,s),
6.84(lH,d,J=8.4Hz) .
Reference Example 38
In substantially the same manner as in Reference
Example 38, ethyl 3-(3-ethoxy-4- hydroxyphenyl) ropionate was allowed to react with benzyl bromide to give ethyl 3-(4-benzyloxy-3- ethoxyphenyl)propionate.
NMR(δ ppm in CDC13): 1.23(3H,t,J=7Hz) ,
1.45(3H,t,J=7Hz) , 2.58(2H,t,J=7.6Hz) , 2.87(2H,t,J=7.6Hz) , 4.09(2H,q,J=7Hz) , 4.12(2H,q,J=7Hz) ,
5.11(2H,s) , 6.66(lH,dd,J=8.3δ.l.9Hz) ,
6.76(lH,d,J=1.9Hz) , 6.82 ( lH,d,J=8.3Hz) , 7.23-
7.61(5H,m) .
Reference Example 39 In substantially the same manner as in Reference
Example 12, starting from ethyl 3-(4-benzyloxy-3- ethoxyphenyl)propionate, 4-(4-benzyloxy-3- ethoxyphenyl)-2-hydroxybutanoate was obtained.
Recrystallization from ethyl acetate - isopropyl ether gave colorless needles, m.p. 62-63°C.
Reference Example 40
In substantially the same manner as in Reference
Example 6, 3-benzyloxy-4-methoxybenzaldehyde was allowed to react with triethyl phosphonoacetate to give ethyl 3-benzyloxy-4-methoxycinnamate.
Recrystallization from ether-hexane gave colorless needles , m . p . 95-96 °C .
Reference Example 41
In substantially the same manner as in Reference
Example 10, ethyl 3-benzyloxy-4-methoxycinnamate was subjected to catalytic reduction to give ethyl 3-(3- hydroxy-4-methoxyphenyl)propionate.
NMR(δ ppm in CDC13): 1.24(3H,t,J=7Hz) ,
2.57(2H,t,J=7.6Hz) , 2.86(2H,t,J=7.6Hz) , 3.86(3H,s),
4.13(2H,q,J=7.2Hz) , 5.58(lH,s), 6.68( lH,dd,J=8.2&2Hz) , 6.77(lH,d,J=8.2Hz) , 6.78( lH,d,J=2Hz) .
Reference Example 42
In substantially the same manner as in Reference
Example 34, ethyl 3-(3-hydroxy-4- methoxyphenyl)propionate was allowed to react with benzyl bromide to give ethyl 3-(3-benzyloxy-4- methoxyphenyl)propionate. Recrystallization from hexane gave colorless needles, m.p. 49.5-50.5°C
Reference Example 43
In substantially the same manner as in Reference Example 12, starting from ethyl 3-( 3-benzyloxy-4- methoxyphenyl)propionate, ethyl 4-( 3-benzyloxy-4- methoxyphenyl)-2-hydroxybutanoate was obtained.
Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 93-94°C. Reference Example 44
In substantially the same manner as in Reference
Example 34, syringaldehyde was allowed to react with benzyl bromide to give 4-benzyloxy-3,5- dimethoxybenzaldehyde. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 65-66°C.
Reference Example 45
In substantially the same manner as in Reference
Example 6, 4-benzyloxy-3,5-dimethoxybenzaldehyde was allowed to react with triethyl phosphonoacetate to give ethyl 4-benzyloxy-3,5-dimethoxycinnamate.
Recrystallization form ether-hexane gave colorless plates, m.p. 68-69°C. Reference Example 46
In substantially the same manner as in Reference Example 30, ethyl 4-benzyloxy-3,5-dimethoxycinnamate was subjected to catalytic reduction with diisobutyl aluminum hydride to give (E)-3-(4-benzyloxy-3,5- dimethoxyphenyl)-2-propen-l-ol . Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 72- 73°C. Reference Example 47
In substantially the same manner as in Reference Example 8, (E)-3-(4-benzyloxy-3,5-dimethoxyphenyl)-2- propen-1-ol was subjected to oxidation with activated manganese dioxide to give 4-benzyloxy-3,5- dimethoxycinnamaldehyde. Recrystallization from ethyl acetate - hexane gave colorless plates, m.p. 114-115°C Reference Example 48
A mixture of 4-isopropoxybenzaldehyde (37.3 g) , sodium pyruvate (25.0 g) , sodium hydrogencarbonate (19.1 g), water (150 ml) and methanol (150 ml) was stirred for 4 hours under reflux. To the mixture was added sodium pyruvate (25.0 g) , which was stirred for further 20 hours under reflux. The reaction mixture was poured into water, which was washed with ether. The aqueous layer was acidified with 6N HCl, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS04) , and, then, the solvent was distilled off to give an oily substance. The oily substance was dissolved in hydrochloric acid - ethanol (5%, 80 ml), which was stirred for 30 minutes at 80°C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ) , and, then, the solvent was distilled off. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:4, v/v), ethyl (E)-(4-isopropoxybenzylidene)pyruvate (21.6 g, 36%) was obtained as an oily product. NMR(δ ppm in CDC13): 1.37 (6H,t,J=6Hz) , 1.41(3H,t,J=6Hz) , 4.39(2H,q,J=7Hz) , 4.55-4.75( lH,m) ,
6.91(2H,d,J=9Hz) , 7.23( lH,d,J=16Hz) , 7.58(2H,d,J=9Hz) , 7.83(lH,d,J=16Hz) . Reference Example 49
In acetic acid - ethanol (20%, 500 ml) was dissolved ethyl (E)-(4-isopropoxybenzylidene)pyruvate (19.0 g). To the solution was added palladium-carbon (5%, 50% wet, 3.0 g) . The mixture was subjected to catalytic reduction under one atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated. The residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:4, v/v), ethyl 2-hydroxy-4-(4-isopropoxyphenyl)butyrate (11.2 g, 58%) was obtained as an oily product. NMR ( δ ppm in CDC13 ) : 1 . 29 ( 3H , t , J=7Hz ) ,
1.32(3H,t,J=6Hz) , 1.8-2.2 (2H,m) , 2.65-2.75(2H,m) , 2.80(lH,d,J=5.5Hz) , 4.1-4.25( lH,m) , 4.21(2H,q,J=7Hz) , 4.4-4.6(lH,m) , 6.81(2H,d,J=8.5Hz) , 7.10(2H,d,J=8.5Hz) . Reference Example 50 To a solution of ethyl 2-hydroxy-4-(4- isopropoxyphenyl)butyrate (5.0 g) in pyridine (50 ml) was added dropwise thionyl chloride (2.68 g) at room temperature. The mixture was stirred for one hour. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0A) . Then the solvent was distilled off, and the residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:9, v/v), ethyl 2-chloro-4-(4-isopropoxyphenyl)butyrate (1.45 g, 27%) was obtained as an oily product. NMR(δ ppm in CDC13): 1.29 (3H,t,J=7Hz) ,
1.32(6H,t,J=6Hz) , 2.1-2.35 (2H,m) , 2.6-2.9(2H,m) , 4.15- 4.3(3H,m), 4.4-4.6(lH,m) , 6.82 (2H,d,J=8.5Hz) , 7.09(2H,d,J=8.5Hz) . Reference Example 51
Sodium hydride (60% oil, 1.05 g) was added, under ice-cooling, to a mixture of 2-( 1, 3-dioxolan-2- yl)ethyltriphenylphosphonium bromide (51.0 g) and N,N- dimethylformamide (DMF) (200 ml). This mixture was stirred for 15 minutes at the same temperature, to which was added 4-isopropoxybenzaldehyde (18.0 g) . The mixture was stirred for 5 hours at temperatures ranging from 80 to 85°C. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous saline solution, successively, which was dried (MgSOA), then the solvent was distilled off. The residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:4, v/v), an oily product (14.5 g) was obtained. This oily product was dissolved in ethanol (250 ml), to which was added palladium-carbon (5%, 50% wet, 5.0 g) . The mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated. The residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:5, v/v), 2-[3-(4- isopropoxyphenyl)propyl]-l, 3-dioxolan (6.70 g, 24%) was obtained as an oily product.
NMR(δ ppm in CDC13): 1.32 (6H,d,J=6Hz) , 1.6-1.8(4H,m) , 2.5-2.65(2H,m) , 3.8-4.0(4H,m) , 4.8-4.9( lH,m) , 6.80(2H,d,J=8.5Hz) , 7.07 (2H,d,J=8.5Hz) . Reference Example 52 4-Benzyloxybenzaldehyde (2.4 g) was added to a mixture of (7-carboxyheptyl)triphenylphosphonium bromide [ (C6H5)3P"(CH2)7COOH.Br+] (6.02 g) , sodium hydride (60%, oil, 1.13 g) and dimethyl sulfoxide (100 ml) - tetrahydrofuran (100 ml) . The mixture was stirred for 4 hours at 40°C. The reaction mixture was poured into ice-water, which was acidified, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0A), which was then concentrated. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:2), 9-(4- benzyloxyphenyl)-8-nonenoic acid (2.57 g, 67%). Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 81-82°C Reference Example 53
To a mixture of 9-(4-benzyloxyphenyl)-8-nonenoic acid (4.5 g) and ethanol (70 ml) was added cone, sulfuric acid (0.1 ml). The mixture was heated for 8 hours under reflux. The reaction mixture was concentrated under reduced pressure, which was poured into ice-water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSOA) and concentrated to give ethyl 9- (4-benzyloxyphenyl)-8-nonenoate (4.35%, 89%). NMR(δ ppm in CDC13): 1.24 ( 3H,t,J=7.2Hz) , 1.20- 1.70(8H,m), 2.10-2.40(4Hfm) , 4.12 (2H,q,J=7.2Hz) , 5.05&5.07(2H,each s), 5.42(0.6H,double t,J=ll .6&7.4Hz) , 6.06(0.4H,double t,J=15.8&6.8Hz) , 6.27-6.36( lH,m) , 6.87-7.47(9H,m) .
Reference Example 54
A mixture of ethyl 9-(4-benzyloxyphenyl)-8- nonenoate (18.7 g) , platinum dioxide (Pt02) (0.4 g) and ethanol (150 ml) was subjected to catalytic reduction at room temperature under hydrogen pressure of 4 kgf/cm2. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:5), ethyl 9-(4- benzyloxyphenyl)nonanoate (10.57, 56%) was obtained as an oily product.
NMR(δ ppm in CDC13) : 1.25(3H,t,J=7.0Hz) , 1.20- 1.70(12H,m), 2.28(2H,t,J=7.8Hz) , 2.53(2H,t,J=7.4Hz) , 4.12(2H,q,J=7.0Hz) , 5.03(2H,s), 6.89(2H,d,J=8.4Hz) , 7.08(2H,d,J=8.4Hz) , 7.20-7.46(5H,m) . Reference Example 55
In substantially the same manner as in Reference Example 12, starting from ethyl 9-(4- benzyloxyphenyl)nonanoate, ethyl 10-(4- benzyloxyphenyl)-2-hydroxydecanoate was obtained. Recrystallization from ethyl acetate - hexane gave colorless crystals, m.p. 40-41°C. Reference Example 56
A solution of ethyl 7-(4- benzyloxyphenyl)heptanoate (11.6 g) in ether (50 ml) was added dropwise to a mixture of lithium aluminum hydride (1.3 g) and ether (250 ml). The mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added dropwise a saturated aqueous saline solution (5 ml). Insolubles were filtered off, and the filtrate was concentrated under reduced pressure to give 7-(4-benzyloxyphenyl)heptanol (8.5 g, 83%). Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 72-73°C Reference Example 57
Methanesulfonyl chloride (8.4 g) was added dropwise to an ice-cooled mixture of 7-(4- benzyloxyphenyl)heptanol (8.4 g) , triethylamine (2.8 g) and ethyl acetate (100 ml), followed by stirring for 30 minutes at the same temperature. The reaction mixture was washed with water, dried (MgS0A) and, then, concentrated to give 7-(4-benzyloxyphenyl)heptyl methanesulfonate (9.9 g, 94%).
NMR(δ ppm in CDC13): 1.20-1.83( 10H,m) ,
2.54(2H,t,J=7.8Hz) , 3.00(3H,s), 4.22(2H,t,J=6.6Hz) , 5.04(2H,s), 6.90(2H,d,J=8.6Hz) , 7.09(2H,d,J=8.6Hz) ,
7.25-7.50(5H,m) .
Reference Example 58
A mixture of 7-(4-benzyloxyphenylJheptyl methanesulfonate (9.9 g), sodium cyanide (1.9 g) and N,N-dimethylformamide (DMF) (50 ml) was stirred for 2 hours at 80°C. The reaction mixture was poured into water (300 ml). The resulting crystalline precipitate was collected by filtration, which was recrystallized from ethyl acetate - hexane to give 8-(4- benzyloxyphenylJoctanenitrile (7.3 g, 90%) as colorless prisms, m.p. 49-50°C.
Reference Example 59
A mixture of 8-(4-benzyloxyphenyl)octanenitrile
(7.2 g), 4N potassium hydroxide (35 ml) and 2- methoxyethanol (35 ml) was stirred for 20 hours under reflux. The reaction mixture was poured into water
(100 ml), which was acidified with 2N hydrochloric acid, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSOA) , and, then concentrated to give 8-(4- benzyloxyphenyl)octanoic acid (6.7 g, 88%) as colorless prisms, m.p. 95-96°C.
Reference Example 60
In substantially the same manner as in Reference Example 54, 8-(4-benzyloxyphenyl)octanoic acid was subjected to esterification to give ethyl 8-(4- benzyloxyphenyl)octanoate.
NMR(δ ppm in CDC13): 1.25(3H,t,J=7.2Hz) , 1.30-
1.40(6H,m), 1.45-1.55(4H,m) , 2.28 (2H,t,J=7.4Hz) , 2.54(2H,t,J=8.0Hz) , 4.12(2H,q,J=7.2Hz) , 5.04(2H,s),
6.89(2H,d,J=8.8Hz) , 7.08(2H,d,J=8.8Hz) , 7.25- 7.50(5H,m) . Reference Example 61
In substantially the same manner as in Reference Example 12, starting from ethyl 8-(4- benzyloxyphenyl)octanoate, ethyl 9-(4-benzyloxyphenyl)- 2-hydroxynonanoate was obtained. NMR(δ ppm in CDC13) : 1.30(3H,t,J=7.0Hz) , 1.31- 1.90(12H,m), 2.54(2H,t,J=7.6Hz) , 2.72(lH,d,J=6.0Hz) , 4.16(lH,s), 4.24(2H,q,J=7.0Hz) , 5.04(2H,s), 6.89(2H,d,J=8.8Hz) , 7.09(2H,d,J=8.8Hz) , 7.28- 7.50(5H,m) . Reference Example 62
In substantially the same manner as in Reference Example 9, 4-benzyloxy-3-ethoxybenzaldehyde was allowed to react with triethyl 4-phosphonocrotonate to give ethyl (E,E)-5-(4-benzyloxy-3-ethoxyphenyl)-2 ,4- pentadienoate. Recrystallization from isopropyl ether gave colorless needles, m.p. 72.5-73.5°C. Reference Example 63 In substantially the same manner as in Reference
Example 10, ethyl (E,E)-5-(4-benzyloxy-3-ethoxyphenyl)- 2,4-pentadienoate was subjected to catalytic reduction to give ethyl 5-(3-ethoxy-4-hydroxyphenyl)pentanoate. NMR(δ ppm in CDC13) : 1.25(3H,t,J=7.0Hz) , 1.43(3H,t,J=7.0Hz) , 1.50-1.76(4H,m) ,
2.31(2H,t,J=7.1Hz) , 2.54(2H,d,J=7.1Hz) , 4.10(2H,q,J=7.0Hz) , 4.12 (2H,q,J=7.0Hz) , 5.52(lH,s), 6.66(lH,d,J=8.4Hz) , 6.66(lH,s), 6.83( lH,d,J=8.4Hz) . Reference Example 64 In substantially the same manner as in Reference Example 34, ethyl 5-(3-ethoxy-4- hydroxyphenyl)pentanoate was allowed to react with benzyl bromide to give ethyl 5-( 4-benzyloxy-3- ethoxyphenyl)pentanoate. NMR( δ ppm in CDC13 ) : 1 . 24 ( 3H , t , J=7 . 0Hz ) ,
1 . 45 ( 3H , t , J=7 . 0Hz ) , 1 . 53- 1 . 73 ( 4H , m ) , 2.31(2H,t,J=7.1Hz) , 2.55 (2H, t , J=7.2Hz) ,
4.10(2H,q,J=7.0Hz) , 4.12 ( 2H,q, J=7.0Hz ) , 5.11(2H,s),
6.64(lH,dd,J=8.1&1.9Hz) , 6.73 ( lH,d, J=l .9Hz ) ,
6.81(lH,d,J=8.1Hz) , 7.23-7.49(5H,m) . Reference Example 65
In substantially the same manner as in Reference
Example 12, starting from ethyl 5-(4-benzyloxy-3- ethoxyphenyl)pentanoate, ethyl 6-(4-benzyloxy-3- ethoxyρhenyl)-2-hydroxyhexanoate was obtained. NMR(δ ppm in CDC13) : 1.31(3H,t,J=7.1Hz) ,
1.45(3H,t,J=7.1Hz) , 1.37-1.92(6H,m) ,
2.54(2H,t,J=7.3Hz) , 2.71( lH,d,J=5.6Hz) ,
4.10(2H,q,J=7.1Hz) , 4.23(2H,q,J=7.1Hz) , 4.04-
4.29(lH,m), 5.11(2H,s), 6.64( lH,dd,J=8.0&1.8Hz) , 6.73(lH,d,J=1.8Hz) , 6.81( lH,d,J=8.0Hz) , 7.27-
7.49(5H,m) .
Reference Example 66
In substantially the same manner as in Reference
Example 9, 3-benzyloxy-4-methoxybenzaldehyde was allowed to react with triethyl 4-phosphonocrotonate to give ethyl (E,E)-5-(3-benzyloxy-4-methoxyphenyl)-2,4- pentadienoate, m.p. 99-100°C.
Reference Example 67
In substantially the same manner as in Reference Example 10, ethyl (E,E)-5-(3-benzyloxy-4- methoxyphenyl)-2,4-pentadienoate was subjected to catalytic reduction to give ethyl 5-(3-hydroxy-4- methoxyphenyl)pentanoate.
NMR(δ ppm in CDC13) : 1.25(3H,t,J=7.2Hz) , 1.54- 1.74(4H,m), 2.31(2H,t,J=7.2Hz) , 2.54 (2H,d,J=7.2Hz) ,
3.86(3H,s), 4.12(2H,q,J=7.2Hz) , 5.56(lH,s),
6.64(lH,dd,J=8.2&2.0Hz), 6.76 ( lH,d,J=2.0Hz) ,
6.77(lH,d,J=8.2Hz) .
Reference Example 68 In substantially the same manner as in Reference
Example 34, ethyl 5-(3-hydroxy-4- methoxyphenyl)pentanoate was allowed to react with benzyl bromide to give ethyl 5-(3-benzyloxy-4- methoxyphenyl)pentanoate.
NMR(δ ppm in CDC13): 1.25( 3H,t,J=7.2Hz) , 1.47- 1.68(4H,m), 2.28(2H,t,J=6.7Hz) , 2.52 (2H,t,J=6.7Hz) , 3.86(3H,s), 4.12(2H,q,J=7.2Hz) , 5.14(2H,ε), 6.70- 6.84(3H,s), 7.29-7.47(5H,m) . Reference Example 69
In substantially the same manner as in Reference Example 12, starting from ethyl 5-(3-benzyloxy-4- methoxyphenyl)pentanoate, ethyl 6-(3-benzyloxy-4- methoxyphenyl)-2-hydroxyhexanoate was obtained. NMR(δ ppm in CDC13) : 1.28(3H,t,J=7.2Hz) , 1.35- 1.87(6H,m), 2.51(2H,t,J=7.4Hz) , 2.70( lH,d,J=5.8Hz) , 3.86(3H,s), 4.06-4.17 ( lH,m) , 4.23(2H,q,J=7.2Hz) , 5.13(2H,s), 6.69-6.84(3H,m) , 7.29-7.48(5H,m) . Reference Example 70
In substantially the same manner as in Reference Example 1, 3,4-dihydro-2-naphthalenecarboxamide was allowed to react with 1, 3-dichloroacetone to give 4- chloromethyl-2-(3,4-dihydro-2-naphthyl)oxazole. Recrystallization from isopropyl ether gave colorless prisms, m.p. 73-74°C. Working Example 1 A mixture of 5-[3-[4-(5-methyl-2-phenyl-4- oxazolylmethoxy)phenyl]propyl]-2 ,4-oxazolidinedione (0.35 g) , 4-chloromethyl-2-[ (E)-2-phenylethenyl]oxazole (0.265 g) , potassium carbonate (0.145 g) and N,N- dimethylformamide (DMF) (10 ml) was stirred for 4 hours at 90-100°C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS0A) , and, then, concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with acetone-hexane (1:3, v/v), 5-[3-[4-(5- methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-3-[2- [(E)-2-phenylethenyl]-4-oxazolylmethyl]-2,4-oxazo¬ lidinedione (0.38 g, 75%). Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 125- 126°C.
Working Example 2
In substantially the same manner as in Working Example 1, 5-[3-[4-(5-methyl-2-phenyl-4- oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-phenyloxazole to give 5-[3-[4-(5-methy1-2-phenyl-4- oxazolylmethoxy)phenyl]propyl]-3-(2-phenyl-4- oxazolylmethyl)-2,4-oxazolidinedione. Recrystallization from acetone - isopropyl ether gave colorless needles, m.p. 115-116°C. Working Example 3
A mixture of 4-isopropoxy-3-methoxycinnamaldehyde (15.68 g) , 2,4-oxazolidinedione (21.58 g), piperidine (6.0 g) and acetic acid (450 ml) was stirred for 15 hours under reflux. The reaction mixture was concentrated under reduced pressure. To the concentrate was poured water, which was neutralized with potassium carbonate, followed by extraction with chloroform. The chloroform layer was washed with water and dried (MgSO ) , which was then concentrated under reduced pressure. Resulting crystalline precipitates were collected by filtration with ethyl acetate - ether. The filtrate was concentrated under reduced pressure, which was subjected to a silica gel column chromatography. From the fraction eluted with chloroform - ethyl acetate (4:1, v/v), crystals were further obtained. The crystals were combined with those obtained previously to give 5-[3-(4-isopropoxy-3- methoxyphenyl )propenylidene]-2, 4-oxazolidinedione (7.6 g, 35%), Recrystallization from ethyl acetate - hexane gave yellow prisms, m.p. 226-227°C. Working Example 4
5-[3-(4-isopropoxy-3-methoxyphenyl)propenylidene]- 2,4-oxazolidinedione (7.1 g) was dissolved in tetrahydrofuran (THF) (150 ml) . To the solution was added palladium-carbon (5%, 7.1 g) , which was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with chloroform - ethyl acetate (4:1, v/v), 5-[3-(4- isopropoxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione (4.29 g, 60%) was obtained as an oily product. NMR(δ ppm in CDC13) : 1.35(6H,d,J=6Hz) , 1.79-2.05(4H,m) , 2.62(2H,t,J=7Hz) , 3.84(3H,s), 4.47(lH,m),
4.84(lH,dd,J=7&5Hz) , 6.67( lH,dd,J=8&2Hz) , 6.69(lH,s), 6.82(lH,d,J=8Hz) , 8.33(lH,s). Working Example 5
A solution of titanium tetrachloride (TiClA) (10.6 g) in dichloromethane (10 ml) was added dropwise, at 0°C, to a solution of 5-[3-(4-isopropoxy-3- methoxyphenyl)propyl]-2,4-oxazolidinedione (4.3 g) in dichloromethane (130 ml). The mixture was stirred for one hour at 0°C, which was poured into 2N HCl. The mixture was stirred for 15 minutes at room temperature. The organic layer was separated, and the aqueous layer was subjected to extraction with chloroform. The chloroform layer was combined with the organic layer separated previously, which was washed with water, 2N HCl and water, successively, followed by drying (MgSOA) and concentration to give 5-[3-(4-hydroxy-3- ethoxyphenyl)propyl]-2 ,4-oxazolidinedione (2.8 g, 76%). Recrystallization from ethanol-hexane gave colorless prisms, m.p. 147-148°C Working Example 6
Sodium hydride (60% oil, 0.32 g) was added, at 0 °C, a solution of 5-[3-(4-hydroxy-3- methoxyphenyl)propyl]-2,4-oxazolidinedione (1.0 g) in N,N-dimethylformamide (DMF) (20 ml). The mixture was stirred for one hour at room temperature. To the reaction mixture was then added 4-chloromethyl-2-[ (E)- 2-phenylethenyl]oxazole (0.87 g) . The mixture was stirred for 3.5 hours at 90°C. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSOA) and concentrated under reduced pressure to give 5-[3-[3- methoxy-4-[2-[ (E)-2-phenylethenyl]-4-oxazolylmeth- oxy]phenyl]propyl]-2,4-oxazolidinedione (1.1 g, 66%). Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 178-179°C Working Example 7
In substantially the same manner as in Working Example 1, 5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]- 4-oxazolylmethoxyJphenyl]propyl]-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenyl]oxazole to give 5-[3-[3-methoxy-4-[2- [(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]- 3-[2-[ (E)-2-phenylethenyl]-4-oxazolylmethyl]-2,4- oxazolidinedione. Recrystallization from acetone - isopropyl ether gave colorless needles, m.p. 123-124°C. Working Example 8
In substantially the same manner as in Working Example 1, 5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]- 4-oxazolylmethoxy]phenyl]propyl ]-2 ,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenyl]thiazole to give 5-[ 3-[3-methoxy-4-[2- [(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]- 3-[2-[ (E)-2-phenylethenyl]-4-thiazolylmethyl]-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 134-135°C. Working Example 9 In substantially the same manner as in Working Example 1, 5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]- 4-oxazolylmethoxy]phenyl]propyl]-2, 4-oxazolidinedione was allowed to react with 4-chloromethyl-2- phenyloxazole to give 5-[3-[3-methoxy-4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-3-(2- phenyl-4-oxazolylmethyl)-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 155-156°C. Working Example 10
Sodium hydride (60% oil, 0.34 g) was added, at 0°C, to a solution of 5-[4-(4-hydroxyphenyl)butyl]-2,4- oxazolidinedione (1.0 g) in N,N-dimethylformamide (DMF) (20 ml). The mixture was stirred for one hour at room temperature. To the reaction mixture was then added 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole (0.93 g) , which was stirred for 3.5 hours at 90°C. The reaction mixture was poured into water, which was neutralized with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried
(MgSO ) and, then, concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - chloroform (1:5, v/v), 5-[4-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxyJphenyl]butyl]-2,4- oxazolidinedione (0.29 g, 17%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 144-145°C. Working Example 11 In the column chromatography of Working Example
10, from the fraction subsequently eluted, 5-[4-[4-[2- [(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]- 3-[2-[ (E)-2-phenylethenyl]-4-oxazolylmethyl]-2, - oxazolidinedione (0.15 g, 12%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless plates, m.p. 162-163°C Working Example 12
In substantially the same manner as in Working Example 10, 5-[4-(4-hydroxyphenyl)butyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl ]thiazole to give 5- [4-[4-[2-[ (E)-2-phenylethenyl]-4- thiazolylmethoxy]phenyl]butyl]-2,4-oxazolidinedione. Recrystallization from chloroform - ethyl acetate gave colorless needles, m.p. 166-167°C. Working Example 13
In the column chromatography of Working Example 12, from the fraction subsequently eluted, 5-[4-[4-[2- [(E)-2-phenylethenyl]-4-thiazolylmethoxy]phenyl]butyl]- 3-[2-[ (E)-2-phenylethenyl]-4-thiazolylmethyl]-2,4- oxazolidinedione was obtained. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 118- 119°C Working Example 14
Sodium hydride (60% oil, 0.13 g) was added, at room temperature, to a solution of 5-[4-(4- hydroxyphenyl)butyl]-2,4-oxazolidinedione (0.35 g) in N,N-dimethylformamide (DMF) (8 ml). The mixture was stirred for 10 minutes, to which was then added 4- chloromethyl-2-[ (E)-2-(2-furyl)ethenyl]oxazole (0.6 g) . The mixture was stirred for 1.5 hour at 90°C. The reaction mixture was poured into water, which was neutralized with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS0A) and, then concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - chloroform (1:5, v/v), 5- [4-[4-[2-[ (E)-2-(2-furyl)ethenyl]-4- oxazolylmethoxy]phenyl]butyl]-3-[2-[ (E)-(2- furyl)ethenyl]-4-oxazolylmethyl]-2,4-oxazolidinedione (0.38 g, 46%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 146-
147°C.
Working Example 15
Sodium hydride (60% oil, 0.067 g) was added, at room temperature, to a solution of 5-[5-(4- hydroxyphenyl)pentyl]-2,4-oxazolidinedione (0.20 g) in N,N-dimethylformamide (DMF) (8 ml). The mixture was stirred for 25 minutes, to which was then added 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole (0.4 g) . The mixture was stirred for one hour at 85°C The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSOA) and, then, concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - chloroform (1:10, v/v), 5-[5-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]phenyl]pentyl]-3-[2- [(E)-2-phenylethenyl]-4-oxazolylmethyl]-2,4- oxazolidinedione (0.25 g, 52%) was obtained.
Recrystallization from acetone-ethanol gave colorless needles, m.p. 125-126°C. Working Example 16
In substantially the same manner as in Working Example 15, 5-[6-(4-hydroxyphenyl)hexyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5- [6-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]hexyl-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2 ,4-oxazolidinedione. Recrystallization from acetone-ethanol gave colorless prisms, m.p. 149-150°C Working Example 17
Sodium hydride (60% oil, 0.065 g) was added at room temperature to a solution of 5-[6-(4- benzyloxyphenyl)hexyl]-2,4-oxazolidinedione (0.50 g) in N,N-dimethylformamide (DMF) (10 ml). The mixture was stirred for 25 minutes, to which was then added 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole (0.354 g) , followed by stirring for 1.5 hour at 90°C. The reaction mixture was poured into water, which was neutralized with 2N HCl and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS0A) and, then, concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - chloroform (1:5, v/v), 5- [6-(4-benzyloxyphenyl)hexyl]-3-[2-[(E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-oxazolidinedione (0.445 g, 59%) was obtained. Recrystallization from acetone-ethanol gave colorless prisms, m.p. 103-104°C. Working Example 18
A mixture of 4-isopropoxy-3-methoxycinnamaldehyde (7.85 g), 2,4-thiazolidinedione (8.35 g) , piperidine (3.03 g) and acetic acid (260 ml) was stirred for 5 hours under reflux. The reaction mixture was poured into water (100 ml). Resulting crystalline precipitate was collected by filtration and dissolved in chloroform (500 ml) . The solution was washed with water, dried (MgSOA) and, then concentrated under reduced pressure to give 5-[3-(4-isopropoxy-3- methoxyphenyl)propenylidene]-2,4-thiazolidinedione (6.95 g, 61%). Recrystallization from ethyl acetate- hexane gave yellow prisms, m.p. 230-231°C. Working Example 19 To a mixture of 5-[3-(4-isopropoxy-3- methoxyphenyl)propenylidene]-2, 4-thiazolidinedione (6.45 g) and tetrahydrofuran (THF) (550 ml) was added palladium-carbon (5%, 17.0 g), which was subjected to catalytic reduction at room temperature under hydrogen pressure of 3 kgf/cm . The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with chloroform - ethyl acetate (4:1, v/v), 5-[3-(4- isopropoxy-3-methoxyphenyl)propyl]-2 ,4-thiazolidi- nedione (4.9 g, 75%) was obtained as an oily product.
NMR(δ ppm in CDC13): 1.35(6H,d,J=6Hz) , 1.67-2.19(4H,m) , 2.62(2H,t,J=7Hz) , 3.85(3H,s), 4.28( lH,dd,J=8&4Hz) , 4.47(lH,m), 6.67 (lH,dd,J=8&2Hz) , 6.69(lH,s), 6.83(lH,d,J=8Hz) , 8.45(lH,s). Working Example 20
In substantially the same manner as in Working Example 5, 5-[3-(4-isopropoxy-3-methoxyphenyl)propyl]- 2,4-thiazolidinedione was allowed to react with titanium tetrachloride to give 5-[3-(4-hydroxy-3- methoxyphenyl)propyl ]-2,4-thiazolidinedione as an oily product.
NMR(δ ppm in CDC13): 1.69-2.17(4H,m) , 2.61(2H,t,J=7Hz) , 3.89(3H,s), 4.28(lH,dd,J=9&4Hz) , 5.51(lH,s), 6.66(lH,dd,J=9&2Hz) , 6.66 ( lH,d,J=2Hz) , 6.84(lH,d,J=9Hz) , 8.37(lH,s). Working Example 21
In substantially the same manner as in Working Example 15, 5-[3-(4-hydroxyphenyl)propyl]-2,4- thiazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5- [3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2 ,4-thiazolidinedione. Recrystallization from acetone-ethanol gave colorless prisms, m.p. 114-115°C Working Example 22
In substantially the same manner as in Working Example 14, 5-[ 3-( -hydroxyphenyl )propyl ]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-(2-furyl)ethenyl]oxazole to give 5-[3-[4-[2-[ (E)-2-(2-furyl)ethenyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[(E)-2-(2- furyl)ethenyl]-4-oxazolylmethyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 162-163°C. Working Example 23
In substantially the same manner as in Working Example 14, 5-[3-(4-hydroxyphenyl)propyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E,E)-4-phenyl-l,3-butadienyl]oxazole to give 5-[3-[4-[2-[ (E,E)-4-phenyl-l,3-butadienyl]-4- oxazolylmethoxy]phenyl]propyl]-3-[2-[ (E,E)-4-phenyl- 1,3-butadienyl]-4-oxazolylmethyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 168-169°C Working Example 24
In substantially the same manner as in Working Example 1, 5-[3-[4-[2-[ (E)-2-phenylethenyl)-4- oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2-(2- furyl)ethenyl]oxazole to give 5-[3-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-3-[2- [ (E)-2-(2-furyl)ethenyl]-4-oxazolylmethyl]-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 157-158°C. Working Example 25
In substantially the same manner as in Working Example 1, 5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenylJpropyl]-2,4-oxazolidinedione was allowed to react with ethyl bromoacetate to give 3- ethoxycarbonylmethyl-5-[3-[4-[2-[ (E)-2-phenylethenyl]- 4-oxazolylmethoxy]phenyl]propyl ]-2 ,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 93-94°C. Working Example 26 4-(4-Benzyloxyphenyl)-2-ethoxycarbonyloxybutan amide (1.0 g) was dissolved in tetrahydrofuran (THF) (30 ml). To the solution was added 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (0.85 g) . The mixture was stirred for 4 hours at room temperature, then for 12 hours under reflux. The reaction mixture was poured into water, which was acidified with IN HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS04) and, then, concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:2, v/v), 5-[2-(4- benzyloxyphenyl)ethyl]-2,4-oxazolidinedione (0.36 g, 41%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 145-146°C Working Example 27
5-[2-(4-Benzyloxyphenyl)ethyl]-2,4- oxazolidinedione (21.8 g) was suspended in tetrahydrofuran (THF) (500 ml), to which was added palladium-carbon (5%, 21.8 g) . The mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 5-[2-(4-hydroxyphenyl)ethyl]-2,4- oxazolidinedione (9.45 g, 61%). Recrystallization from methanol gave colorless prisms, m.p. 174-175°C Working Example 28
In substantially the same manner as in Working Example 14, 5-[2-(4-hydroxyphenyl)ethyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [2-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]ethyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2 ,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 185-186°C. Working Example 29 A mixture of ethyl 8-(4-benzyloxyphenyl)-2- hydroxyoctanoate (14.0 g) , potassium cyanate (KCNO) (15.3 g) and butanol (200 ml) was stirred for 4 days under reflux. The reaction mixture was concentrated under reduced pressure, which was acidified with IN HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS0 ) and, then concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - chloroform (1:4, v/v), 5-[6-(4- benzyloxyphenyl)hexyl]-2,4-oxazolidinedione (10.2 g, 73%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 137-138°C. Working Example 30
In tetrahydrofuran (THF) (100 ml) was suspended 5- [6-(4-benzyloxyphenyl)hexyl]-2,4-oxazolidinedione (8.0 g) . To the suspension was added palladium-carbon (5%, 2.0 g) . The mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 5-[6-(4-hydroxyphenyl)hexyl]-2,4-oxazolidinedione (5.9 g, 98%). Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 151-152°C. Working Example 31
In substantially the same manner as in Working Example 29, ethyl 6-(4-benzyloxyphenyl)-2- hydroxyhexanoate was allowed to react with potassium cyanate (KCNO) to give 5-[4-(4-benzyloxyphenyl)butyl]- 2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 144-145°C. Working Example 32
In substantially the same manner as in Working Example 30, 5-[4-(4-benzyloxyphenyl)butyl]-2,4- oxazolidinedione was subjected to catalytic reduction to give 5-[4-( -hydroxyphenyl)butyl]-2,4- oxazolidinedione. Working Example 33
In substantially the same manner as in Working Example 6, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4- thiazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5- [3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-2,4-thiazolidinedione. Recrystallization from chloroform-ethanol gave pale orange prisms, m.p. 154-155°C. Working Example 34
In substantially the same manner as in Working Example 6, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2 ,4- thiazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]thiazole to give 5- [3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- thiazolylmethoxy]phenyl]propyl]-2,4-thiazolidinedione. Recrystallization from chloroform-ethanol gave pale orange prisms, m.p. 161-162°C. Working Example 35
A mixture of 5-[3-(4-hydroxyphenyl)propyl]-2,4- oxazolidinedione (0.30 g) , 4-chloromethyl-2-[ (E)-2- phenylethenyl]oxazole (0.28 g) , potassium carbonate (0.18 g) and N,N-dimethyIformamide (DMF) (20 ml) was stirred for 3 hours at temperatures ranging from 85 to 90°C. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS0A) and, then, concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (2:3, v/v), 5-[3-(4- hydroxyphenyl)propyl]-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethyl]-2,4-oxazolidinedione (0.28 g, 52%) was obtained as an oily product. NMR(δ ppm in CDC13): 1.6-2.15(4H,m) , 2.58(2H,t,J=7Hz) , 4.66(2H,s), 4.80(lH,dd,J=6.5&4.5Hz) , 4.94 ( lH,br s) , 6.72(2H,d,J=8.5Hz) , 6.88( lH,d,J=16.5Hz) , 7.00(2H,d,J=8.5Hz), 7.3-7.55(6H,m) , 7.64(lH,s). Working Example 36
A mixture of 5-[3-(4-hydroxyphenyl)propyl]-2,4- oxazolidinedione (0.50 g) , 4-chloromethyl-2-[ (E)-2- phenylethenyl]oxazole (1.03 g), potassium carbonate (0.65 g) and N,N-dimethylformamide (DMF) (20 ml) was stirred for 12 hours at temperatures ranging from 85 to 90°C. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ) and, then concentrated under reduced pressure to give 5-[3-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-3-[2- [(E)-2-phenylethenyl]-4-oxazolylmethyl]-2,4- oxazolidinedione (0.75 g, 59%). Recrystallization from acetone-methanol gave colorless needles, m.p. 166- 167°C.
Working Example 37
A mixture of 4-isopropoxycinnamaldehyde (6.0 g) , 2,4-thiazolidinedione (5.54 g) , piperidine (2.69 g) and acetic acid (30 ml) was stirred for 5 hours under reflux. The reaction mixture was concentrated under reduced pressure. The resulting crystalline precipitate (4.40 g) , 5-(4-isopropoxycinnamylidene)- 2,4-thiazolidinedione, was collected by filtration, which was washed with ethyl acetate. The crystalline product was dissolved in tetrahydrofuran (THF) (100 ml), to which was added palladium-carbon (5%, 2.20 g) . The mixture was subjected to catalytic reduction at room temperature under hydrogen pressure of 3.8 kgf/cm . The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fraction eluted with chloroform - ethyl acetate (9:1, v/v), 5-[3-(4- isopropoxyphenyl)propyl]-2,4-thiazolidinedione (3.61 g, 39%) was obtained as an oily product. NMR(δ ppm in CDC13) : 1.32(6H,d,J=6Hz) , 1.6-2.3(4H,m) , 2.61(2H,t,J=7.5Hz) , 4.28( lH,dd,J=8.5&4.5Hz) , 4.4- 4.65(lH,m), 6.82(lH,m), 6.82(2H,d,J=8.5Hz) , 7.06(2H,d,J=8.5Hz) , 8.34(lH,br s). Working Example 38 In substantially the same manner as in Working Example 5, 5-[3-(4-isopropoxyphenyl)propyl]-2,4- thiazolidinedione was allowed to react with titanium tetrachloride to give 5-[3-(4-hydroxyphenyl)propyl]- 2,4-thiazolidinedione. Recrystallization from acetone - isopropyl ether gave colorless prisms, m.p. 129-130°C Working Example 39
In substantially the same manner as in Working Example 6, 5-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-5-methyl-2-phenyloxazole to give 5-[2-[4- (5-methyl-2-phenyl-4-oxazolylmethoxy)-3- methoxyphenyl]ethyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - chloroform gave colorless prisms, m.p. 194-195°C. Working Example 40
In substantially the same manner as in Working Example 6, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4- oxazolidinedione was allowed to react with 4- bromoacetyl-5-methyl-2-phenyloxazole to give 5-[3-[3- methoxy-4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxo- ethoxy]phenyl]propyl]-2,4-oxazolidinedione as an oily product. NMR(δ ppm in CDC13) : 1.7-2.15(4H,m) , 2.63(2H,t,J=7Hz) , 2.73(3H,s), 3.91(3H,s), 4.85( lH,dd,J=6.5&5Hz) ,
5.43(2H,s), 6.65(lH,dd,J=8&2Hz) , 6.73( lH,d,J=2Hz) , 6.79(lH,d,J=8Hz) , 7.45-7.55(3H,m) , 7.95( lH,br s) , 8.0- 8.1(2H,m) . Working Example 41
Sodium borohydride (0.045 g) was added, at room temperature in limited amounts, to a solution of 5-[3- [3-methoxy-4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxo- ethoxy]phenyl]propyl]-2,4-oxazolidinedione (0.37 g) in tetrahydrofuran (THF) (5 ml) - ethanol (5 ml). The mixture was stirred for further two hours at room temperature. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSOA) and, then, the solvent was distilled off. The oily residue was subjected to a silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:1, v/v) , 5-[3-[4-[2-hydroxy-2-(5-methyl-2-phenyl-4- oxazolyl)ethoxy]-3-methoxyphenyl]propyl]-2,4- oxazolidinedione (0.31 g, 83%). Recrystallization from acetone - isopropyl ether gave colorless prisms, m.p. 151-152°C. Working Example 42
In substantially the same manner as in Working Example 3, 3-methoxy-4-[ l-(5-methyl-2-phenyl-4- oxazolyl)ethoxy]cinnamaldehyde was condensed with 2,4- oxazolidinedione. The condensate was subjected to catalytic reduction to give 5-[3-[3-methoxy-4-[ l-(5- methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-2,4- oxazolidinedione. NMR(δ ppm in CDC13): 1.73( 3H,d,J=6.5Hz) , 1.7-2.1(4H,m) , 2.28(3H,s), 2.59(2H,t,J=7Hz) , 3.85(3H,s), 4.82(lH,dd,J=7&4.5Hz) , 5.32 ( lH,q,J=6.5Hz) , 6.59(lH,dd,J=8&2Hz) , 6.68( lH,d,J=2Hz) , 6.78(lH,d,J=8Hz) , 7.35-7.5(3H,m) , 7.95-8.1(2H,m) , 8.66(lH,br s) .
Working Example 43 A mixture of 5-[3-[3-methoxy-4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2,4- oxazolidinedione (0.64 g), palladium-carbon (5%, 1.3 g) and tetrahydrofuran (THF) (35 ml) was subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated to give 5-[3-[3- methoxy-4-[2-(2-phenylethyl)-4- oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione (0.43 g, 67%). Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 122-123°C. Working Example 44
In substantially the same manner as in Working Example 43, 5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]- 4-thiazolylmethoxyJphenyl]propyl]-2,4-oxazolidinedione was subjected to catalytic hydrogenation at room temperature under atmospheric pressure to give 5-[3-[3- methoxy-4-[2-(2-phenylethyl)-4-thiazolylmethoxyJp¬ henyl]propyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 136-137°C. Working Example 45
In substantially the same manner as in Working Example 6, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-5-methyl-2-phenylthiazole to give 5-[3-[3- methoxy-4-(5-methyl-2-phenyl-4- thiazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione.
Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 128-129°C. Working Example 46
In substantially the same manner as in Working Example 6, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4- oxazolidinedione was allowed to react with 5- chloromethyl-3-phenyl-l,2,4-oxadiazole to give 5-[3-[3- methoxy-4-(3-phenyl-l,2,4-oxadiazol-5- ylmethoxy)phenyl]propyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 110-111°C. Working Example 47 A mixture of ethyl 6-(4-benzyloxy-3- methoxyphenyl)-2-hydroxyhexanoate (15.22 g), potassium cyanate (KCNO) (13.26 g) and butanol (180 ml) was stirred for 72 hours under reflux. The reaction mixture was concentrated under reduced pressure, which was poured into water and acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0A) , and, then, the solvent was distilled off to give an oily product, which was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:1, v/v), 5-[4-(4-benzyloxy-3- methoxyphenyl)butyl]-2,4-oxazolidinedione (11.22 g, 74%). Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 92-93°C. Working Example 48
In substantially the same manner as in Working Example 6, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-5-methyl-2-[ (E)-2-phenylethenyl]oxazole to give 5-[4-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]butyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 171-172°C. Working Example 49 In substantially the same manner as in Working
Example 6, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-5-methyl-2-[ (E)-2-phenylethenyl]thiazole to give 5-[4-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- thiazolylmethoxy]phenyl]butyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 167-168°C Working Example 50
In substantially the same manner as in Working Example 47, ethyl 4-(4-benzyloxy-3-ethoxyphenyl)-2- hydroxybutanoate was allowed to react with potassium cyanate (KCNO) to give 5-[2-(4-benzyloxy-3- ethoxyphenyl)ethyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 143-144°C. Working Example 51
In substantially the same manner as in Working Example 47, ethyl 4-(3-benzyloxy-4-methoxyphenyl)-2- hydroxybutanoate was allowed to react with potassium cyanate (KCNO) to give 5-[2-(3-benzyloxy-4- methoxyphenyl)ethyl]-2,4-oxazolidinedione as an oily product.
NMR(δ ppm in CDC13) : 1.95-2.25(2H,m) , 2.59-2.84(2H,m) , 3.87(3H,s), 4.58(lH,dd,J=8.2&4.8Hz) , 5.15(2H,s), 6.72- 6.86(3H,m), 7.26-7.45(5H,m) , 8.52 ( lH,br s) . Working Example 52
In substantially the same manner as in Working Example 6, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-(2-naphthyl)ethenyl]oxazole to give 5-[4-[3-methoxy-4-[2-[ (E)-2-(2-naphthyl)ethenyl]- 4-oxazolylmethoxy]phenyl]butyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 169-170°C. Working Example 53 In substantially the same manner as in Working
Example 3, 4-benzyloxy-3,5-dimethoxycinnamaldehyde was subjected to condensation with 2, 4-oxazolidinedione to give 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave yellow prisms, m.p. 181-182°C. Working Example 54 In substantially the same manner as in Working Example 4, 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)- 2,4-oxazolidinedione was subjected to catalytic reduction to give 5-[3-(4-hydroxy-3,5- dimethoxyphenyl)propyl]-2,4-oxazolidinedione.
Recrystallization from ethanol-hexane gave colorless prisms, m.p. 155-156°C. Working Example 55
In substantially the same manner as in Working Example 6, 5-[3-(4-hydroxy-3,5-dimethoxyphenyl)propyl]- 2,4-oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5- [3-[3,5-dimethoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-2 ,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 94-95°C. Working Example 56
A mixture of ethyl 2-hydroxy-4-(4-hydroxy-3- methoxyphenyl)butanoate (0.73 g) , potassium cyanate (KCNO) (0.7 g) and butanol (25 ml) was stirred for 18 hours under reflux. The reaction mixture was concentrated under reduced pressure, which was poured into water and acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSOA) . The solvent was distilled off, and the oily residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - chloroform (1:4, v/v) , 5-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2,4- oxazolidinedione (0.2 g, 28%) was obtained.
NMR(δ ppm in CDC13): 2.12-2.16(2H,m) , 2.73-2.83(2H,m) , 3.89(3H,s), 4.80(lH,dd,J=8s_5Hz) , 5.53(lH,s), 6.70(lH,d,J=2Hz) , 6.72 ( lH,dd,J=7&2Hz) , 6.86(lH,d,J=9Hz) , 8.21( lH,br s) . Working Example 57
In substantially the same manner as in Working Example 4, 5-[4-(4-benzyloxy-3-methoxyphenyl)butyl]- 2,4-oxazolidinedione was subjected to catalytic reduction to give 5-[4-(4-hydroxy-3- methoxyphenyl)butyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 115-116°C Working Example 58
In substantially the same manner as in Working Example 4, 5-[2-(4-benzyloxy-3-ethoxyphenyl)ethyl]-2,4- oxazolidinedione was subjected to catalytic reduction to give 5-[2-(4-hydroxy-3-ethoxyphenyl)ethyl]-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 154.5-155°C. Working Example 59 In substantially the same manner as in Working Example 4, 5-[2-(3-benzyloxy-4-methoxyphenyl)ethyl]- 2,4-oxazolidinedione was subjected to catalytic reduction to give 5-[2-(3-hydroxy-4- methoxyphenyl)ethyl]-2,4-oxazolidinedione. Recrystallization from isopropyl ether - hexane gave colorless prisms, m.p. 121-122°C. Working Example 60
1-Dodecanethiol (2.37 g) was added, at 0 °C, to a suspension of aluminum chloride (1.56 g) in dichloromethane (30 ml). The mixture was stirred for 10 minutes, to which was then added dropwise, at the same temperature, a solution of 5-[3-[4-[2-(2-furyl)-5- methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4- oxazolidinedione (0.5 g) in dichloromethane (10 ml) . The reaction mixture was stirred for 2 hours at room temperature, which was then poured into ice-water, followed by extraction with dichloromethane. The dichloromethane layer was washed with water and dried (MgSOA) . The solvent was then distilled off, and the residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - chloroform (1:3, v/v), 5-[ 3-[4-[2-(2- furyl)-5-methyl-4-oxazolylmethoxy]-3- hydroxyphenyl]propyl]-2,4-oxazolidinedione (0.21 g, 43%) was obtained. Recrystallization from dichloromethane-methanol gave colorless prisms, m.p. 152-153°C. Working Example 61
In substantially the same manner as in Working Example 15, 5-(4-hydroxybenzyl)-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenyl]oxazole to give 5-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]benzyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-oxazolidinediσne. Recrystallization from acetone gave colorless crystals, m.p. 159-160°C.
Working Example 62
In substantially the same manner as in Working Example 15, 5-(4-hydroxybenzyl)-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenyl]thiazole to give 5-[4-[2-[ (E)-2- phenylethenyl]-4-thiazolylmethσxy]benzyl]-3-[2-[ (E)-2- phenylethenyl]-4-thiazolylmethyl]-2,4-oxazolidinedione. Recrystallization from acetone gave colorless crystals, m.p. 153-155°C. Working Example 63
In substantially the same manner as in Working Example 17, 5-(4-benzyloxybenzyl)-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenyl]oxazole to give 5-(4-benzyloxybenzyl)-3- [2-[ (E)-2-phenylethenyl]-4-oxazolylmethyl]-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless crystals, m.p. 134-135°C. Working Example 64
In substantially the same manner as in Working Example 43, 5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-2 ,4-oxazolidinedione was - I l l -
subjected to catalytic reduction to give 5-[3-[4-[2-(2- phenylethyl)-4-oxazolylmethoxy]phenyl]propyl]-3-[2-(2- phenylethyl)-4-oxazolylmethyl]-2 ,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 113-114°C. Working Example 65
In substantially the same manner as in Working Example 15, 5-[2-(4-hydroxyphenyl)ethyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E,E)-4-phenyl-l, 3-butadienyl]oxazole to give 5-[2-[4-[2-[ (E,E)-4-phenyl-l,3-butadienyl]-4- oxazolylmethoxy]phenyl]ethyl]-3-[2-[(E,E)-4-phenyl-l, 3- butadienyl]-4-oxazolylmethyl]-2,4-oxazolidinedione. Recrystallization from tetrahydrofuran-ethanol gave colorless prisms, m.p. 196-197°C. Working Example 66
A mixture of 5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione (0.30 g), 4-(2-chloroethyl)morpholine hydrochloride (0.15 g), potassium carbonate (0.22 g) and N,N- dimethylformamide (DMF) (10 ml) was stirred for 5 hours at 100°C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ) . The solvent was then distilled off, and the residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with chloroform - ethyl acetate (4:1, v/v), 3-(2- morpholinoethyl)-5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-2 ,4-oxazolidinedione (0.14 g, 37%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 105- 106°C. Working Example 67 In substantially the same manner as in Working Example 66, 5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione was allowed to react with 4-chloromethylpyridine hydrochloride to give 5-[3-[4-[2-[ (E)-2-phenylethenyl]- 4-oxazolylmethoxy]phenyl]propyl]-3-(4-pyridylmethyl)- 2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 151-152°C. Working Example 68
In substantially the same manner as in Working Example 6, 5-[2-(4-hydroxyphenyl)ethyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [2-[4-[2-[(E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]ethyl]-2,4-oxazolidinedione. Recrystallization from ethanol gave colorless prisms, m.p. 156-158°C.
Working Example 69
In substantially the same manner as in Working Example 15, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]- 2,4-oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]thiazole to give 5- [3-[3-methoxy-4-[ (E)-2-phenylethenyl]-4- thiazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione. Recrystallization from chloroform-methanol gave colorless prisms, m.p. 202-203°C. Working Example 70
In substantially the same manner as in Working Example 1, 5-(2,4,5-triisopropoxybenzyl)-2,4- thiazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 3- [2-[ (E)-2-phenylethenyl]-4-oxazolylmethyl]-5-(2,4 ,5- triisopropoxybenzyl)-2,4-thiazolidinedione. Recrystallization from isopropyl ether gave colorless prisms, m.p. 100-101°C. Working Example 71 In substantially the same manner as in Working
Example 15, 5-(4-hydroxybenzyl)-2,4-thiazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenyl]oxazole to give 5-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]benzyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-thiazolidinedione, Recrystallization from acetone-ethanol gave colorless prisms, m.p. 165-166 °C.
Working Example 72
In substantially the same manner as in Working
Example 15, 5-[4-(4-hydroxyphenyl)butyl]-2,4- thiazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5-
[4-[4-[2-[(E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]butyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-thiazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 134-135°C.
Working Example 73
In substantially the same manner as in Working
Example 15, 5-[5-(4-hydroxyphenyl)pentyl]-2,4- thiazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5-
[5-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]pentyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-thiazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 98-99°C.
Working Example 74
In substantially the same manner as in Working
Example 6, 5-[6-(4-hydroxyphenyl)hexyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5-
[6-[4-[2-[(E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]hexyl]-2 ,4-oxazolidinedione.
Recrystallization from ethanol gave colorless prisms, m.p. 136-137°C.
Working Example 75 In substantially the same manner as in Working Example 15, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2 ,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJthiazole to give 5- [4-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- thiazolylmethoxy]phenyl]butyl]-3-[2-[(E)-2- phenylethenyl]-4-thiazolylmethyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 108-109°C. Working Example 76
In substantially the same manner as in Working Example 1, 5-[3-[4-[5-methyl-2-(2-naphthyl)-4- oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenyl]oxazole to give 5-[3-[4-[5-methyl-2-(2- naphthyl)-4-oxazolylmethoxy]phenyl]propyl]-3-[2-[(E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-oxazolidinedione. Recrystallization from acetone - isopropyl ether gave colorless prisms, m.p. 150-151°C. Working Example 77
In substantially the same manner as in Working Example 1, 5-[3-[4-[5-methyl-2-(2-naphthyl)-4- oxazolylmethoxy]phenylJpropyl]-2,4-oxazolidinedione was allowed to react with 1-bromodecane to give 3-decyl-5- [3-[4-[5-methyl-2-(2-naphthyl)-4- oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione. Recrystallization from acetone - isopropyl ether gave colorless prisms, m.p. 116-117°C. Working Example 78 In substantially the same manner as in Working Example 1, 5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-2, 4-oxazolidinedione was allowed to react with 1-bromodecane to give 3-decyl-5- [3-[4-[2-[(E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 103-104°C. Working Example 79
To a solution of 4-(2-chloroethyl)morpholine hydrochloride (0.32 g) in water (1 ml) was added potassium carbonate (0.24 g) . The mixture was subjected to extraction with toluene. The toluene layer was dried (MgS0 ) , to which were added 5-[3-[3- methoxy-4-(5-methyl-2-phenyl-4- oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione (0.50 g) and potassium carbonate (0.24 g) . The mixture was stirred for 5 hours at temperatures ranging from 90 to 100°C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0A), from which the solvent was distilled off. The residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:1, v/v), 5-[3-[3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-3- (2-morpholinoethyl)-2,4-oxazolidinedione (0.32 g, 51%) was obtained. Recrystallization from acetone - isopropyl ether gave colorless prisms, m.p. 105-106°C. Working Example 80
In substantially the same manner as in Working Example 79, 5-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]benzyl]-2,4-oxazolidinedione was allowed to react with 4-(2-chloroethyl)morpholine to give 3-(2-morpholinoethyl)-5-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]benzyl]-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 141-142°C. Working Example 81
In substantially the same manner as in Working Example 79, 5-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]benzyl]-2,4-oxazolidinedione was allowed to react with l-(2-chloroethyl)piperidine to give 5-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]benzyl]-3-(2-piperidinoethyl)-2,4- oxazolidinedione. Recrystallization from ethyl acetate
- hexane gave colorless prisms, m.p. 130-131°C. Working Example 82
In substantially the same manner as in Working Example 79, 5-[4-[2-[ (E)-2-phenylethenyl)-4- oxazolylmethoxy]benzyl]-2,4-oxazolidinedione was allowed to react with N,N-dimethylaminoethyl chloride to give 3-(2-dimethylaminoethyl)-5-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxyJbenzyl]-2,4- oxazolidinedione. Recrystallization from ethyl acetate
- hexane gave colorless prisms, m.p. 106-107°C. Working Example 83 In substantially the same manner as in Working Example 47, ethyl 10-(4-benzyloxyphenyl)-2- hydroxydecanoate was allowed to react with potassium cyanate (KCNO) to give 5-[8-(4-benzyloxyphenyl)octyl]- 2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 148-149°C. Working Example 84
In substantially the same manner as in Working Example 4, 5-[8-(4-benzyloxyphenyl)octyl]-2 ,4- oxazolidinedione was subjected to catalytic reduction to give 5-[8-(4-hydroxyphenyl)octyl]-2,4- oxazolidinedione. Recrystallization from ethyl acetate
- hexane gave colorless prisms, m.p. 150-151°C. Working Example 85
In substantially the same manner as in Working Example 15, 5-[ 8-(4-hydroxyphenyl)octyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5- [8-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]octyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2 ,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 156-157°C. Working Example 86
In substantially the same manner as in Working Example 6, 5-[8-(4-hydroxyphenyl)octyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5- [8-[4-[2-[(E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]octyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 141-142°C. Working Example 87
In substantially the same manner as in Working Example 79, 5-[2-[4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxy]phenyl]ethyl]-2,4-oxazolidinedione was allowed to react with 4-(2-chloroethyl)morpholine to give 3-(2-morpholinoethyl)-5-[2-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]phenyl]ethyl]-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 122-123°C. Working Example 88
In substantially the same manner as in Working Example 79, 5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenylJpropyl]-2,4-oxazolidinedione was allowded to react with l-(2-chloroethyl)piperidine to give 5-[3-[4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxy]phenylJpropyl]-3-(2-piperidinoethyl)- 2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 103-104°C. Working Example 89 To a solution of 5-[3-[4-[2-[ (E)-2-phenylethenyl]- 4-oxazolylmethoxyJphenylJpropyl]-2 ,4-oxazolidinedione (0.25 g) in N,N-dimethylformamide (DMF) (10 ml) was added at 0°C sodium hydride (60% oil, 0.026 g) . The mixture was stirred for one hour, to which was added methyl iodide (0.17 g) . The mixture was stirred for one hour at the same temperature, which was poured into water and acidified, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0A) , and, then, the solvent was distilled off. The residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:2, v/v), 3- methyl-5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJpropyl]-2,4-oxazolidinedione (0.14 g, 54%) was obtained. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 129- 130°C. Working Example 90
In substantially the same manner as in Working Example 89, 5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJpropyl]-2,4-oxazolidinedione was allowed to react with geranyl bromide to give 3- geranyl-5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJpropylJ-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 97-98°C. Working Example 91
To a solution of 5-[3-[4-[2-[ (E)-2-phenylethenylJ- 4-oxazolylmethoxyJphenylJpropyl]-3-(2-piperidinoethyl)- 2,4-oxazolidinedione (0.8 g) in methanol (100 ml) was added hydrochloric acid - methanol (10%, 0.58 g) . The mixture was stirred for one hour at room temperature. The resulting crystalline precipitate was collected by filtration, which was recrystallized from N,N- dimethylformamide-ether to give 5-[3-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxyJphenylJpropyl]-3-(2- piperidinoethyl)-2,4-oxazolidinedione hydrochloride (0.40 g, 47%) as colorless prisms, m.p. 212-213°C. Working Example 92
In substantially the same manner as in Working Example 15, 5-[2-(4-hydroxyphenyl)ethyl]-2,4- thiazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [2-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenyl]ethyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethyl]-2,4-thiazolidinedione. Recrystallization from acetone-ethanol gave colorless prisms, m.p. 114-115°C. Working Example 93
In substantially the same manner as in Working Example 15, 5-[7-(4-hydroxyphenyl)heptyl]-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [7-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenylJheptyl]—3—[2—[ (E)-2- phenylethenyl]-4-oxazolylmethylJ-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 120-121°C. Working Example 94
In substantially the same manner as in Working Example 47, ethyl 9-(4-benzyloxyphenyl)-2- hydroxynonanoate was allowed to react with potassium cyanate (KCNO) to give 5-[7-(4-benzyloxyphenyl)heptyl]- 2,4-oxazolidinedione. Recrystallization from ethanol gave colorless prisms, m.p. 93-95°C. Working Example 95 In substantially the same manner as in Working Example 4, 5-[7-(4-benzyloxyphenyl)heptylj-2,4- oxazolidinedione was subjected to catalytic reduction to give 5-[7-(4-hydroxyphenyl)heptyl]-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 94-95°C. Working Example 96
In substantially the same manner as in Working Example 3, 4-benzyloxy-3,5-dimethoxycinnamaldehyde was subjected to condensation with 2,4-thiazolidinedione to give 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)-2,4- thiazolidinedione. Recrystallization from chloroform- ethanol gave yellow prisms, m.p. 217-218°C.
Working Example 97
In substantially the same manner as in Working
Example 4, 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)- 2,4-thiazolidinedione was subjected to catalytic reduction to give 5-[3-(4-benzyloxy-3,5- dimethoxyphenyl)propylJ-2,4-thiazolidinedione.
Recrystallization from ethanol-hexane gave colorless prisms, m.p. 101-102°C. Working Example 98
In substantially the same manner as in Working
Example 5, 5-[3-(4-benzyloxy-3,5- dimethoxyphenyl)propylJ-2,4-thiazolidinedione was allowed to react with titanium tetrachloride to give 5- [3-(4-hydroxy-3,5-dimethoxyphenyl)propyl]-2,4- thiazolidinedione as an oily product.
NMR ( δ ppm in CDC13 ) : 1 . 75-2 . 12 ( 4H , m ) , 2 . 61 ( 2H , t , J=7Hz ) ,
3 . 88 ( 6H , s ) , 4 . 29 ( lH , dd , J=8&4Hz ) , 5 . 42 ( lH , s ) ,
6.39(2H,s) . Working Example 99
In substantially the same manner as in Working
Example 6, 5-[3-(4-hydroxy-3,5-dimethoxyphenyl)propyl]-
2,4-thiazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [3-[3,5-dimethoxy-4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJpropylJ-2,4-thiazolidinedione.
Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 163-164°C
Working Example 100 In substantially the same manner as in Working
Example 1, 5-[ 3-[3,5-dimethoxy-4-[2-[ (E)-2- phenylethenylj-4-oxazolylmethoxyJphenylJpropylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [3-[3,5-dimethoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJpropyl]-3-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethyl]-2,4-oxazolidinedione as an oily product.
NMR(δ ppm in CDC13): 1.78-1.90(4H,m) , 2.62(2H,t,J=7Hz) , 3.82(6H,s), 4.66(2H,s), 4.84( lH,dd,J=6&4Hz) , 4.99(2H,s), 6.37(2H,s), 6.89 ( lH,d,J=16Hz) ,
6.94(lH,d,J=16Hz) , 7.33-7.56( 12H,m) , 7.64(lH,s), 7.69(lH,s) . Working Example 101
In substantially the same manner as in Working Example 15, 5-[4-(4-hydroxy-3-methoxyphenyl)butylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-(2-naphthyl)ethenylJoxazole to give 5-[4-[3-methoxy-4-[2-[ (E)-2-(2-naphthyl)ethenylJ- 4-oxazolylmethoxyJphenyl]butyl]-3-[2-[(E)-2-(2- naphthyl)ethenylJ-4-oxazolylmethylJ-2,4- oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 125-126°C. Working Example 102
In substantially the same manner as in Working Example 79, 5-[4-[3-methoxy-4-[2-[ (E)-2-(2- naphthyl)ethenylJ-4-oxazolylmethoxy]phenylJbutyl]-2,4- oxazolidinedione was allowed to react with 4-(2- chloroethyl)morpholine to give 5-[4-[3-methoxy-4-[2- [ (E)-2-(2-naphthyl)ethenylJ-4- oxazolylmethoxyJphenyl]butyl]-3-(2-morpholinoethyl)- 2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 118-119°C. Working Example 103
In substantially the same manner as in Working Example 47, ethyl 6-(4-benzyloxy-3-ethoxyphenyl)-2- hydroxyhexanoate was allowed to react with potassium cyanate (KCNO) to give 5-[4-(4-benzyloxy-3- ethoxyphenyl)butyl]-2,4-oxazolidinedione. Recrystallization from isopropyl ether gave colorless prisms, m.p. 80-81°C. Working Example 104 In substantially the same manner as in Working Example 4, 5-[4-(4-benzyloxy-3-ethoxyphenyl)butylJ-2,4- oxazolidinedione was subjected to catalytic reduction to give 5-[4-(3-ethoxy-4-hydroxyphenyl)butyl] J-2,4- oxazolidinedione as an oily product.
NMR(δ ppm in CDC13) : 1.44(3H,t,J=7.0Hz) , 1.47- 2.14(6H,m), 2.55(2H,t,J=7.4Hz) , 4.10(2H,q,J=7.0Hz) , 4.83(lH,dd,J=7.2&4.4Hz) , 5.66(lH,br s), 6.64(lH,d,J=8.4Hz) , 6.66(lH,s), 6.83 ( lH,d,J=8.4Hz) , 8.45(lH,br s) .
Working Example 105
In substantially the same manner as in Working Example 6, 5-[2-(4-hydroxy-3-ethoxyphenyl)ethylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [2-[3-ethoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJethylJ-2,4-oxazolidinedione. Recrystallization from ethyl acetate - tetrahydrofuran gave colorless prisms, m.p. 175-176°C. Working Example 106
In substantially the same manner as in Working Example 6, 5-[2-(4-hydroxy-3-ethoxyphenyl)ethylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-5-methyl-2-(2-naphthylJoxazole to give 5- [2-[3-ethoxy-4-[5-methyl-2-(2-naphthyl)-4- oxazolylmethoxyJphenylJethylJ-2 ,4-oxazolidinedione. Recrystallization from tetrahydrofuran gave colorless prisms, m.p. 204-205°C. Working Example 107 To a mixture of 5-[2-[3-ethoxy-4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxyJphenylJethylJ-2,4- oxazolidinedione (1.35 g) , potassium carbonate (0.622 g) and N,N-dimethyIformamide (DMF) (10 ml) was added at room temperature 2-iodo ethanol (1.03 g) . The mixture was stirred for 2 hours at 50°C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ) . Then, the solvent was distilled off to give 5-[2-[3-ethoxy-4-[2- [(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenylJethyl]- 3-(2-hydroxyethyl)-2,4-oxazolidinedione (1.15 g, 78%). Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 120-121°C. Working Example 108
To a mixture of 5-[2-[3-ethoxy-4-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJphenylJethylJ-3-(2- hydroxyethyl)-2,4-oxazolidinedione (0.985 g) , triethylamine (0.304 g) and ethyl acetate (50 ml) was added dropwise, at room temperature, methanesulfonyl chloride (0.344 g) . The mixture was stirred for one hour, which was poured into water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ) . The solvent was then distilled off to give an oily substance, which was dissolved in N,N-dimethylformamide (DMF) (10 ml). To this solution was added sodium iodide (0.899 g) , which was stirred for 4 hours at 80°C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgS0 ) . The solvent was then distilled off to give 5-[2-[3-ethoxy-4-[2-
[(E)-2-phenylethenyl]-4-oxazolylmethoxyJphenyl]ethyl]- 3-(2-iodoethyl)-2,4-oxazolidinedione (0.753 g, 62%). Recrystallization from ethyl acetate gave colorless needles, m.p. 149-150°C. Working Example 109
To a mixture of 5-[2-[3-ethoxy-4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]phenylJethyl]-3-(2- iodoethyl)-2,4-oxazolidinedione (0.301 g) , potassium carbonate (0.104 g) and N,N-dimethylformamide (DMF) (5 ml) was added 4-methyl piperazine (0.10 g) . The mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into water, which was acidified with 0. IN HCl, followed by washing with ethyl acetate. The aqueous layer was basified with an aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0 ) . Then, the solvent was distilled off, and the residual oily substance was dissolved in ethyl acetate (5 ml). To this solution was added hydrochloric acid - ethanol (10%, 0.8 ml), which was concentrated under reduced pressure. The residual solid substance was recrystallized from ethanol-methanol to give 5-[2-[3- ethoxy-4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJethyl]-3-[2-(4-methyl-l- piperazinyl)ethylJ-2,4-oxazolidinedione dihydrochloride (0.13 g, 40%) as colorless prisms, m.p. 143-145°C. Working Example 110
In substantially the same manner as in Working Example 109, 5-[2-[3-ethoxy-4-[2-[ (E)-2-phenylethenyl]- 4-oxazolylmethoxyJphenylJethyl]-3-(2-iodoethyl)-2,4- oxazolidinedione was allowed to react with 4- piperidinopiperidine to give 5-[2-[3-ethoxy-4-[2-[ (E)- 2-phenylethenyl]-4-oxazolylmethoxyJphenylJethylJ-3-[2- (4-piperidino-l-piperidinyl)ethylJ-2,4-oxazolidinedione dihydrochloride. Recrystallization from ethanol- methanol gave colorless prisms, m.p. 210-212°C. Working Example 111
In substantially the same manner as in Working Example 6, 5-[2-(3-hydroxy-4-methoxyphenyl)ethylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [2-[4-methoxy-3-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJethyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate gave colorless needles, m.p. 157-158°C. Working Example 112 In substantially the same manner as in Working Example 15, 5-[2-(3-hydroxy-4-methoxyphenyl)ethylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-(2-naphthyl)ethenylJoxazole to give 5-[2-[4-methoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJethyl]-3-[2-[ (E)-2- phenylethenylJoxazolylmethylJ-2,4-oxazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 117-118°C. Working Example 113
In substantially the same manner as in Working Example 6, 5-[2-(3-hydroxy-4-methoxyphenylJethylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-5-methyl-2-(2-naphthyl)oxazole to give 5- [2-[4-methoxy-3-[5-methyl-2-(2-naphthyl)-4- oxazolylmethoxyJphenylJethyl]-2,4-oxazolidinedione. Recrystallization from ethyl acetate gave colorless crystals, m.p. 161-162°C. Working Example 114 A mixture of 5-[2-[4-methoxy-3-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJphenylJethylJ-2,4- oxazolidinedione (435 mg) , 4-(2-chloroethyl)morpholine hydrochloride (373 mg) , potassium carbonate (277 mg) , sodium iodide (150 mg) and N,N-dimethyIformamide (DMF) (10 ml) was stirred for 14 hours at 80°C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSOA) . The solvent was then distilled off, and the residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate - hexane (1:1, v/v), 5-[2-[4-methoxy-3-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJethyl]-3-(2-morpholinoethyl )- 2,4-oxazolidinedione was obtained as an oily substance. This oily substance was led to hydrochloride by substantially the same procedure as in Working Example 91 .
Elemental Analysis for C30H33N3O7 - HCl • 1 /2H20 :
Calcd . : C , 60 . 76 ; H , 5 . 95 ; N, 7 . 09
Found : C, 60.83; H, 6.00; N, 7.03 Working Example 115
In substantially the same manner as in Working Example 114, 5-[2-[4-methoxy-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]phenyl]ethylJ-2,4- oxazolidinedione was allowed to react with l-(2- chloroethyl)piperidine to give 5-[2-[4-methoxy-3-[2-
[(E)-2-phenylethenyl]-4-oxazolylmethoxyJphenylJethylJ- 3-(2-piperidinoethyl)-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 91.
Elemental Analysis for C31H35N306-HCl • 3/4H20:
Calcd.: C, 62.51; H, 6.35; N, 7.06
Found : C, 62.50; H, 6.25; N, 7.24 Working Example 116 In substantially the same manner as in Working Example 114, 5-[2-[4-methoxy-3-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJphenylJethylJ-2,4- oxazolidinedione was allowed to react with l-(3- chlorophenyl)-4-(3-chloropropyl)piperazine to give 5- [2-[4-methoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyjphenylJethylJ-3-[3-[4-(3- chlorophenyl)piperazin-l-ylJpropyl]-2,4- oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 91. Elemental Analysis for C37H39N06-HCl:
Calcd.: C, 62.80; H, 5.70; N, 7.92
Found : C, 62.87; H, 5.71; N, 8.00 Working Example 117 In substantially the same manner as in Working
Example 89, 5-[2-[4-methoxy-3-[2-(E)-2-phenylethenyl]- 4-oxazolylmethoxy]phenylJethylJ-2,4-oxazolidinedione was allowed to react with methyl iodide to give 5-[2- [4-methoxy-3-[2-[ (E)-2-phenylethenylJ-4-oxazolylmeth¬ oxyJphenylJethylJ-3-methyl-2,4-oxazolidinedione as colorless crystals, m.p. 140-141°C. Working Example 118
In substantially the same manner as in Working Example 107, 5-[2-[4-methoxy-3-[2-(E)-2-phenylethenylJ- 4-oxazolylmethoxyJphenylJethylJ-2,4-oxazolidinedione was allowed to react with l-chloro-3-iodopropane to give 3-(3-chloroρropyl)-5-[2-[4-methoxy-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxyJphenyl]ethyl]-2,4- oxazolidinedione as colorless needles, m.p. 107-108°C. Working Example 119 To a mixture of 3-( 3-chloropropyl)-5-[2-[4- ethoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJethyl]-2,4-oxazolidinedione (0.256 g) , potassium carbonate (0.069 g) , sodium iodide (0.075 g) and N,N-dimethyIformamide (DMF) (5 ml) was added 1-methylpiperazine (0.076 g) . The mixture was stirred for 12 hours at 80°C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSOA) . Then, the solvent was distilled off, and the residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with chloroform-ethanol (19:1, v/v) , 5-[2-[4-methoxy-3-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJethyl]-3-[3-[4-methylpiperazin- 1-ylJpropylJ-2,4-oxazolidinedione was obtained as an oily product. This oily product was processed, by substantially the same procedure as in Working Example 91, with HCl-ethanol (10%) to give the corresponding dihydrochloride (0.186 g, 58%). Elemental Analys is for C32H38NA06 • 2HC1 - H20 :
Calcd . : C , 57 . 74 ; H , 6 . 36 ; N , 8 . 42 Found : C, 57.98; H, 6.06; N, 8.39
Working Example 120
In substantially the same manner as in Working
Example 47, ethyl 6-(3-benzyloxy-4-methoxyphenyl)-2- hydroxyhexanoate was allowed to react with potassium cyanate (KCNO) to give 5-[4-(3-benzyloxy-4- methoxyphenyl)butylJ-2,4-oxazolidinedione as an oily product.
NMR(δ ppm in CDC13): 1.41-2.02(6H,m) , 2.52(2H,t,J=7.2Hz) , 3.87(3H,s),
4.79(lH,dd,J=7.4&4.6Hz) , 5.15(2H,s) ,
6.71(lH,dd,J=8.6&2.0Hz) , 6.72( lH,d,J=2.0Hz) ,
6.82(lH,d,J=8.6Hz) , 7.29-7.48(5H,m) , 8.09 ( lH,br s) .
Working Example 121 In substantially the same manner as in Working
Example 4, 5-[4-(3-benzyloxy-4-methoxyphenyl)butylJ-
2,4-oxazolidinedione was subjected to catalytic reduction to give 5-[4-(3-hydroxy-4- methoxyphenyl)butylJ-2,4-oxazolidinedione, m.p. 90- 91°C.
Elemental Analysis for C1 H17N05:
Calcd.: C, 60.21; H, 6.14; N, 5.02 Found : C, 60.13; H, 6.21; N, 5.02
Working Example 122 In substantially the same manner as in Working
Example 6, 5-(4-hydroxybenzyl)-2,4-thiazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenylJoxazole to give 5-[4-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJbenzyl]-2,4- thiazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 182-183°C
Working Example 123
In substantially the same manner as in Working
Example 79, 5-[4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJbenzylJ-2,4-thiazolidinedione was allowed to react with 4-(2-chloroethyl)morpholine to give 3-(2-morpholinoethyl)-5-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxyJbenzylJ-2,4- thiazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 129-130°C Working Example 124
In substantially the same manner as in Working Example 79, 5-[4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJbenzyl-2,4-thiazolidinedione was allowed to react with 4-(2-chloroethyl)piperidine to give 5-[4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJbenzyl]-3-(2-piperidinoethyl)-2,4- thiazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 125-127°C, Working Example 125 In substantially the same manner as in Working Example 79, 5-[4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJbenzyl]-2,4-thiazolidinedione was allowed to react with N,N-dimethylaminoethyl chloride to give 3-(2-dimethylaminoethyl)-5-[4-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJbenzylJ-2,4- thiazolidinedione. Recrystallization from ethyl acetate - hexane gave colorless prisms, m.p. 89-90°C. Working Example 126
In substantially the same manner as in Working Example 6, 5-[3-(4-hydroxy-3,5-dimethoxyphenyl)propyl]- 2,4-oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-(2-naphthyl)ethenylJoxazole to give 5-[3-[3,5-dimethoxy-[4-[2-[ (E)-2-(2- naphthyl)ethenyl]-4-oxazolylmethoxyJphenylJpropylJ-2,4- oxazolidinedione. Recrystallization from chloroform- ethanol gave colorless prisms, m.p. 181-182°C. Working Example 127
In substantially the same manner as in Working Example 79, 5-[3-[3,5-dimethoxy-[4-[2-[ (E)-2-(2- naphthyl)ethenylJ-4-oxazolylmethoxy]phenylJpropyl]-2,4- oxazolidinedione was allowed to react with 4-(2- chloroethyl)morpholine to give 5-[3-[3,5-dimethoxy-[4- [2-[ (E)-2-(2-naphthyl)ethenyl]-4- oxazolylmethoxy]phenylJpropylJ-3-(2-morpholinoethyl)- 2,4-oxazolidinedione as an oily product. This oily product was processed with HCl-methanol (10%) to give the corresponding hydrochloride. Elemental Analysis for C36H39N308-HC1 • 1/2H20: Calcd.: C, 62.92; H, 6.01; N, 6.11 Found : C, 62.68; H, 6.30; N, 5.98 Working Example 128
In substantially the same manner as in Working Example 79, 5-[3-[3,5-dimethoxy-[4-[2-[ (E)-2-(2- naphthyl)ethenyl]-4-oxazolylmethoxyJphenylJpropylJ-2,4- oxazolidinedione was allowed to react with l-(2- chloroethyl)piperidine to give 5-[3-[3,5-dimethoxy-[4- [2-[ (E)-2-(2-naphthyl)ethenylJ-4- oxazolylmethoxyJphenylJpropylJ-3-(2-piperidinoethyl)- 2,4-oxazolidinedione as an oily product. This oily product was processed with HCl-methanol (10%) to give the corresponding hydrochloride.
Elemental Analysis for C37HA1N307-HCl-H20: Calcd.: C, 64.01; H, 6.39; N, 6.05 Found : C, 64.31; H, 6.47; N, 5.97 Working Example 129 In substantially the same manner as in Working Example 79, 5-[3-[3-methoxy-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxyJphenylJpropyl]-2,4- oxazolidinedione was allowed to react with 4-(2- chloroethyl)morpholine to give 5-[ 3-[3-methoxy-[4-[2- [(E)-2-phenylethenyl]-4-oxazolylmethoxyJphenylJpropyl]- 3-(2-morpholinoethyl)-2,4-oxazolidinedione as an oily product. This oily product was processed with HCl- methanol (10%) to give the corresponding hydrochloride. Elemental Analysis for C31H35N307-HCl • 1/2H20: Calcd.: C, 61.33; H, 6.14; N, 6.92 Found : C, 61.49; H, 6.34; N, 6.87 Working Example 130
In substantially the same manner as in Working Example 79, 5-[3-[3-methoxy-[4-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJphenylJpropylJ-2,4- oxazolidinedione was allowed to react with l-(2- chloroethyl)piperidine to give 5-[3-[3-methoxy-[4-[2- [(E)-2-phenylethenylJ-4-oxazolylmethoxyJphenylJpropyl]- 3-(2-piperidinoethyl)-2,4-oxazolidinedione as an oily product. This oily product was processed with HCl- methanol (10%) to give the corresponding hydrochloride. Elemental Analysis for C32H37N306-HCl -H20: Calcd.: C, 62.58; H, 6.56; N, 6.84 Found : C, 62.29; H, 6.75; N, 6.87 Working Example 131 A mixture of ethyl 2-chloro-4-(4- isopropoxyphenyl)butyrate (1.4 g), thiourea (1.5 g) , sodium acetate (1.61 g) and ethanol (30 ml) was stirred for 7 hours under reflux, which was poured into water. Resulting crystalline precipitate was collected by filtration, which was added to ethanol (30 ml) - 2N HCl (30 ml). The mixture was stirred for 16 hours under reflux, which was poured into water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS0A) . Then, the solvent was distilled off to give 5-[2-(4- isopropoxyphenyl)ethylJ-2,4-thiazolidinedione (1.37 g, 100%) as an oily product.
NMR(δ ppm in CDC13): 1.32 (6H,d,J=6Hz) , 2.05-2.9(4H,m) , 4.19(lH,dd,J=9.5&4.0Hz) , 4.4-4.6( lH,m) , 6.83(2H,d,J=8.5Hz) , 7.08 (2H,d,J=8.5Hz) , 8.29 ( lH,br s) . Working Example 132
In substantially the same manner as in Working Example 5, 5-[2-(4-isopropoxyphenyl)ethylJ-2,4- thiazolidinedione was allowed to react with titanium i tetrachloride to give 5-[2-(4-hydroxyphenyl)ethylJ-2 , - thiazolidinedione. Recrystallization from acetone - isopropyl ether gave colorless prisms, m.p. 175-176°C. Working Example 133
A mixture of 2-[3-(4-isopropoxyphenyl) ropylJ-l,3- dioxolan (2.53 g) , 2,4-thiazolidinedione (1.78 g), piperidine (0.86 g) and acetic acid (30 ml) was stirred for 3 hours under reflux, which was then concentrated under reduced pressure. The concentrate was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ) . Then, the solvent was distilled off, and the residual oily substance was subjected to a silica gel column chromatography. From the fraction eluted with chloroform - ethyl acetate (9:1, v/v), 5-[4-(4-isopropoxyphenyl)butylideneJ-2,4- thiazolidinedione was obtained as an oily product.
This oily product was subjected to catalytic reduction in substantially the same manner as in Working Example 4, to give 5-[4-(4-isopropoxyphenyl)butyl] J-2,4- thiazolidinedione. Recrystallization from ether-hexane gave colorless prisms, m.p. 72-73°C. Working Example 134
In substantially the same manner as in Working Example 5, 5-[4-(4-isopropoxyphenyl)butylJ-2,4- thiazolidinedione was allowed to react with titanium tetrachloride to give 5-[4-(4-hydroxyphenyl)butylJ-2,4- thiazolidinedione. Recrystallization from dichloromethane - isopropyl ether gave colorless prisms, m.p. 125-126°C. Working Example 135 In substantially the same manner as in Working
Example 6, 5-[4-(3-hydroxy-4-methoxyphenyl)butylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [4-[4-methoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJbutylJ-2,4-oxazolidinedione. Recrystalization from ethyl acetate gave colorless needles, m.p. 159-160°C. Working Example 136
In substantially the same manner as in Working Example 6, 5-[4-(3-ethoxy-4-hydroxyphenyl)butylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenyl]oxazole to give 5- [ -(3-ethoxy-4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenyl]butylJ-2,4-oxazolidinedione. Recrystalization from ethyl acetate gave colorless needles, m.p. 160-161°C. Working Example 137
In substantially the same manner as in Working Example 15, 5-[4-(3-hydroxy-4-methoxyphenyl)butylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [4-[4-methoxy-3-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenyl]butyl]—3—[2—[ (E)-2- phenylethenylJ-4-oxazolylmethyl]-2,4-oxazolidinedione. Recrystalization from ethyl acetate gave colorless needles, m.p. 118-119°C. Working Example 138
In substantially the same manner as in Working Example 15, 5-[4-( 3-ethoxy-4-hydroxyphenyl)butylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 5- [4-[3-ethoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJbutyl]-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethylJ-2,4-oxazolidinedione. Recrystalization from ethyl acetate gave colorless needles, m.p. 113-114°C. Working Example 139
In substantially the same manner as in Working Example 114, 5-[4-[4-methoxy-3-[2-(E)-2-phenylethenyl]- 4-oxazolylmethoxyJphenylJbutylJ-2,4-oxazolidinedione was allowed to react with l-(3-chlorophenyl)-4-(3- chloropropyl)piperazine to give 3-[3-[4-(3- chlorophenyl)piperazin-l-ylJpropyl]-5-[4-[4-methoxy-3-
[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxy]phenylJbutylJ-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in
Working Example 79.
Elemental Analysis for C39HA3C1N06-HCl • 0.5H20 Calcd.: C, 62.90; H, 6.09; N, 7.52 Found : C, 62.84; H, 6.21; N, 7.40 Working Example 140
In substantially the same manner as in Working
Example 107, 5-[4-[4-methoxy-3-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJphenylJbutylJ-2,4- oxazolidinedione was allowed to react with l-(3- chloropropyl)-4-phenylpiperazine to give 5-[4-[4- methoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJbutyl]-3-[3-(4-phenylpiperazin-
1-yl)propyl]-2,4-oxazolidinedione. Reacrystalization from ethyl acetate - ethanol gave crystals, m.p. 102- 103°C.
Working Example 141
In substantially the same manner as in Working
Example 114, 5-[4-[3-ethoxy-4-[2-[ (E)-2-phenylethenyl]-
4-oxazolylmethoxyJphenylJbutylJ-2,4-oxazolidinedione was allowed to react with l-(3-chlorophenyl)-4-(3- chloropropyl)piperazine to give 3-[3-[4-(3- chlorophenyl)piperazin-1-ylJpropyl]-5-[4-[3-ethoxy-4-
[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJbutylJ-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in
Working Example 79.
Elemental Analysis for CAOH5C1NA06•2HC1 Calcd.: C, 61.11; H, 6.03; N, 7.13 Found : C, 61.21; H, 5.91; N, 7.00
Working Example 142 In substantially the same manner as in Working Example 107, 5-[4-[3-ethoxy-4-[2-[ (E)-2-phenylethenyl]- 4-oxazolylmethoxy]phenylJbutylJ-2,4-oxazolidinedione was allowed to react with 1-(3-chloropropyl)-4- phenylpiperazine to give 5-[4-[3-ethoxy-4-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJphenylJbutyl]-3-[3-(4- phenylpiperazin-1-yl)propylJ-2,4-oxazolidinedione. Recrystalization from ethyl acetate - ethanol gave crystals, m.p. 92-93°C. Working Example 143
In substantially the same manner as in Working Example 107, 5-[2-[3-ethoxy-4-[2-[ (E)-2-phenylethenyl]- 4-oxazolylmethoxyJphenyl]ethylJ-2,4-oxazolidinedione was allowed to react with l-(3-chloropropyl)-4- phenylpiperazine to give 5-[2-[3-ethoxy-4-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxyJphenylJethyl]-3-[3-(4- phenylpiperazin-1-ylJpropylJ-2,4-oxazolidinedione. Recrystalization from ethyl acetate - ethanol gave crystals, m.p. 112-114°C. Working Example 144
In substantially the same manner as in Working Example 119, 3-(3-chloropropyl)-5-[2-[4-methoxy-3-[2- [(E)-2-phenylethenylJ-4-oxazolylmethoxyJphenylJethyl]- 2,4-oxazolidinedione was allowed to react with l-(4- fluorophenylJpiperazine to give 3-[3-[4-(4- fluorophenyl)piperazin-1-ylJpropylJ-5-[2-[4-methoxy-3- [2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJethylJ-2 ,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
Elemental Analys is for C37H39FNA06 - HCl - H20 : Calcd . : C , 62 . 66 ; H , 5 . 97 ; N , 7 . 90 Found : C , 62 . 62 ; H , 6 . 04 ; N , 7 . 76 Working Example 145
In substantially the same manner as in Working Example 119, 3-(3-chloropropyl)-5-[2-[4-methoxy-3-[2- [ (E)-2-phenylethenyl]-4-oxazolylmethoxyJphenylJethyl J- 2,4-oxazolidinedione was allowed to react with l-(4- methoxyphenyl)piperazine to give 5-[2-[4-methoxy-3-[2- [(E)-2-phenylethenylJ-4-oxazolylmethoxyJphenylJethyl]- 3-[3-[4-(4-methoxyphenyl)piperazin-1-yl]propyl]-2,4- oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79. Elemental Analysis for C38HA2NA07•2HC1 •0.25H20: Calcd.: C, 61.33; H, 6.03; N, 7.53 Found : C, 61.38; H, 5.97; N, 7.30 Working Example 146
In substantially the same manner as in Working Example 119, 3-(3-chloropropyl)-5-[2-[4-methoxy-3-[2- [(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenylJethylJ- 2,4-oxazolidinedione was allowed to react with l-(2- pyridyl)piperazine to give 5-[2-[4-methoxy-3-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethoxy]phenyl]ethyl]-3-[3-[4- (2-pyridyl)piperazin-1-ylJpropylJ-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79. Elemental Analysis for C36H39N506• 3HC1 • 1.5H20: Calcd.: C, 55.85; H, 5.86; N, 9.05 Found : C, 55.95; H, 5.61; N, 9.01 Working Example 147
In substantially the same manner as in Working Example 119, 3-(3-chloropropyl)-5-[2-[4-methoxy-3-[2- [ (E)-2-phenylethenyl]-4-oxazolylmethoxyJphenylJethylJ- 2,4-oxazolidinedione was allowed to react with 1- phenylpiperazine to give 5-[2-[4-methoxy-3-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxyJphenylJethyl]-3-[3-(4- phenylpiperazin-1-ylJpropylJ-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
Elemental Analys is for C37HA0NAO6 • 2HC1
Calcd.: C, 62.62; H, 5.97; N, 7.89 Found : C, 62.47; H, 6.12; N, 7.81 Working Example 148
In substantially the same manner as in Working Example 119, 3-(3-chloropropyl)-5-[2-[4-methoxy-3-[2- [ (E)-2-phenylethenylJ-4-oxazolylmethoxyjphenylJethyl]- 2,4-oxazolidinedione was allowed to react with l-(2- pyrimidyl)piperazine to give 5-[2-[4-methoxy-3-[2-[ (E)- 2-phenylethenylJ-4-oxazolylmethoxyJphenylJethyl]-3-[3- [4-(2-pyrimidyl)piperazin-1-ylJpropylJ-2,4- oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
Elemental Analys is for C35H38N606 - HC1 • 0 . 5H20 : Calcd . : C , 6 1 . 44 ; H , 5 . 89 ; N , 12 . 28 Found : C , 61 . 43 ; H , 5 . 93 ; N , 12 . 24 Working Example 149 In substantially the same manner as in Working
Example 119, 3-(3-chloropropyl)-5-[2-[4-methoxy-3-[2- [(E)-2-phenylethenylJ-4-oxazolylmethoxyJphenylJethylJ- 2,4-oxazolidinedione was allowed to react with l-(4- trifluoromethylphenyl)piperazine to give 5-[2-[4- methoxy-3-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJethyl]-3-[3-[4-(4- trifluoromethylphenyl)piperazin-1-ylJpropylJ-2,4- oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
Elemental Analys is for C38H39F3N 06 • 2HC1
Calcd.: C, 58.69; H, 5.31; N, 7.20 Found : C, 59.00; H, 5.49; N, 7.25 Working Example 150 In substantially the same manner as in Working Example 6, 5-[3-(4-hydroxyphenyl)propylJ-2,4- oxazolidinedione was allowed to react with 4- chloromethyl-2-( 3,4-dihydro-2-naphthylJoxazole to give 5-[3-[4-[2-(3,4-dihydro-2-naphthyl)-4- oxazolylmethoxyJphenylJpropyl]-2,4-oxazolidinedione. Recrystalization from ethyl acetate gave colorless prisms, m.p. 180-181°C. Working Example 151
In substantially the same manner as in Working Example 15, 5-[2-(3-hydroxy-4-methoxyphenyl)ethylJ-2,4- oxazolidinedione was allowed to react with l-(3- chlorophenyl)-4-(3-chloropropyl)piperazine to give 5- [2-[3-[3-[4-(3-chlorophenyl)piperazin-l-ylJpropoxyJ-4- methoxyphenylJethyl]-3-[3-[4-(3-chlorophenyl)piperazin- l-yl)propylJ-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
Elemental Analysis for C38HA8C12N505•4HC1 • 0.5H20: Calcd.: C, 51.83; H, 6.07; N, 7.95 Found : C, 51.62; H, 6.02; N, 7.83 Working Example 152
In substantially the same manner as in Working Example 10, 5-[2-(3-hydroxy-4-methoxyphenylJethylJ-2,4- oxazolidinedione was allowed to react with l-(3- chlorophenyl)-4-(3-chloropropylJpiperazine, which was subjected to a silica gel column chromatography. From the fraction eluted with ethanol-chloroform (1:49, v/v) , 5-[2-[3-[3-[4-(3-chlorophenyl)piperazin-1- yl]propoxyJ-4-methoxyphenylJethylJ-2,4-oxazolidinedione was obtained as an oily product.
NMR(δ ppm in CDC13): 2.00-2.31(4H,m) , 2.64-2.83(8H,m) , 3.25(4H,t,J=5.0Hz) , 3.82(3H,s), 4.09(2H,t,J=6.2Hz) , 4.62(lH,dd,J=4.4&7.6Hz) , 6.71-6.87(6H,m) , 7.15(lH,t,J=8.2Hz) , 7.20(lH,s). From the following fraction, 3-[3-[4-(3- chlorophenyl)piperazin-1-ylJpropyl]-5-[2-(3-hydroxy-4- methoxyphenyl)ethylJ-2,4-oxazolidinedione was obtained as an oily product.
NMR(δ ppm in CDC13): 1.84 (2H,quint,J=7.0Hz) , 2.00- 2.33(2H,m), 2.43(2H,t,J=6.8Hz) , 2.53(4H,t,J=5.0Hz) , 2.67-2.76(2H,m) , 3.15(4H,t,J=5.0Hz) , 3.61(2H,t,J=7.0Hz) , 3.82(3H,ε), 4.69(lH,dd,J=4.4&8.4Hz), 6.62-6.85(6H,m) , 7.15(lH,t,J=8.2Hz) . Working Example 153 In substantially the same manner as in Working
Example 1, 5-[2-[3-[3-[4-(3-chlorophenyl)piperazin-l- ylJpropoxyJ-4-methoxyphenylJethyl]-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[ (E)-2- phenylethenylJoxazole to give 5-[2-[3-[3-[4-(3- chlorophenyl)piperazin-1-yl)propoxy]-4- methoxyphenyl]ethylJ-3-[2-[(E)-2-phenylethenylJ-4- oxazolylmethylJ-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
Elemental Analysis for C37H39C1N06•2HC1 • 0.5H20: Calcd.: C, 59.01; H, 5.62; N, 7.44 Found : C, 59.30; H, 5.67; N, 7.16 Working Example 154 In substantially the same manner as in Working Example 1, 3-[3-[4-(3-chlorophenyl)piperazin-l- ylJpropyl]-5-[2-(3-hydroxy-4-methoxyphenyl)ethylJ-2,4- oxazolidinedione was allowed to react with 4-[(E)-2- phenylethenylJbenzylchloride to give 3-[3-[4-(3- chlorophenyl)piperazin-1-yl Jpropyl]-5-[2-[4-methoxy-3- [4-[ (E)-2-phenylethenylJbenzyloxyJphenylJethylJ-2,4- oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79. Elemental Analys is for CAOHA C1N305 • 2HC1 • 0 . 75H20 :
Calcd . : C , 62 . 67 ; H , 5 . 98 ; N , 5 . 48 Found : C , 62 . 65 ; H , 6 . 11 ; N , 5 . 41
Working Example 155
In substantially the same manner as in Working
Example 3, 4-benzyloxycinnamaldehyde was subjected to condensation with 1-methylhydantoin to give 5-(4- benzyloxycinnamylidene)-l-methylhydantoin, which was subjected to catalytic reduction in substantially the same manner as in Working Example 4 to give 5-[3-(4- hydroxyphenyl)propylJ-1-methylhydantoin. Recrystalization from N,N-dimethylformamide (DMF) - water gave colorless prisms, m.p. 179-180°C.
Working Example 156
In substantially the same manner as in Working
Example 15, 5-[3-(4-hydroxyphenyl)propylJ-l- methylhydantoin was allowed to react with 4- chloromethyl-2-[ (E)-2-phenylethenylJoxazole to give 1- methyl-5-[3-[4-[2-[(E)-2- phenylethenyl]oxazolylmethoxy]phenyl]propyl]-3-[2-[(E)-
2-phenylethenyl]oxazolylmethyl]hydantoin. Recrystalization from chloroform - hexane gave colorless prisms, m.p. 154-155°C.
Working Example 157
In substantially the same manner as in Working
Example 107, 5-[3-[4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJpropylJ-2,4-oxazolidinedione was allowed to react with l-( 3-chloropropyl)-4- phenylpipeazine to give 5-[3-[4-[2-[ (E)-2- phenylethenyl]-4-oxazolylmethoxy]phenylJpropyl]-3-[3-
(4-phenylpiperazin-1-yl)propylJ-2,4-oxazolidinedione. Recrystalization from ethyl acetate - hexane gave colorless needles, m.p. 130-131°C
Working Example 158
In substantially the same manner as in Working
Example 107, 5-[2-(3-benzyloxy-4-methoxyphenyl)ethylJ- 2,4-oxazolidinedione was allowed to react with l-(3- chloropropyl)-4-phenylpiperazine to give 5-[2-(3- benzyloxy-4-methoxyphenyl)ethyl ]-3-[3-(4- phenylpiperazin-1-yl)propylJ-2,4-oxazolidinedione as an oily product.
NMR(δ ppm in CDC13): 1.85(2H,quint,J=7.0Hz) , 1.95- 2.26(2H,m), 2.44(2H,t,J=6.7Hz) , 2.56 (4H,t,J=4.9Hz) ,
2.65-2.76(2H,m) , 3.16 (4H,t,J=4.9Hz) ,
3.61(2H,t,J=7.0Hz) , 3.85(3H,s),
4.55(lH,dd,J=4.4&8.2Hz) , 5.41(2H,s), 6.71-6.93(6H,m) ,
7.22-7.45(7H,m) . Working Example 159
In substantially the same manner as in Working
Example 4, 5-[2-(3-benzyloxy-4-methoxyphenyl)ethylJ-3-
[3-(4-phenylpiperazin-l-ylJpropylJ-2,4-oxazolidinedione was subjected to catalytic reduction to give 5-[2-(3- hydroxy-4-methoxyphenyl)ethyl]-3-[3-(4-phenylpiperazin-
1-ylJpropylJ-2,4-oxazolidinedione as an oily product.
NMR ( δ ppm in CDC13 ) : 1 . 86 ( 2H , quint , J=6 . 8Hz ) , 1 . 96-
2.34(2H,m), 2.45(2H,t,J=6.8Hz) , 2.56(4H,t,J=5.OHz) ,
2.68-2.77(2H,m) , 3.17 (4H,t,J=5. OHz) , 3.63(2H,t,J=6.8Hz) , 3.84(3H,s),
4.70(lH,dd,J=4.4&8.4Hz) , 6.63-6.77 (3H,m) , 6.82-
6.94(3H,m), 7.27(2H,t,J=8.OHz) .
Working Example 160
In substantially the same manner as in Working Example 1, 5-[2-(3-hydroxy-4-methoxyphenyl)ethyl]-3-[3-
(4-phenylpiperazin-1-ylJpropylJ-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-5-methyl-2-(2- naphthylJoxazole to give 5-[2-[4-methoxy-3-[5-methyl-2-
(2-naphthyl)-4-oxazolylmethoxyJphenylJethyl]-3-[3-(4- phenylpiperazin-1-ylJpropyl]-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in
Working Example 79.
Elemental Analysis for CA0HA2NAO6 • 2HC1 Calcd . : C , 64 . 25 ; H , 5 . 93 ; N , 7 . 49
Found : C , 64 . 32 ; H , 5 . 92 ; N , 7 . 47 Working Example 161
In substantially the same manner as in Working Example 1, 5-[2-(3-hydroxy-4-methoxyphenyl)ethylJ-3-[3- (4-phenylpiperazin-l-yl)propylJ-2,4-oxazolidinedione was allowed to react with 2-(2-benzofuranyl)-4- chloromethyl-5-methyloxazole to give 5-[2-[4-methoxy-3- [2-(2-benzofuranyl)-5-methyl-4- oxazolylmethoxyJphenylJethylJ-3-[3-(4-phenylpiperazin- l-yl)propylJ-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example
79.
Elemental Analys is for C38HA0NAO7 • 2HC1
Calcd . : C , 61 . 87 ; H , 5 . 74 ; N , 7 . 60 Found : C, 61.60; H, 5.79; N, 7.52 Working Example 162
In substantially the same manner as in Working Example 1, 5-[2-(3-hydroxy-4-methoxyphenyl)ethyl]-3-[3- (4-phenylpiperazin-l-yl)propyl]-2,4-oxazolidinedione was allowed to react with 2-(2-benzothienyl)-4- chloromethyl-5-methyloxazole to give 5-[2-[4-methoxy-3- [2-(2-benzothienyl)-5-methyl-4- oxazolylmethoxyJphenylJethylJ-3-[3-(4-phenylpiperazin- l-ylJpropylJ-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example
79.
Elemental Analysis for C38H 0N O6S ■ 2HC1
Calcd . : C , 60 . 55 ; H , 5 . 62 ; N , 7 . 43 Found : C, 60.35; H, 5.85; N, 7.30 Working Example 163
In substantially the same manner as in Working Example 1, 5-[2-(3-hydroxy-4-methoxyphenyl)ethylJ-3-[3- (4-phenylpiperazin-l-ylJpropyl]-2, 4-oxazolidinedione was allowed to react with 4-chloromethyl-2-(3,4- dihydro-2-naphthylJoxazole to give 5-[2-[3-[2-(3,4- dihydro-2-naphthyl)-4-oxazolylmethoxy]-4- methoxyphenylJethylJ-3-[3-(4-phenylpiperazin-l- ylJpropylJ-2,4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
Elemental Analysis for C39H 2NA06 -HCl • 1.5H20: Calcd.: C, 64.50; H, 6.38; N, 7.71 Found : C, 64.83; H, 6.12; N, 7.74 Working Example 164
In substantially the same manner as in Working Example 1, 5-[2-(3-hydroxy-4-methoxyphenylJethyl]-3-[3- (4-phenylpiperazin-l-yl)propylJ-2,4-oxazolidinedione was allowed to react with 2-[3,5- bis(trifluoromethyl)phenyl]-4-chloromethyl-5- methyloxazole to give 5-[2-[3-[2-(3,5- bis(trifluoromethyl)phenylJ-5-methyl-4- oxazolylmethoxy]-4-methoxyphenyl]ethyl]-3-[3-(4- phenylpiperazin-1-ylJpropylJ-2, 4-oxazolidinedione as an oily product. This oily product was led to hydrochloride by substantially the same procedure as in Working Example 79.
Elemental Analysis for C38H38F6N 06 -HCl • 1.0H2O: Calcd.: C, 55.99; H, 5.07; N, 6.87 Found : C, 56.11; H, 5.04; N, 6.67 Working Example 165
In substantially the same manner as in Working Example 1, 5-[2-( 3-hydroxy-4-methoxyphenylJethylJ-3-[ 3- (4-phenylpiperazin-l-ylJpropylJ-2,4-oxazolidinedione was allowed to react with 4-[(EJ- phenylethenyljbenzylchloride to give 5-[2-[4-methoxy-3- [4-[ (E)-2-phenylethenylJbenzyloxyJphenylJethyl]-3-[3- (4-phenylpiperazin-l-ylJpropyl]-2 ,4-oxazolidinedione. Recrystalization from ethyl acetate gave colorless needles, m.p. 138-140°C.
Formulation Example 1 (dosage per tablet) (1) Compound of Working Example 36 10.0 mg
(2) Lactose 60.0 mg
(3) Corn starch 35.0 mg
(4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg
A mixture of 10.0 mg of the compound of Working Example 36, 60.0 mg of lactose and 35.0 mg of corn starch was granulated, by using 0.03 ml of a 10 weight % aqueous solution of gelatin (3.0 mg in terms of gelatin), through a sieve of 1 mm mesh. The granules were dried at 40 °C, which were again subjected to sieving. The resulting granules were mixed with 2.0 mg of magnesium stearate, which was compressed. Thus- obtained core tablets was sugar-coated with a suspension consisting of sucrose, titanium dioxide, talc and gum arabic, followed by polishing with bee wax.
Formulation Example 2 (dosage per tablet) (1) Compound of Working Example 36 10.0 mg (2) Lactose 70.0 mg
(3) Corn starch 50.0 mg
(4) Soluble starch 7.0 mg
(5) Magnesium stearate 3.0 mg
A mixture of 10.0 mg of the compound of Working Example 36 and 3.0 mg of magnesium stearate was granulated by using 0.07 ml of an aqueous solution of soluble starch (7.0 mg in terms of soluble starch) and dried, which was mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture was compressed to give a tablet.

Claims

1. A heterocyclic compound represented by the formula:
Figure imgf000147_0001
wherein D stands for hydrogen atom or an optionally substituted hydrocarbon group;
X stands for CH or N;
A stands for a divalent aliphatic hydrocarbon group,
R stands for a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group,
(2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) a hydroxyl group optionally substituted by a hydrocarbon group or an acyl group, (7) a thiol group optionally substituted by a hydrocarbon group or an acyl group, (8) an optionally esterified carboxyl group, (9) cyano group or (10) oxo group;
Q stands for -N(R )- (R stands for hydrogen atom or a lower alkyl group), oxygen atom or sulfur atom;
Z stands for oxygen atom or sulfur atom;
L and M independently stand for hydrogen atom, or they may optionally be combined with each other to form one bond; and ring E may optionally be further substituted, and the substituent may optionally be combined with D to form a ring; or a salt thereof.
2. A compound or a salt thereof according to Claim 1, wherein the partial formula:
Figure imgf000148_0001
3. A compound or a salt thereof according to Claim 1, wherein D and R are respectively hydrocarbon groups substituted by an optionally substituted heterocyclic group.
4. A compound or a salt thereof according to Claim 1, wherein R is a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group, (2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) an optionally esterified carboxyl group, (7) cyano group or (8) oxo group.
5. A compound or a salt thereof according to Claim 4, wherein the substituent in the optionally substituted heterocyclic group is 6 alkyl, C2.8 alkenyl, C3_8 cycloalkyl, C6.1 aryl, C7.1A aralkyl, C6.1A aryl-Cz_6 alkenyl, an aromatic heterocyclic group, an aromatic heterocyclic-Ci.g alkyl group or an aromatic heterocyclic-C2_6 alkenyl group.
6. A compound or a salt thereof according to Claim 4, wherein the optionally substituted amino group is a Cj. 10 acylamino group, a mono- or di-Cj.jo alkylamino group or a 4- to 6-membered cyclic amino group.
7. A compound or a salt thereof according to Claim 3, wherein the heterocyclic group is oxazolyl or thiazolyl .
8. A compound or a salt thereof according to claim 1, wherein X is CH.
9. A compound or a salt thereof according to claim 1, wherein A is a C η divalent aliphatic hydrocarbon group.
10. A compound or a salt thereof according to claim 1, wherein Q and Z are oxygen atom.
11. A compound or a salt thereof according to claim 1, wherein L and M are hydrogen atom.
12. A compound or a salt thereof according to claim 1, wherein ring E may optionally have one to four substituents selected from Cj. alkyl, C^ alkoxy, halogen, amino, nitro and hydroxyl.
13. A compound or a salt thereof according to claim 1, which is
5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenylJpropyl]-3-[2-[ (E)-2- phenylethenylJ-4-oxazolylmethyl]-2,4-oxazolidinedione; 5-[3-[3-methoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenyl]propyl]—3—[2—[ (E)-2- phenylethenylJ-4-thiazolylmethyl]-2,4-oxazolidinedione; 5-[3-[4-[2-[ (E)-2-phenylethenylJ-4- oxazolylmethoxyJphenyl]propylJ-3-[2-[(E)-2- phenylethenylJ-4-oxazolylmethylJ-2,4-oxazolidinedione; 5-[3-[3,5-dimethoxy-4-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJpropyl]—3—[2—[ (E)-2- phenylethenyl]-4-oxazolylmethylJ-2,4-oxazolidinedione; 5-[2-[4-methoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxy]phenylJethyl]-3-[3-[4-(4- methoxyphenyl)piperadin-1-yl]propylJ-2,4- oxazolidinedione; or
5-[2-[4-methoxy-3-[2-[ (E)-2-phenylethenyl]-4- oxazolylmethoxyJphenylJethyl]-3-[3-(4-phenylpiperadin- 1-ylJpropyl]-2,4-oxazolidinedione.
14. A pharmaceutical composition comprising a compound or a salt thereof as claimed in Claim 1.
15. An antitumor agent which comprises a compound represented by the formula:
Figure imgf000149_0001
wherein D stands for hydrogen atom or an optionally substituted hydrocarbon group;
X stands for CH or N;
A stands for a bond or a divalent aliphatic hydrocarbon group;
R stands for hydrogen atom or a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group, (2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) a hydroxyl group optionally substituted by a hydrocarbon group or an acyl group, (7) a thiol group optionally substituted by a hydrocarbon group or an acyl group, (8) an optionally esterified carboxyl group, (9) cyano group or (10) oxo group;
Q stands for -N(R )- (R stands for hydrogen atom or a lower alkyl group), oxygen atom or sulfur atom;
Z stands for oxygen atom or sulfur atom;
L and M independently stand for hydrogen atom or they may optionally be combined with each other to form one bond; and ring E may optionally be further substituted, and the substituent may optionally be combined with D to form a ring; and when A1 stands for a bond, D stands for an optionally substituted hydrocarbon group; or a salt thereof.
16. An antitumor agent according to claim 15, wherein A1 is a Cj.7 divalent aliphatic hydrocarbon group.
17. An antitumor agent according to claim 15, wherein R is an optionally substituted hydrocarbon group.
18. An antitumor agent according to Claim 15, which is a therapeutic agent of breast cancer.
19. A tyrosine kinase inhibitor which comprises a compound represented by the formula:
Figure imgf000151_0001
wherein D stands for hydrogen atom or an optionally substituted hydrocarbon group;
X stands for CH or N;
A stands for a bond or a divalent aliphatic hydrocarbon group;
R stands for hydrogen atom or a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group, (2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) a hydroxyl group optionally substituted by a hydrocarbon group or an acyl group, (7) a thiol group optionally substituted by a hydrocarbon group or an acyl group, (8) an optionally esterified carboxyl group, (9) cyano group or (10) oxo group;
Q stands for -N(R )- (R stands for hydrogen atom or a lower alkyl group) , oxygen atom or sulfur atom;
Z stands for oxygen atom or sulfur atom;
L and M independently stand for hydrogen atom or they may optionally be combined with each other to form one bond; and ring E may optionally be further substituted, and the substituent may optionally be combined with D to form a ring; and when A stands for a bond, D stands for an optionally substituted hydrocarbon group; or a salt thereof.
20. A method of producing a compound represented by the formula:
Figure imgf000152_0001
wherein D stands for hydrogen atom or an optionally substituted hydrocarbon group;
X stands for CH or N;
A stands for a divalent aliphatic hydrocarbon group,
R stands for a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group,
(2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) a hydroxyl group optionally substituted by a hydrocarbon group or an acyl group, (7) a thiol group optionally substituted by a hydrocarbon group or an acyl group, (8) an optionally esterified carboxyl group, (9) cyano group or (10) oxo group;
Q stands for -N(R )- (R stands for hydrogen atom or a lower alkyl group), oxygen atom or sulfur atom;
Z stands for oxygen atom or sulfur atom;
L and M independently stand for hydrogen atom, or they may optionally be combined with each other to form one bond; and ring E may optionally be further substituted, and the substituent may optionally be combined with D to form a ring; or a salt thereof, which is characterized by allowing a compound represented by the formula:
Figure imgf000152_0002
wherein each symbol is of the same meaning as defined above, or a salt thereof, to react with a compound represented by the formula:
R-W wherein W stands for a leaving group and R is of the same meaning as defined above, or a salt thereof,
21. A method of producing a compound represented by the formula:
Figure imgf000153_0001
wherein
X stands for CH or N;
A stands for a divalent aliphatic hydrocarbon group,
R stands for a hydrocarbon group optionally substituted by (1) an optionally substituted heterocyclic group,
(2) a halogen atom, (3) nitro group, (4) an optionally substituted amino group, (5) an optionally substituted acyl group, (6) a hydroxyl group optionally substituted by a hydrocarbon group or an acyl group, (7) a thiol group optionally substituted by a hydrocarbon group or an acyl group, (8) an optionally esterified carboxyl group, (9) cyano group or (10) oxo group;
Q stands for -N(R )- (R stands for hydrogen atom or a lower alkyl group) , oxygen atom or sulfur atom;
Z stands for oxygen atom or sulfur atom;
L and M independently stand for hydrogen atom, or they may optionally be combined with each other to form one bond; and ring E may optionally be further substituted; or a salt thereof, which is characterized by allowing compound represented by the formula:
Figure imgf000153_0002
wherein each symbol is of the same meaning as defined above, or a salt thereof, to react with a compound represented by the formula: R-W wherein W stands for a leaving group and R is of the same meaning as defind above, or a salt thereof.
22. Method for treating cancer in a mammal in need thereof, which comprises administering such mammal a therapeutically effective amount of a compound as defined in claim 15 or a pharmaceutically acceptable salt thereof.
23. Method for treating diabetes in a mammal in need thereof, which comprises administering such mammal a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof.
24. Use of a compound as defined in claim 15 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating cancer.
25. Use of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating diabetes .
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EP1014982A1 (en) * 1997-03-04 2000-07-05 The Board Of Regents, The University Of Texas System Troglitazone compounds for treating climacteric
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WO2001016123A1 (en) * 1999-08-31 2001-03-08 Maxia Pharmaceuticals, Inc. Benzylidene-thiazolidinediones and analogues and their use in the treatment of inflammation
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JP2003040877A (en) * 2001-07-24 2003-02-13 Sumika Fine Chemicals Co Ltd Method for producing 5-[6-(2-fluorobenzyloxy)-2- naphthyl]methyl-2,4-thiazolidinedione and method for refining the same
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US7071218B2 (en) 2001-11-15 2006-07-04 Incyte San Diego Incorporated N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders; cancer, and other diseases
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EP1014982A1 (en) * 1997-03-04 2000-07-05 The Board Of Regents, The University Of Texas System Troglitazone compounds for treating climacteric
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US7153875B2 (en) 2001-03-07 2006-12-26 Incyte San Diego Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
US7265139B2 (en) 2001-03-08 2007-09-04 Incyte San Diego Inc. RXR activating molecules
JP2003040877A (en) * 2001-07-24 2003-02-13 Sumika Fine Chemicals Co Ltd Method for producing 5-[6-(2-fluorobenzyloxy)-2- naphthyl]methyl-2,4-thiazolidinedione and method for refining the same
US7071218B2 (en) 2001-11-15 2006-07-04 Incyte San Diego Incorporated N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders; cancer, and other diseases
WO2003059907A1 (en) * 2002-01-17 2003-07-24 Takeda Chemical Industries, Ltd. Nitrogenous heterocyclic compounds, process for preparation of the same and use thereof
US7102000B2 (en) 2002-03-08 2006-09-05 Incyte San Diego Inc. Heterocyclic amide derivatives for the treatment of diabetes and other diseases
US7196108B2 (en) 2002-03-08 2007-03-27 Incyte San Diego Inc. Bicyclic heterocycles for the treatment of diabetes and other diseases
US7205325B2 (en) 2003-03-28 2007-04-17 Hoffmann-La Roche Inc. Oxazole derivatives
US7541472B2 (en) 2004-05-24 2009-06-02 Cropsolution, Inc. 3-Aryl-3-hydroxy-2-methylenepropionic acid esters as fungicides
JP2008543792A (en) * 2005-06-17 2008-12-04 アンドルシェルシュ・インコーポレイテッド Helix 12-directed non-steroidal antiandrogen
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CN102408337B (en) * 2010-09-20 2014-02-19 四川大学 (E)-3-[4-(alkoxy)phenyl]acrylate compounds and preparation method and applications thereof

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