[go: up one dir, main page]

WO1998017629A1 - Derives de 1,4-benzoquinone - Google Patents

Derives de 1,4-benzoquinone Download PDF

Info

Publication number
WO1998017629A1
WO1998017629A1 PCT/JP1997/003873 JP9703873W WO9817629A1 WO 1998017629 A1 WO1998017629 A1 WO 1998017629A1 JP 9703873 W JP9703873 W JP 9703873W WO 9817629 A1 WO9817629 A1 WO 9817629A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mmol
fabms
substituted
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1997/003873
Other languages
English (en)
Japanese (ja)
Inventor
Hitomi Hamai
Yutaka Maeda
Yutaka Kanda
Mitsunobu Hara
Kazuhito Akasaka
Shiro Akinaga
Chikara Murakata
Shun-Ichi Ikeda
Kendo Shono
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KH Neochem Co Ltd
Original Assignee
Kyowa Hakko Kogyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co Ltd filed Critical Kyowa Hakko Kogyo Co Ltd
Priority to AU47238/97A priority Critical patent/AU4723897A/en
Publication of WO1998017629A1 publication Critical patent/WO1998017629A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/32—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
    • C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/41—Y being a hydrogen or an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a novel 1,4-benzoquinone derivative or a pharmaceutically acceptable salt thereof, which has a pharmacotransferase inhibitory activity and is useful as an antitumor agent.
  • the ras oncogene is point-mutated in many human tumor tissues and is detected in an active form that can transform normal cells.
  • binding to the cell membrane by pharmacosylation of cysteine residues present in the C-terminal region is essential. is there.
  • This reaction is catalyzed by pharmacotransferase. Therefore, it is expected that the pharmacologic inhibitor of pharmacosyltransferase will suppress the function of the ras oncogene product, and can be expected to have an antitumor effect [Gibbs et al. (Cell), Vol. 77, pp.
  • An epoxycyclohexene derivative is known as a pharmacophorase inhibitor (WO95Z085646).
  • X and Y are both hydrogen atoms
  • R 1 and R 2 are taken together as an oxygen atom
  • R 3 is 2,6,10 -Trimethyl-1,5,9-indene force
  • a compound represented by trienyl is described.
  • the present invention provides a compound of the formula (I)
  • X and Y are the same or different and each represents a hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower Alkoxy, lower alkanoyl, amino, substituted or unsubstituted mono- or di-lower alkylamino, arylamino, aralkylamino, lower alkenylamino, substituted or unsubstituted heterocyclic amino, substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclic Thio, substituted or unsubstituted arylthio, substituted or unsubstituted aralkylthio, lower alkenylthio, lower alkenyloxy, substituted or unsubstituted aryloxy, aralkyloxy, Z (CH 2 CH 2 ⁇ ) n R 4 (where n is represents an integer of 2 ⁇ 5, Z is an oxygen atom, NH
  • halogen means each atom of iodine, bromine, chlorine or fluorine.
  • alkyl moiety of the alkylthio include linear or branched alkyl having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isobenzyl, Hexyl, heptyl, octyl, nonyl, decyl, pendecyl, dodecyl, pencil decyl and the like.
  • the lower alkenyl moiety in lower alkenyloxy, lower alkenylthio and lower alkenylamino is a straight or branched chain having 2 to 6 carbon atoms, for example, vinyl, aryl, crotyl, prenyl, 3-butenyl, 2-pentenyl. , 4-pentenyl, 2-hexenyl, 5-hexenyl and the like.
  • the aralkyl moiety in aralkyloxy, aralkylamino and aralkylthio includes, for example, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like having 7 to 15 carbon atoms.
  • the aryl portion in aryloxy, arylamino and arylthio includes phenyl, naphthyl, biphenyl, anthryl and the like.
  • Examples of the alicyclic heterocyclic group include pyrrolidinyl, piberidinyl, piperidino, N-methylbiperidino, piperazinyl, morpholino, thiomorpholino, homopiberidinyl, homopiperazinyl, tetrahydropyranyl and the like.
  • Examples of the heterocyclic group of the heterocyclic thio and heterocyclic amino are the following: Examples include an aromatic complex group and an alicyclic heterocyclic group as defined above.
  • Substituents for substituted lower alkyl, substituted lower alkoxy, substituted mono- or di-lower alkylamino, and substituted alkylthio include halogens having 1 to 3 substituents, hydroxy, ethoxylated, ethoxylated carbamoyl, mercapto, amino, and lower alkoxy. And lower alkoxy propyl, lower alkylthio, lower alkanol, lower alkanol, mono- or di-lower alkylamino, hydroxy lower alkyl, trialkylsilyl, and heterocyclic groups.
  • Substituent aryloxy, substituted arylthio, substituted aralkylthio, substituted heterocyclic thio, substituted heterocyclic amino, and substituted alicyclic heterocyclic groups may be the same or different, and may have 1 to 4 hydroxy, halogen, and nitro substituents. , Amino, mono- or di-lower alkylamino, carboxy, lower alkyl, lower alkoxy, lower alkoxyl propyl, lower alkanoyl, lower alkanoyloxy, lower alkanoylamino, lower alkanoyloxymethyl and the like.
  • each substituent lower alkyl, hydroxy lower alkyl, mono- or di-lower alkylamino, lower alkylthio, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkanoylamino and lower alkanoyl
  • the lower alkyl moiety and the halogen in xmethyl have the same meanings as described above, respectively, and the heterocyclic group has the same meaning as the heterocyclic group of the heterocyclic thio and the heterocyclic amino.
  • Pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts.
  • Acid salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, and phosphate, formate, acetate, benzoate, maleate, fumarate, succinate, and tartrate.
  • organic acid salts such as citrate, oxalate, methanesulfonate, P-toluenesulfonate, aspartate, and glutamate.
  • the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt.
  • ammonium salt examples include ammonium and tetramethyl.
  • the organic amine addition salts include addition salts such as morpholine and piperidine, and the amino acid addition salts include addition salts such as glycine, phenylalanine, glutamic acid, and lysine.
  • Compound (I) can be produced, for example, by the following reaction step.
  • R 5 represents a hydrogen atom or lower alkyl
  • R 6 represents lower alkyl
  • R la and R 2a are the same or different and represent lower alkoxy
  • X, Y, and R 3 have the same meanings as defined above. Is.
  • the lower alkoxy has the same meaning as the lower alkoxy.
  • Compound (III) can be synthesized by reducing nitro group of known compound (II) with an appropriate reducing agent.
  • the reducing agent to be used may be any method as long as it is a method usually used for reduction of a nitro group, for example, a method by hydrogenation or hydrazine treatment in the presence of a catalyst such as palladium or platinum, zinc, tin under acidic conditions, etc.
  • the reduction method using a single metal is used.
  • the reaction temperature is preferably from 0 to 150 ° C. in the presence of 0.1 to 1 equivalent of the catalyst, and the reaction time is usually from 10 minutes to 5 hours.
  • the reaction temperature is preferably 0 to 100 ° C. in the presence of 1 to 50 equivalents of a reducing agent, and the reaction time is usually 10 minutes to 10 hours.
  • the compound (IV) represents the compound (III) or its hydrochloride by 1 to 10 equivalents of the formula R 3 C ⁇ Hal (wherein R 3 has the same meaning as described above, and Hal represents chlorine or bromine). It can be synthesized by reacting with an acid halide to be used in the presence of 1 to 10 equivalents of a base such as pyridine, triethylamine, N, N-dimethylaniline and the like. The reaction can be carried out in an inert solvent such as dichloromethane, chloroform and tetrahydrofuran. The reaction temperature is preferably from 130 to 150, and the reaction time is usually from 5 minutes to 5 hours.
  • compound (III) is obtained by mixing 1 to 10 equivalents of a carboxylic acid represented by the formula R 3 CO 2 H (wherein R 3 has the same meaning as described above) with 1 to 50 equivalents of ⁇ , ⁇ ′. It can also be synthesized by reacting in the presence of a condensing agent such as -dicyclohexylcarposimide.
  • a condensing agent such as -dicyclohexylcarposimide.
  • the compound (I) a in which R 1 and R 2 are the same or different and are lower alkoxy is a compound (IV) obtained by converting 1 to 10 equivalents of rhodobenzene in a lower alcohol such as methanol or ethanol. It can be obtained by treating with oxidizing agents such as diacetate and bis (trifluoroacetoxy) chloride.
  • the reaction temperature is preferably from ⁇ 30 to 100 ° C., and the reaction time is usually from 10 minutes to 5 hours.
  • (I) b can be synthesized by subjecting compound (IV) to the same oxidation reaction as in step 3 in a water-containing solvent such as water-containing acetonitrile as a solvent.
  • a water-containing solvent such as water-containing acetonitrile
  • the oxidizing agent 1 to 10 equivalents of benzenebenzene acetic acid, bis (trifluoroacetoxy) benzene or the like is used.
  • the reaction temperature is preferably 130 to 100 ° C, and the reaction time is usually 10 minutes to 5 hours. is there.
  • Compound (I) b is obtained by converting compound (I) a obtained in step 3 to an inorganic acid such as sulfuric acid, perchloric acid, hydrochloric acid, hydrobromic acid or acetic acid in a solvent such as tetrahydrofuran, furan, dioxane, or acetonitrile. It can also be synthesized by treating with an organic acid such as trifluoroacetic acid, p-toluenesulfonic acid and the like. Usually, 0.1 to 100 equivalents of an inorganic acid or an organic acid are used, the reaction temperature is preferably -80 to 50 ° C, and the reaction time is usually 10 minutes to 10 hours.
  • an inorganic acid such as sulfuric acid, perchloric acid, hydrochloric acid, hydrobromic acid or acetic acid in a solvent such as tetrahydrofuran, furan, dioxane, or acetonitrile. It can also be synthesized by treating with an organic
  • the compound (I) b—2 having a functional group at the X or Y site is the compound (I) b — 1 in which R 1 and R 2 are in the form of It can also be manufactured by a process.
  • R 3 is as defined above, X a and X b are as defined above X, although Y a and Y b have the same meanings as defined above Y, when X a is the same as X b at the same time Y a is never the same as Y b.
  • Compound (I) b_2 is compound (I) b-1 with acetonitrile and tetrahydride
  • an inert solvent such as furan, ether, dioxane, dimethylformamide, chloroform, and dichloromethane
  • it can be obtained by addition reaction or substitution reaction of 1 to 10 equivalents of the corresponding alcohol, amine, or thiol.
  • the alcohol itself may be used as the solvent, and 1 to 10 equivalents of a base such as sodium hydrogencarbonate, potassium carbonate, sodium hydroxide, pyridine, triethylamine, or 0.001.
  • the reaction can also be promoted by adding a palladium catalyst such as ⁇ 1 equivalent of tetrakis (triphenylphosphine) palladium (o).
  • a palladium catalyst such as ⁇ 1 equivalent of tetrakis (triphenylphosphine) palladium (o).
  • the oxidation reaction to quinone can also be performed by adding 1 to 10 equivalents of an oxidizing agent such as cerium ammonium nitrate or potassium nitrosodisulfonate to the reaction system after the addition reaction. Can be promoted.
  • the position and number of addition or substitution vary depending on the compound (I) b-1 used and the type of alcohol, amine or thiol to be added or substituted, as well as the reaction temperature, reaction time and the type of base used.
  • the reaction temperature is preferably from 120 to 150 ° C, and the reaction time is usually completed in 10 minutes to 40 hours.
  • Compound (I) b-2 in which Y is a hydroxyl group can also be synthesized by demethylation of compound (I) b-1 in which Y is methoxy using lithium iodide or the like.
  • X c represents a group obtained by removing a hydrogen atom from the definition of X, and Y, R la , R 2a and R 3 are as defined above. )
  • Compound (I) d is Asetonitoriru Compound (I) c, tetrahydrofuran, ether, Jiokisan, dimethylformamide, black hole Holm, an inert solvent such as Jikurorome evening down from 1 to 1 0 equivalents of the formula X e -H
  • X e has the same meaning as described above, and can be obtained by an addition reaction of a thiol, alcohol, or amine represented by the formula:
  • the reaction can also be promoted by adding 1 to 10 equivalents of a base such as sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, pyridine, and triethylamine.
  • the reaction temperature is preferably 120 to 150, and the reaction time is usually completed in 10 minutes to 40 hours.
  • the isolation and purification of the product in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like.
  • the intermediate can be subjected to the next reaction without purification.
  • the compound (I) may have isomers such as positional isomers, geometric isomers or optical isomers, but the possible isomers and mixtures of the isomers in any ratio are also included in the present invention. .
  • the compound (I) may be purified as it is when the salt of the compound (I) is obtained, or may be dissolved or suspended in an appropriate solvent when the salt of the compound (I) is obtained in a free form.
  • a salt may be formed by adding a base.
  • Compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and such adducts are also included in the present invention.
  • Table 1 shows the structures of typical examples of the compound (I).
  • the extract obtained by crushing bovine brain is applied to DEAE-Sephacel (manufactured by Pharmacia) column chromatography, and the active fraction is subjected to ultrafiltration.
  • [20 mM Tris-HCl (pH 8.0), 50 mM sodium chloride (NaCl), 20 mM zinc chloride (ZnCl 2 ), ImM dithiothreitol (DTT) and 0.2 mM phenylmethylsulfonyl fluoride (PMSF)] was used as a crude enzyme solution.
  • Activity measurement is as above The measurement was carried out by measuring the amount of the enzyme obtained by the method, which transfers [ 3 H] pharynesyl pyrophosphate to Ras protein produced in Escherichia coli.
  • Cytostatic activity was measured using 3Y1-B cells (hereinafter, HR-3Y1 cells) transformed with the oncogene vH-ras.
  • HR-3Y1 cells 3Y1-B cells transformed with the oncogene vH-ras.
  • DMEM medium containing 10% fetal bovine serum [Nissui] (hereinafter, the medium will leave A) 1.0 X 10 4 cells in / ml of HR-3Y1 cells adjusted to 0.1ml was dispensed.
  • Compound (I) or a pharmaceutically acceptable salt thereof may be administered as it is or orally or parenterally as various pharmaceutical compositions.
  • dosage form of such a pharmaceutical composition include tablets, pills, powders, granules, capsules, suppositories, injections, and drops.
  • the usual methods are applied for formulating the above dosage forms, for example, containing various excipients, lubricants, binders, disintegrants, suspending agents, isotonic agents, emulsifiers, absorption promoters, etc. It may be.
  • Carriers used in pharmaceutical compositions include, for example, water, distilled water for injection, physiological saline, glucose, fructoses, sucrose, mannitol, lactose, starch, corn * starch, cellulose, methylcellulose, carboxy Methylcellulose, hydroxypropylcellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitol fatty acid ester, glycerin fatty acid ester, etc. Is appropriately selected according to the conditions.
  • the dosage and frequency of administration vary depending on the desired therapeutic effect, administration method, treatment period, age, body weight, etc., but oral or parenteral (eg, injection, infusion, rectal administration by suppository, skin patch, etc.) It is usually 0.01 to 200 mg / kg per adult, depending on the method of administration.
  • ordinary post-treatment means the following post-reaction treatment.
  • Example 14 Using the same method as in Example 13, 1.37 g of compound 6 obtained in Example 6 was dissolved in 50 ml of tetrahydrofuran, and 418 mg (2.2 mmol) of P-toluenesulfonic acid monohydrate and 3N hydrochloric acid 15 ml was added, and the mixture was stirred at room temperature for 6 hours. After usual post-treatment, recrystallization from chloroform-methanol-hexane gave 1.13 g (92%) of compound 14.
  • Example 33 N- ⁇ 4- [2- (2-methoxyethoxy) ethoxy] -3,6-dioxocyclohexa-1,4-genyl ⁇ -4-benzyloxyphenoxyacetamide (compound 3 3) 22.0 mg (0.055 mm) of compound 14 obtained in Example 14 in the same manner as in Example 24 01), 1 ml of 2- (2-methoxyethoxy) ethanol and 32.4 mg (0.40 mmol) of titanium bicarbonate gave 5.5 mg (21%) of compound 33.
  • Example 29 Using a method similar to that in Example 29, the compound was obtained from 26.7 mg (0.071 mmol) of compound 13 obtained in Example 13, 18.0 mg (0.21 mmol) of sodium hydrogen carbonate, and 2.0 ml of triethylene glycol. 24.9 mg (72%) of 34 were obtained.
  • Example 40 Using the same method as in Example 40, the compound was obtained from 20.5 mg (0.047 mmol) of compound 15 obtained in Example 15 and 0.5 ml (5.3 mmol) of diethylene glycol and 4.4 mg (0.052 mmol) of sodium hydrogen carbonate. 4 1 was obtained in an amount of 14.5 mg (61%).
  • Example 48 N- [4-forcerubamoylmethylamino-3,6-dioxocyclohexa-1,4 -Genenyl] -3,7,11-trimethyl-2,6,10-dodecatrienamide (Compound 48) Using a method similar to that of Example 45, compound 13 obtained in Example 13 From 22.5 mg (0.060 mmol), 13.3 mg (0.12 mmol) of glycinamide hydrochloride, and 10.2 mg (0.13 mmol, 2.2 eq) of sodium hydrogen carbonate, 3.8 mg (15%) of compound 48 was obtained.
  • Example 50 N- [4- (2-methoxyethylamino) -3,6-dioxocyclohexa-1,4-genyl] -3,7,11-trimethyl-2,6,10-dodeca Trienamide (Compound 50) Using the same method as in Example 45, 22.1 mg (0.059 mmol) of compound 13 obtained in Example 13 and 10 PLl (0.12 mmol) of 2-methoxyethylamine were used. mmol), 13.7 mg (56%) of compound 50 was obtained.
  • Example 51 1 N- ⁇ 4- [2- (N, N-dimethylamino) ethylamino 3,6-dioxocyc-hexa-1,4-genyl ⁇ -3,7,11-trimethyl-2,6,10 -Dodecatrienamide (Compound 51)
  • Example 53 Using a method similar to that of Example 52, 26.1 mg (0.066 mmol) of compound 14 obtained in Example 14, 17.4 mg (0.12 mmol) of / 3-alanine methyl ester hydrochloride, and triethylamine 10 From Hl (0.066 mmol), 14.9 mg (49%) of a compound 53 was obtained.
  • Example 45 Using a method similar to that in Example 45, a compound was obtained from 24.5 mg (0.065 mmol) of compound 13 obtained in Example 13 and 10 l (O.lOmmol) of 2- (2-aminoethoxy) ethanol. 12.7 mg (44%) of 54 were obtained.
  • Example 45 Using the same method as in Example 45, 18.5 mg (0.049 mmol) of the compound 13 obtained in Example 13 was dissolved in 3 ml of methanol, and 10 l (0.15 mmol) of pyrrolidine was added to the solution. 7.4 mg (37%) was obtained.
  • Example 62 N- [4- (N-methylbiperazino) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide hydrochloride (compound 62)
  • Example 65 N- (4-ethylthio-3,6-dioxocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (compound 65) and N- [4,5 -Bis (ethylthio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 66)
  • Example 66 N- (4-chloro-5-decane-3,6-dioxocyclohexa-1,4-phenyl) _4-benzyloxyphenoxyacetamide (compound 67) and N- [4,5-bis (decanethio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (compound 68)
  • Example 75 N- [4- (2,3-dihydroxypropylthio) -3,6-dioxocyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 78) ) Using the same method as in Example 64, 21.3 mg (0.054 mmol) of compound 14 obtained in Example 14, 4.5 til (0.054 mmol) of 3-mercapto-1-propanediol and 8.1 l of triethylamine (0.054 mmol), 6.5 mg (25%) of compound 78 was obtained.
  • Example 88 N- [4- (3,4,5-triacetoxy-6-acetoxymethyltetrahydropyran-2-ylthio) -3,6-dioxocyclohexa-1,4-genyl] -4- Benzyloxy phenoxyacetamide (Compound 91) Using a method similar to that of Example 64, 6.9 mg (0.043 mmol) of compound 14 obtained in Example 14 and 15.5 mg of 1-thio-; 3-D-glucose tetraacetate (0.043 mmol) ) And 6.4 l (0.043 mmol) of triethylamine to give 25.3 mg (82%) of compound 91.
  • Example 64 Using a method similar to that in Example 64, 20.8 mg (0.052 mmol) of compound 14 obtained in Example 14, 7.0 mg (0.056 mmol) of 4-aminothiophenol and 7.9 l (0.053 mmol) of triethylamine were used. As a result, 16.2 mg (64%) of compound 94 was obtained.
  • Example 95 N- (6,6-dimethoxy 5-benzylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (compound 98), N- ⁇ 6, 6-Dimethoxy 5- (4-acetamidophenyl) thio-3-oxocyclohex-1-enyl ⁇ -4-benzyldioxyphenoxyacetamide (Compound 101), N- (6,6 -Dimethoxy-5-carboxyphenylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (Compound 104), N- ⁇ 6,6-dimethoxy 5- (4-pyridylthio ) -3-Oxocyclohexoxyenyl ⁇ -4-benzyloxyphenoxyacetamide (Compound 105), N- ⁇ 6,6-dimethoxy 5- (2-pyridylthio) -3-oxocyclo Xyl
  • Example 97 N- ⁇ 6,6-dimethoxy-5- (4-hydroxyphenyl) thio-3-oxosic-hexoxy-1-enyl ⁇ -4-benzyloxyphenoxyacetamide (Compound 1 0 2) Similarly to Example 96, 410 mg (1.00 mmol) of compound 2 obtained in Example 2 and 4- From 206 mg (1.63 mmol) of hydroxythiophenol, 452 mg (84.2%) of compound 102 was obtained.
  • Example 98 N- ⁇ 6,6-dimethoxy-5- (4-methoxyphenyl) thio-3-oxocyclohex-1-enyl ⁇ -4-benzyloxyphenoxyacetamide (Compound 10 3)
  • Compound 103 was obtained from 14.9 mg (0.036 mmol) of Compound 2 obtained in Example 2 and 4.5 Hl (0.037 mmol) of P-methoxythiophenol. (5 0.5%).
  • Example 99 N- ⁇ 6,6-dimethoxy-5- (2,5-dichlorophenyl) thio-3-oxosic-hexoxy-1-enyl ⁇ -4-benzyloxyphenoxyacetamide ( Compound 1 15)
  • 25.9 mg (0.063 mmol) of compound 2 obtained in Example 2 and 18.4 mg (0.103 mmol) of 2,5-dichlorothiophenol were used to obtain 27.3 of compound 115. mg (73.3%).
  • Example 96 22.8 mg (90.0%) of compound 122 was obtained from 21.6 mg (0.049 mmol) of compound 6 obtained in Example 6 and 3.5 l (0.049 mmol) of mercaptophenol. Obtained.
  • Example 104 N- ⁇ 4-chloro-6,6-dimethoxy-5- (4-ethylthio) -3-oxocyclohexyl-1-enyl ⁇ -4-benzyloxyphenoxyacetamide (Compound 12 9)
  • Example 105 N- (6,6-dimethoxy-5-aminophenylthio-3-oxocyclohex-1-enyl) -4-benzyloxyphenoxyacetamide (Compound 130) 9.6 mg (24.3%) of Compound 130 from 18.0 mg (0.041 mmol) of Compound 6 obtained in Example 6 and 5.8 mg (0.046 mmol) of p-aminothiophenol obtained in Example 6 using the same method as 96. Obtained.
  • Example 13 Using a method similar to that of Example 13, the compound was obtained from 12 mg (0.032 mmol) of Compound 1331 obtained in Example 106 and 6.0 mg (0.032 mmol) of p-toluenesulfonic acid monohydrate. 4.5 mg (43%) of product 132 were obtained.
  • Example 108 N- (3,6-dioxo-4-trimethylsilylethylthiocyclohexa-1,4-genyl) -4-benzyloxyphenoxyacetamide (Compound 133) and N- [3,6-Dioxo-4,5-bis (trimethylsilylethylthio) cyclohexa-1,4-genenyl] -4-benzyloxyphenoxyacetamide (Compound 134) From 18.0 mg (0.045 mmol) of compound 14 obtained in Example 14 and 7.3 l (0.046 mmol) of 2-trimethylsilylethanethiol obtained in Example 14 using the same method as in 64, thin layer chromatography after usual post-treatment (Only in the form of black mouth) to obtain 19.8 mg (88.3%) of compound 133 and 1.8 mg (6.3%) of compound 134.
  • Example 14 From the compound 14 obtained in Example 14 23.5 mg (0.059 mmol), methyl thioglycolate 5.3 Hl (0.059 mmol) and triethylamine 9.8 l (0.059 mmol) using the same method as in Example 64. 13.5 mg (48.9%) of compound 135 was obtained.
  • Example 114 N- [3,6-dioxo-4- (4-methoxyphenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 144) ) 16.4 mg (0.042 mmol) of compound 14 obtained in Example 14 and 5.2-H p-methoxybenzenethiol (0.042 mmol) obtained in Example 14 using the same method as in Example 6 mg (68.5%).
  • Example 115 N- [3,6-dioxo-5- (4-methoxyphenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 14 1 ) 23.4 mg (0.043 mmol) of compound 14 obtained in Example 14 was dissolved in 3 ml of tetrahydrofuran using a method similar to that of Example 64, and 17 mg (0.090 mmol) of p-toluenesulfonic acid monohydrate was dissolved. Was added, and then 3.0 ml (3.0 mmol) of 1N hydrochloric acid was added, followed by stirring at room temperature for 7 days.
  • Example 1 16 N- [3,6-dioxo-4- (2-methoxyphenylthio) cyclohexa-1,4-genenyl] -4-benzyloxyphenoxyacetamide (Compound 144) ) From 21.6 mg (0.054 mmol) of compound 14 obtained in Example 14 and 6.6 l (0.054 mmol) of o-methoxybenzenethiol obtained in Example 14 using the same method as in Example 6, 25.0 mg of compound 14 2 (91.8%).
  • Example 1 222 N- [3,6-dioxo-4- (2-chlorophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 1 4 8)
  • Example 124 N- [3,6-dioxo-4- (3-bromophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 150 ) From 15.8 mg (0.040 mmol) of the compound 14 obtained in Example 14 and 4.1 Hl (0.040 mmol) of 3-bromothiophenol obtained in Example 14 using the same method as in Example 64, 17.8 mg of Compound 150 was obtained. (81.4%).
  • Example 1 25 N- [3,6-dioxo-4- (2-bromophenylthio) cyclohexa-1,4-genyl] -4-benzyloxyphenoxyacetamide (Compound 15 1 )
  • Reference Example 4 Compound d 495 mg (2.1 mmol) of 3,7,11-trimethyl-2,6,10-dodecatrienoic acid was dissolved in 5 ml of toluene, 0.5 ml of oxalyl chloride was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain a crude product of 3,7,11-trimethyl-2,6,10-dodecatrienic chloride.
  • the compound g was obtained from 433 mg (l.7 mmol) of 4-benzyloxyphenoxyacetic acid and 300 mg (1.4 mmol) of 3,2-dimethoxy-2,5-dimethoxynitrobenzene. 523 mg (89%) were obtained.
  • Example 2 Using the same method as in Example 1, the compound was prepared from 488 mg (1.8 mmol) of 2,3-bis (methoxymethoxy) -5-methoxynitrobenzene and 557 mg (2.0 mmol) of 4-benzyloxyphenoxyacetic acid. 567 mg (66%) of S was obtained.
  • the present invention provides a 1,4-benzoquinone derivative or a pharmacologically acceptable salt thereof, which has a pharmacotransferase inhibitory activity and is useful as an antitumor agent.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Dérivés de 1,4-benzoquinone représentés par la formule générale (I) ou des sels pharmacologiquement acceptables de ceux-ci, formule dans laquelle ----- représente une liaison simple ou double, x et y représentent chacun hydrogène, halogéno, etc, R1, R2 représentent chacun alcoxyle inférieur ou bien sont tous les deux oxygène, et R3 représente 2,6,10-triméthyl-1,5,9-undécatriényle représenté par la formule (A) ou aryloxyméthyle représenté par la formule (B) dans laquelle W représente hydrogène, halogéno, etc. Les composés ont une activité inhibitrice de farnésyl-transférase et sont utiles en tant qu'agents antitumoraux.
PCT/JP1997/003873 1996-10-24 1997-10-24 Derives de 1,4-benzoquinone Ceased WO1998017629A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47238/97A AU4723897A (en) 1996-10-24 1997-10-24 1,4-benzoquinone derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/282445 1996-10-24
JP28244596 1996-10-24

Publications (1)

Publication Number Publication Date
WO1998017629A1 true WO1998017629A1 (fr) 1998-04-30

Family

ID=17652522

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/003873 Ceased WO1998017629A1 (fr) 1996-10-24 1997-10-24 Derives de 1,4-benzoquinone

Country Status (2)

Country Link
AU (1) AU4723897A (fr)
WO (1) WO1998017629A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014528453A (ja) * 2011-10-07 2014-10-27 パイシーズ セラピューティックス エルエルシーＰｉｓｃｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｌｃ Ｒａｓアンタゴニストによる悪性および非悪性疾患の治療
CN106146367A (zh) * 2015-04-24 2016-11-23 北京大学 烯丙硫基氨基对苯醌类化合物、其制备及应用
US9738614B2 (en) 2011-10-07 2017-08-22 Pisces Therapeutics, Llc Malignant and non-malignant disease treatment with Ras antagonists

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008546A1 (fr) * 1993-09-22 1995-03-30 Kyowa Hakko Kogyo Co., Ltd. Derive d'epoxycyclohexenedione
JPH07112930A (ja) * 1993-10-14 1995-05-02 Kyowa Hakko Kogyo Co Ltd 血管平滑筋細胞増殖抑制剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008546A1 (fr) * 1993-09-22 1995-03-30 Kyowa Hakko Kogyo Co., Ltd. Derive d'epoxycyclohexenedione
JPH07112930A (ja) * 1993-10-14 1995-05-02 Kyowa Hakko Kogyo Co Ltd 血管平滑筋細胞増殖抑制剤

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014528453A (ja) * 2011-10-07 2014-10-27 パイシーズ セラピューティックス エルエルシーＰｉｓｃｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｌｃ Ｒａｓアンタゴニストによる悪性および非悪性疾患の治療
US9738614B2 (en) 2011-10-07 2017-08-22 Pisces Therapeutics, Llc Malignant and non-malignant disease treatment with Ras antagonists
CN106146367A (zh) * 2015-04-24 2016-11-23 北京大学 烯丙硫基氨基对苯醌类化合物、其制备及应用
CN106146367B (zh) * 2015-04-24 2017-12-26 北京大学 烯丙硫基氨基对苯醌类化合物、其制备及应用

Also Published As

Publication number Publication date
AU4723897A (en) 1998-05-15

Similar Documents

Publication Publication Date Title
CN101014572B (zh) 具有hiv整合酶抑制活性的氨基甲酰基吡啶酮衍生物
EP2952503B1 (fr) Dérivés d'acides carboxiliques en tant qu'inhibiteurs de la réplication du vih
KR101118807B1 (ko) Ｏ-치환 히드록시아릴 유도체
WO2012070114A1 (fr) Dérivé sulfamide ayant un antagonisme du récepteur npy y5
FR2540875A1 (fr) Nouveaux derives de la cephalosporine et leur procede de preparation
ES2426482T3 (es) Inhibidor de IGF-1R
JP2006516137A (ja) Ｃｂ−１リガンドとしての４，５−ジアリールチアゾール誘導体
WO2006013948A1 (fr) Dérivé de traizol
FR2530626A1 (fr) Composes de carbostyryle
FR2503712A1 (fr) Composes de la cephalosporine et procede pour leur preparation
JP2002542238A (ja) ヒドロキサム酸誘導体
CA2512502A1 (fr) Derives d'indol-phenylsulfonamide utilises comme composes activant le recepteur ppar-delta
WO2004043956A1 (fr) Composes pyridopyrimidinone, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
TW201305152A (zh) 具有血管內皮脂肪酶抑制活性之苯并噻唑及吖苯并噻唑衍生物
AU2007249952B2 (en) Modified chalcone compounds as antimitotic agents
CA2071659A1 (fr) Derives d'acide dicarboxylique et methode de preparation
WO1998017629A1 (fr) Derives de 1,4-benzoquinone
JP2025504791A (ja) ヒドロキシフェニル部分を含む化合物及びその使用
JP2021107393A (ja) カリケアマイシン誘導体を合成するための中間体および方法
CN100427472C (zh) 芳基-杂芳族化合物、含有它们的组合物及其用途
WO1998023606A1 (fr) Derives dithio cycliques, remedes contre des maladies renales diabetiques, agents hypoglycemiques, agents hypolipidemiques et agents lenitifs contre les troubles digestifs
WO2006109729A1 (fr) Dérivé de pyridylméthylsulfone
JP2011088833A (ja) Ｎｐｙｙ５受容体拮抗作用を有するスルファミド誘導体
JP2007502847A (ja) チアゾリジンジオン誘導体およびその化合物を製造する方法
JPWO1998017629A1 (ja) １，４−ベンゾキノン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BG BR CA CN CZ HU JP KR MX NO NZ PL RO SG SI SK UA US VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA