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WO1997017321A1 - Derives cycliques d'acide amique - Google Patents

Derives cycliques d'acide amique Download PDF

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Publication number
WO1997017321A1
WO1997017321A1 PCT/JP1996/003239 JP9603239W WO9717321A1 WO 1997017321 A1 WO1997017321 A1 WO 1997017321A1 JP 9603239 W JP9603239 W JP 9603239W WO 9717321 A1 WO9717321 A1 WO 9717321A1
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Prior art keywords
group
general formula
reaction
lower alkyl
compound
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PCT/JP1996/003239
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English (en)
Japanese (ja)
Inventor
Yoshikazu Iwasawa
Tetsuya Aoyama
Kumiko Kawakami
Sachie Arai
Toshihiko Satoh
Yoshiaki Monden
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Banyu Pharmaceuticals Co., Ltd.
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Priority to AU75051/96A priority Critical patent/AU7505196A/en
Publication of WO1997017321A1 publication Critical patent/WO1997017321A1/fr

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    • 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
    • C07C233/12—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 halogen atoms or by nitro or nitroso groups
    • C07C233/13—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 halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom

Definitions

  • the present invention relates to novel substituted amide derivatives. More specifically, the substituted amide derivative of the present invention inhibits the function of the oncogene protein Ras by inhibiting the protein clear-fuarnesyltransferase (PFT) in the living body, thereby inhibiting the oncogenic effect.
  • PFT protein clear-fuarnesyltransferase
  • the ras oncogene is activated by mutation, and its translation product, Ras protein, plays an important role in transforming normal cells into cancer cells. This activation of the ras oncogene is observed in many cancers such as colorectal cancer and kidney cancer, and its rate is said to reach about 20% of all human cancers. Therefore, if the activation of these ras oncogenes is suppressed, or if the function of the Ras protein, which is a product of the ras oncogenes, is inhibited, an anticancer effect can be expected in suppressing canceration.
  • Ras protein function requires phanesylation of the Ras protein itself, and inhibition of the phanesylation suppresses the localization of the Ras protein to the cell membrane, resulting in the transformation of cancer cells into cancer cells. It was found to be inhibited.
  • Protein-Pharnesyltransferase (PFT) is an enzyme that catalyzes the pharmacosylation of this Ras protein, and inhibiting this enzyme can suppress the functional expression of the oncogenic Ras protein.
  • PFT Protein-Pharnesyltransferase
  • this enzyme is involved only in the pharmacosylation of a very limited number of proteins in vivo, and therefore, inhibitors of this enzyme are expected to be safe and highly selective anticancer agents.
  • An object of the present invention is to inhibit protein-farnesyltransferase (PFT), thereby suppressing the expression of the oncogene protein Ras, thereby resulting in a novel antitumor agent or antitumor agent having an antitumor or anti-AIDS effect.
  • PFT protein-farnesyltransferase
  • Q is — (C3 ⁇ 4) m- (where m is an integer of 1 to 6) Or (CH 2 ) n — W— (CH 2 ) P- (where W is an oxygen atom, a sulfur atom, a vinylene group or an ethynylene group; n and p are the same or different and are 0
  • R ′ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, or a halogen atom, a lower alkyl group, and a lower alkoxy group.
  • R 2 , R 7 and R 8 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group; group or a lower alkoxy group;
  • R 3 and R 4 are the same or different, a hydrogen atom, A hydrogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkyl group, a lower alkyl group, a lower hydroxyalkyl group, a lower hydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy group;
  • R 5 is a lower alkyl group;
  • R 6 is a hydrogen atom or a lower alkyl group;
  • R 9 and R ′
  • R ' 1 is a hydroxyl group, a carboxyl group, a lower alkyl group, a lower hydroxyalkyl group or a lower alkoxy group
  • X and z are the same or different and Or an integer of 2
  • y represents 0 or 1] which inhibits protein-phagenesyltransferase (PFT), thereby suppressing the functional expression of the oncogene protein Ras;
  • PFT protein-phagenesyltransferase
  • the present invention relates to a compound represented by the general formula [I], a pharmaceutically acceptable salt or ester thereof, and use thereof.
  • the aryl group means a phenyl group, a naphthyl group or an anthryl group, and a phenyl group and a naphthyl group are preferable.
  • a heteroaromatic group is a group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • An aliphatic cyclic group which may contain 1 or 2 oxygen atoms means a 3- or 7-membered saturated or unsaturated aliphatic carbocyclic group or a 3- or 7-membered oxygen atom containing 1 or 2 oxygen atoms.
  • aliphatic oxygen-containing heterocyclic group for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, oxilanyl group, oxetanyl group, oxolanyl group, oxanil Group, oxepanyl group, 1,3-dioxetanyl group, 1.3-dioxolanyl group, 1,3-dioxanyl group, 1,3-dioxepanyl group, 1,4-dioxepanyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl Group, cycloheptenyl group, oxylenyl group, oxetyl group, 2,3-dihydrofuranyl group, 2,5-dihydrofuranyl group, 3,4 Dihydrovinyly
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a fluorine atom and a chlorine atom are preferable.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group and a tert-butyl group. And a pentyl group, a hexyl group and the like, and among them, a methyl group, an ethyl group and the like are preferable.
  • the lower alkoxy group means an alkoxy group having 1 to 6 carbon atoms or an alkylene dioxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, butoxy, tert-butyne, methylene dioxy, and the like.
  • alkylene dioxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, butoxy, tert-butyne, methylene dioxy, and the like.
  • Examples thereof include an ethylenedioxy group and a trimethylenedioxy group, and among them, a methoxy group, an ethoxy group, and a methylenedioxy group are preferable.
  • the lower alkoxyl alkoxyl group means an alkoxycarbonyl group having 1 to 7 carbon atoms, such as a methoxycarbonyl group, an ethoxyquincarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and a tert-butoxycarbonyl group. And the like, among which methoxycarbonyl group, ethoxycarbonyl group and the like are preferable.
  • lower alkyl group refers to a mono- or di-substituted group formed by the lower alkyl group, such as a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, and a getylcarbamoyl group.
  • the lower hydroxyalkyl group means the lower alkyl group having a hydroxyl group, that is, a hydroxyalkyl group having 1 to 6 carbon atoms, for example, a hydroxymethyl group, a hydroxyxethyl group, a hydroxypropyl group, a hydroxypropyl group.
  • a hydroxymethyl group, a hydroxyxetyl group and the like are preferable.
  • the lower fluoroalkyl group means the lower alkyl group having a fluorine atom, that is, a fluoroalkyl group having 1 to 6 carbon atoms, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group,
  • Examples thereof include a 2-fluoroethyl group, a 2,2,2-trifluoroethyl group, and a pentafluoroethyl group.
  • the salt of the compound represented by the general formula [I] means a conventional pharmaceutically acceptable salt, for example, a base addition salt at a carboxyl group or, when the compound has an amino group, the amino group or the basic complex.
  • a base addition salt at a carboxyl group or, when the compound has an amino group, the amino group or the basic complex in the case of having an aromatic ring, salts of acid addition salts on the basic heteroaromatic ring can be mentioned.
  • the base addition salt examples include an alkaline metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; an ammonium salt: for example, a trimethylamine salt; And organic amine salts such as triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, proforce salt, and ⁇ , ⁇ ′-dibenzylethylenediamine salt.
  • an alkaline metal salt such as a sodium salt and a potassium salt
  • an alkaline earth metal salt such as a calcium salt and a magnesium salt
  • an ammonium salt for example, a trimethylamine salt
  • organic amine salts such as triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, proforce salt, and ⁇ , ⁇ ′-dibenzylethylenediamine salt.
  • the acid addition salts include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate; for example, maleate, fumarate, tartrate, citrate, ascorbate, Organic acid salts such as trifluoroacetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate and ⁇ -toluenesulfonate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate
  • maleate, fumarate, tartrate, citrate, ascorbate Organic acid salts such as trifluoroacetate
  • sulfonates such as methanesulfonate, isethionate, benzenesulfonate and ⁇ -toluenesulfonate.
  • the ester of the compound represented by the general formula [I] means a conventional pharmaceutically acceptable carboxyl group at the terminal or a carboxyl group in the case where R or R "is a carbonyl group.
  • Esters with lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl group, cyclopropyl group and cyclopentyl group, and aralkyl groups such as benzyl group and phenyl group
  • Esters with lower alkenyl groups such as aryl, 2-butenyl, etc., and lower alkoxyalkyl groups such as methoxymethyl, 2-methoxyl, 2-ethoxyquinethyl, etc.
  • lower alkoxycarbonylalkyl groups such as methoxycarbonylmethyl group, isopropoxycarbonylmethyl group, etc.
  • esters with lower alkenyloxyalkyl groups such as acetyloxymethyl group, bivaloyloxymethyl group and 1-pivaloyloxyquinethyl group.
  • Okiso one Lou 4 one I le) an ester of methyl group an ester of methyl group.
  • the compound of the present invention may have stereoisomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of the substituent. Also encompasses stereoisomers and mixtures thereof. Among them, the general formula [ ⁇ ⁇ 1]
  • Q is a group represented by — (CH 2 ) m — (where m has the meaning described above), m is preferably 1 to 4, and — (CH 2 ) n — W — (CH 2 ) P — (wherein W, n and p have the same meanings as above), W is a vinylene group or an ethynylene group, more preferably a vinylene group.
  • N and p are the same or different, and 0 or 1 is preferred.
  • R ' is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, or an aryl group or a hetero group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group.
  • R 2 represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group
  • An aryl group or a heteroaromatic group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group in R 1 is the unsubstituted aryl group or the heterocyclic group.
  • R ' represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group:
  • R 2a represents a hydrogen atom, a halogen atom or a lower alkyl group
  • a naphthyl group a benzofuranyl And benzothienyl, benzothiazolyl, benzoxazolyl and benzoimidazolyl groups, and more specifically, phenyl, 2-benzo [b] furanyl, 2-benzo [ b] A phenyl group, a 2-naphthyl group, a 2-benzoxazolyl group and the like are preferred.
  • R 3 and the same or different, hydrogen atom, halogen atom, hydroxyl group, amino group, nitro group, cyano group, carboxyl group, lower alkoxycarbonyl group, rubamoyl group, lower alkyl group A hydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy group,
  • R 3 and R also have the same meaning as described above
  • a naphthyl group and a pyridyl group, a furyl group or a phenyl group having R 3 on the ring and more specifically, 4 —Fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 3,4-dichlorophenyl Group, 3,4-dimethylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 412-nitrophenyl, 4-aminophenyl, 4-hydroxyphenyl, 4-hydroxy Rubamoylphenyl, 4-methylcarbamoylphenyl, 4-hydroxymethylphenyl, 4-trifluoromethylphenyl, 4-sia Fuweniru group, 4-main Bok Kin carbonyl full
  • R 6 is preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group or the like, and particularly preferably a hydrogen atom, a methyl group or the like.
  • R 7 and R 8 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group,
  • R 7a and R ea are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, a naphthyl group, a quinolyl group, a benzoxazolyl group Benzofuranyl group and benzophenyl group. More specifically, 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dimethylphenyl group, 2-naphthyl group, 2-benzoxazolyl group , 2-benzo [b] furanyl, 2-benzo [b] thenyl, 5-benzo [b] thenyl and the like are preferred.
  • R ; 'and R 1 are the same or different and each represent a hydrogen atom, a hydroxyl group or a lower alkyl group.
  • R y represents a hydrogen atom, a hydroxyl group, a methyl group, or the like;
  • R 10 represents a hydrogen atom; Hydroxyl groups and the like are preferred.
  • R represents a hydroxyl group, a carboxyl group, a lower alkyl group, a lower hydroxyalkyl group or a lower alkoxy group, and among them, a carboxyl group is preferable.
  • X and z are the same or different and each represents an integer of 0 to 2; y represents 0 or 1; X is preferably 0 or 1 and y is 0, and z is preferably 1 or 2.
  • the compound of the present invention represented by the general formula [I] can be produced by, for example, the following production methods 1, 2, 3, 4, It can be prepared by the method shown in 5 or 6 (
  • Q is one (where m represents an integer of 1 to 6) or-(CH 2 ) n -W— (CH 2 ) P- (Where W is an oxygen atom, a sulfur atom, a vinylene group or an ethynylene group; n and p are the same or different and each represents an integer of 0 to 3); and R ′ p is hydrogen.
  • R 2P , R 7P and R sp are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, a lower alkyl group or a lower alkoxy group;
  • R 5 represents a lower alkyl group;
  • R s represents a hydrogen atom or a lower alkyl group] and a compound represented by the general formula [III]
  • R 9P and R ′ ° p are the same or different and each represents a hydrogen atom
  • R '' p represents a lower alkyl group, a lower alkoxy group or an optionally protected hydroxyl group, a carboxyl group or a lower hydroxyalkyl group
  • x and z are the same or different
  • y is 0 or 1
  • R p is a hydrogen atom or a carboxyl group-protecting group]
  • R IOp R p, x, y, z and R p have the meanings given above]
  • the compound represented by the general formula [I] can be obtained by removing the protecting group as necessary.
  • the reactive derivative of the carboxylic acid represented by the general formula [III] for example, an acid halide, a mixed acid anhydride, an active ester, an active amide and the like are used.
  • a carboxylic acid of the general formula [III] ⁇ , ⁇ '-dicyclohexyl
  • the reaction is preferably performed in the presence of a condensing agent such as silcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 2-chloro-1,3-dimethylimidazolinolechloride, and the like.
  • reaction between the compound represented by the general formula [II] and the carboxylic acid represented by the general formula [III] or a reactive derivative thereof is performed based on 1 mol of the compound represented by the general formula [III] Of the carboxylic acid or a reactive derivative thereof is used in an amount of 1 mol to excess mol, preferably 1 to 5 mol.
  • the reaction is usually carried out in an inert solvent.
  • the inert solvent include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and trichloroethylene; for example, ethyl ether and tetrahydrofuran.
  • Ethers such as benzene, dioxane and the like: aromatic hydrocarbons such as benzene, toluene, black benzene, xylene and the like; non-hydrocarbons such as dimethylformamide, acetonitrile, acetone, ethyl acetate, hexamethylphosphate triamide and the like.
  • a protic polar solvent, a mixed solvent thereof, and the like are included.
  • the reaction temperature is usually from about 70 ° C to the boiling point of the solvent used in the reaction, preferably
  • the reaction time is generally 5 minutes to 7 days, preferably 10 minutes to 24 hours.
  • the above reaction can be carried out in the presence of a base in order to smoothly carry out the reaction.
  • the base include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, lithium carbonate, sodium hydrogencarbonate, and the like, or triethylamine, N-ethyldiisopropylamine, pyridine, and the like. It is preferable to carry out the reaction in the presence of an organic base such as 2,4-dimethylaminopyridine, ⁇ , ⁇ -dimethylaniline and ⁇ -methylmorpholine.
  • the amount of the base to be used is 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the reactive derivative of the carboxylic acid of the general formula [ ⁇ ].
  • the acid halide of the compound of the general formula [III] can be obtained by reacting the carboxylic acid of the general formula [III] with a halogenating agent according to a conventional method.
  • a halogenating agent for example, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxyphosphorus chloride, phosphorus tribromide, oxalyl chloride, phosgene and the like are used.
  • the mixed acid anhydride of the compound of the general formula [III] is usually a carboxylic acid of the general formula [III].
  • an intramolecular acid anhydride is formed between the carboxyl groups at both ends, or, when R ′ ′ P represents a carboxyl group, the compound involved in the reaction with the carboxyl group is carboxylic acid.
  • An intramolecular acid anhydride may be formed between the groups to form a reactive derivative of the carboxylic acid.
  • the active ester of the compound of the general formula [III] can be prepared by a conventional method using a carboxylic acid of the general formula [III], for example, ⁇ , ⁇ '-zinclohexylcarpoimide, 1-ethyl-3- (3-dimethylamino)
  • a condensing agent such as propyl) propylamide
  • ⁇ -hydroxy compounds such as ⁇ -hydroxysuccinimide, ⁇ -hydroxyphthalimid, 1-hydroxybenzotriazole, and the like: 4-nitrophenol , 2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol, and other phenol compounds.
  • the active amide of the compound of the general formula [III] is prepared by reacting the carboxylic acid of the general formula [III] with, for example, ⁇ , ⁇ -carbonyldiimidazole, 1. 1.-carbonylbis (2-methylimidazole) or the like according to a conventional method. Can be obtained.
  • ⁇ ⁇ -carbonyldiimidazole
  • R "P or R 'if ° P means a hydroxyl group and R' '[rho water group, carboxyl
  • R "P or R 'if ° P means a hydroxyl group and R' '[rho water group, carboxyl
  • R "P or R 'if ° P means a hydroxyl group and R' '[rho water group, carboxyl
  • the hydroxyl group, the lower hydroxyalkyl group, the amino group or the carboxyl group is appropriately protected by a hydroxyl group-protecting group, an amino group-protecting group or a carboxyl group-protecting group. It is preferred to carry out the reaction later and to remove the protecting group after the reaction.
  • hydroxyl-protecting group examples include: lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyquinethoxymethyl group; for example tetrahydropyranyl group; Aralkyl groups such as benzyl group, P-methoxybenzyl group, p-nitrobenzyl group and trityl group; and aralkyl groups such as formyl group and acetyl group; particularly, methoxymethyl group and tetrahydroviranyl Group, trityl group, tert-butyldimethylsilyl group, acetyl group and the like.
  • lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group
  • lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyquinethoxymethyl group
  • Examples of the protecting group for the amino group include aralkylidene groups such as benzylidene group, p-chlorobenzylidene group, and p-nitrobenzylidene group; for example, benzyl group, P-methoxybenzyl group, and p-nitrobenzene.
  • Aralkyl groups such as benzyl group, benzhydryl group and trityl group: lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, and bivaloyl group; lower haloalkanol groups such as trifluorescetyl group; A lower alkoxycarbonyl group such as a carbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a tert-butyne carbonyl group; a lower haloalkoxycarbonyl group such as a 2,2,2-trichloromouth ethoxycarbonyl group; Propenyloxy force Alkenyloxycarbonyl such as rubonyl group An aralkyloxycarbonyl group such as a benzyloxycarbonyl group and a p-nitrobenzoylcarbonyl group; a lower alkylsilyl group such as a trimethylsilyl group and
  • Examples of the carboxyl-protecting group include lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group: lower haloalkyl groups such as 2,2,2-trichloromethylethyl group; Lower alkenyl groups such as 2-propenyl group: for example, benzyl groups, p-methoxybenzyl groups, p-nitrobenzyl groups, benzhydryl groups, aralkyl groups such as trityl groups, etc., and especially methyl Group, ethyl group, tert-butyl group, 2-propenyl group, benzyl group, P-methoxybenzyl group, benzhydryl group and the like.
  • lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group: lower haloalkyl groups such as 2,2,2-trich
  • the compound represented by the general formula [IV] is purified according to a conventional method, or without purification, if necessary, a protecting group for a hydroxyl group, an amino group and a carboxyl group.
  • the compound of the general formula [I] can be produced by appropriately combining the removal reactions.
  • protecting groups depends on the type, but the method described in the literature [Protective Groups in Organic Synthesis, TW Greene, TW Greene, John Wiley & Sons, Inc. (1981)] or a method analogous thereto, for example, using an acid or a base, using a solvolysis, a metal hydride complex, or using a chemical reduction or a radium-one carbon catalyst, a Raney nickel catalyst, or the like. It is performed by catalytic reduction or the like.
  • R ′ p , R 2P and n have the above-mentioned meanings] and a compound represented by the general formula [VI]
  • T represents a triphenylphosphonio group, a dimethoxyphosphoryl group or a methoxyphosphoryl group;
  • Ar 2 ⁇ Ar 3 - Cy p , R 3P, R 'p, R 5, R 6, R 7P, R 8P, R 9P, R'. p , R ′ lp , x, y, z and R p have the above-mentioned meanings]
  • n, p, R lp , R 2P , R 3P , R 4P , R 5 , R 6 , R 7p , R 8p , R 9P , R IOp , R " ⁇ x, y, z and R p have the above meanings Having the general formula [I-11] by removing a protecting group as necessary.
  • R ′, R 2 , R 3 , R ⁇ R 5 , RR 7 , R 8 , R H , R 10 , R u , x, y and z have the above-mentioned meanings. it can.
  • the portion represented by Q in the formula represents one (CH—CH —CH— (CH, one (where n and p Is).
  • the reaction of the compound represented by the general formula [v] with the compound represented by the general formula [VI] is usually carried out using both in equimolar amount or using a slight excess of either one.
  • the reaction is usually performed in an inert solvent.
  • the inert solvent include ethers such as ethyl ether, tetrahydrofuran, and dioxane: aromatic hydrocarbons such as benzene, toluene, benzene, xylene, and the like;
  • aprotic polar solvents such as dimethylformamide, acetonitrile, acetone, ethyl acetate, and hexamethylphosphate triamide, or a mixed solvent thereof can be used.
  • the reaction temperature is usually from 100 ° C. to the boiling point of the solvent used in the reaction, preferably from ⁇ 70 ° C. to 5 (TC).
  • the reaction time is generally 5 minutes to 7 days, preferably 10 minutes to 24 hours.
  • the above reaction can be carried out in the presence of a base in order to smoothly carry out the reaction.
  • T in the general formula [VI] is a triphenylphosphonio group, for example, sodium hydride, n-butyllithium, sodium methoxide, potassium tert-butoxide, hydroxide It is preferable to carry out the reaction in the presence of a base such as sodium or hydroxylated lime.
  • the amount of the base to be used is 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula [VI], wherein T is a triphenylphosphonio group. .
  • Examples of the protecting group for a hydroxyl group, the protecting group for an amino group, and the protecting group for a carboxyl group include the protecting groups described in the above Production Method 1.
  • the thus-obtained compound represented by the general formula [IV-1] is purified by a conventional method or, without purification, if necessary, removal of protecting groups for a hydroxyl group, an amino group and a carboxyl group.
  • the compound of the general formula [1-1] can be produced by appropriately combining the reactions.
  • the method for removing the protecting group varies depending on the type of the protecting group, the stability of the target compound [I-1], and the like, and can be appropriately performed, for example, according to the method described in the above-mentioned literature or a method analogous thereto.
  • T, ⁇ , R ′ p and R 2P have the above-mentioned meanings] and a compound represented by the general formula [VIII] COORD
  • n, p, R 'p, R 2p, R 3p, R, R 5, R 6, R 7p, R 8p, R 9p, R ⁇ 0p, R llp, x, y , z and RP are as defined above Having the general formula [1-1] by removing a protecting group as necessary.
  • R ', R 2, R 3 , R ⁇ R 5, R 6, RRR 9, R 10, R u, x, y and z can be obtained a compound represented by have the meanings above.
  • Production method 3 is equivalent to the reaction of production method 2 in which compound [V] and compound [VI] as the starting compounds are replaced with compound [VIII] and compound [VII], respectively. Can all be carried out according to Production Method 2.
  • n and Pl are the same or different and each represents an integer of 0 to 3.
  • R lp , R 2p , R 3P , R A R 5 , R 6 , R 7P , R 8p , R 9p , R ′ ° p , R p , x, y, z and R p have the above-mentioned meanings (however, , N, and p, the sum of which does not exceed 4)], reducing the compound represented by the general formula [1-2] [1-2]
  • Q 2 represents a group represented by the formula: (CH 2 ) m — (where m has the meaning described above):
  • R ', R 2, R 3 , RR 5, R 6, R 7, R 8, R 9, R'. , R ", x, y, and z have the above-mentioned meanings].
  • the reaction for reducing the compound represented by the general formula [IV- ⁇ ] is usually preferably carried out in an inert solvent by catalytic reduction using a palladium-carbon catalyst, a Raney nickel catalyst, a platinum catalyst or the like.
  • inert solvent examples include alcohols such as methanol, ethanol, and propanol, and acetic acid.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably from 0 ° C. to room temperature.
  • the reaction time is generally 5 minutes to 7 days, preferably 10 minutes to 24 hours.
  • the hydrogen pressure in the catalytic reduction reaction is preferably from normal pressure to 5 atm, and the amount of the catalyst used is usually 0.01 to 1 mol, preferably 1 to 1 mol, relative to 1 mol of the starting compound [IV- ⁇ ]. Is 0.05 to 0.2 mol.
  • W 1 represents an oxygen atom or a sulfur atom
  • Z 1 represents a leaving group
  • R 3-Way R is 'p R 5 R 6 R 7p R 8p R 9P R' p R p xyz and R p is reacted with a compound represented by have the meanings of the general formula [IV- 3]
  • ⁇ has the meaning of ⁇
  • R ′, RR 3 , RR 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R ⁇ ′, x, y and z have the above-mentioned meanings]. .
  • the part of the compound of the present invention represented by the general formula [I] represented by Q in the formula is represented by-(CH 2 ) n -W '— (CH 2 ) P- (where , N, p and W have the same meaning as described above), that is, a production method for synthesizing a compound represented by the general formula [1-3].
  • the reaction between the compound represented by the general formula [IX] and the compound represented by the general formula [X] is usually performed by reacting the compound represented by the general formula [IX] with respect to 1 mol of the compound represented by the general formula [X].
  • the reaction is carried out using the compound represented by 1 mol to excess mol, preferably 1 to 3 mol.
  • the reaction is usually performed in an inert solvent.
  • the inert solvent include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and trichloroethylene: for example, ethyl ether, tetrahydrofuran.
  • Ethers such as benzene, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, black benzene, xylene and the like: dimethylformamide, acetonitrile, acetone, ethyl acetate, hexamethyl phosphate triamide Etc. non Examples thereof include a protonic polar solvent, a mixed solvent thereof, and the like.
  • the reaction temperature is usually from -70 ° C to the boiling point of the solvent used in the reaction, preferably
  • the reaction time is generally 5 minutes to 7 days, preferably 10 minutes to 24 hours.
  • the above reaction is preferably performed in the presence of a base to smoothly carry out the reaction.
  • the base include sodium hydride, n-butyllithium, sodium hydroxide, lithium hydroxide, and hydroxide.
  • Inorganic bases such as calcium, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and the like or organic bases such as triethylamine, N-ethyldiisopropylamine, pyridine, 4-dimethylaminopyridine, ⁇ , ⁇ -dimethylaniline and the like. No.
  • the amount of the base to be used is 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of compound represented by general formula [IX].
  • the leaving group represented by Z ′ is, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or an organic sulfo such as a methanesulfonyloxy group, a ⁇ -toluenesulfonyloxy group or a benzenesulfonyloxy group. And a carbonyl group.
  • an amino group when there is a carboxyl group or a lower heat Dorokishia alkyl group, when R or R iep means a hydroxyl group and R l lp water group, a carboxyl group or a lower Hidorokin
  • the reaction is carried out after protecting the hydroxyl group, lower hydroxyalkyl group, amino group or carboxyl group with a hydroxyl group-protecting group, amino group-protecting group or carboxyl group-protecting group as appropriate.
  • the protecting group is removed. Examples of the protecting group for a hydroxyl group, the protecting group for an amino group, and the protecting group for a carboxyl group include the protecting groups described in the above Production Method 1.
  • the thus-obtained compound represented by the general formula [IV-3] is purified by a conventional method, or without purification, where necessary, removal of protecting groups for hydroxyl, amino and carboxyl groups.
  • the compound of the general formula [I-13] can be produced by appropriately combining the reactions.
  • the method for removing the protecting group can be appropriately determined according to the type of the protecting group and the stability depending on the stability of the target compound [I-3], for example, the method described in the above-mentioned literature or a method analogous thereto.
  • R ', R 2 , R 3, R', R 5, R 6, R 7, R 8, RR 10, R u, x, y and z are represented by have the meanings of the compound Can be obtained.
  • the isolation and purification of the compound of the general formula [1], [1-1], [1-2] or [1-3] obtained by the above method can be performed, for example, by column chromatography using silica gel or an adsorption resin. This can be achieved by using conventional separation means such as liquid chromatography, solvent extraction or recrystallization / reprecipitation alone or in appropriate combination.
  • the compound of the general formula [1], [1-1], [1-2] or [1-3] can be converted into a pharmaceutically acceptable salt or ester by a conventional method.
  • the conversion of the ter to the free carboxylic acid can also be performed according to a conventional method.
  • the compounds according to the present invention can be all produced by the same method as the above-mentioned production method, using raw materials corresponding to the target compound.
  • X represents a halogen atom
  • Y represents a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a cycloformyl group, or a ⁇ -methoxy ⁇ -methylcarbamoyl group
  • a leaving group selected from the group consisting of an atom, a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and a ⁇ -toluenesulfonyloxy group;
  • the target compound [ ⁇ ] is represented by the general formula
  • An alkyllithium reagent represented by the general formula 2 or an alkyl Grignard reagent (or an alkyl Gilman reagent) represented by the general formula 3 is formed on a ril or carboxylic acid derivative.
  • the compound can be produced by reacting an amine compound represented by
  • the above reaction step will be specifically described below with reference to suitable reaction conditions and the like.
  • the alkyl lithium or alkyl Grignard reagent (1 mol) is used per 1 mol of the starting compound ⁇ .
  • an alkyl Gilman reagent is reacted with 1 mol to an excess mol, preferably 1 to 5 mol, and then, if necessary, hydrolyzed under acidic conditions.
  • the reaction temperature is usually from 80 ° C to the boiling point of the solvent used in the reaction, preferably from -70 ° C to 50 ° C, and the reaction time is generally from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours. Time.
  • the substituent Y in the formula of the starting compound i is a cyano group
  • the reaction is carried out in the presence of an acid such as toluenesulfonic acid, for example, in methanol, ethanol, tetrahydrofuran or a mixed solvent thereof with water.
  • the reaction temperature is usually from 0 ° C. to the boiling point of the solvent used in the reaction, and the reaction time is from 30 minutes to 24 hours.
  • the compound represented by the general formula 6 In the step of producing the compound represented by the general formula 6 from the ketone compound, the compound represented by the general formula 6
  • the reaction can be carried out by reacting the alkylating agent represented by 5 with 1 mol to excess mol, preferably 1 to 2 mol.
  • the inert solvent examples include ethers such as ethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; and dimethylformamide, dimethylsulfoxide, and hexamethylphosphate triamide. And aprotic polar solvents, and mixtures of the above solvents.
  • the base used in this reaction includes, for example, alkali metal hydrides such as sodium hydride, lithium hydride and potassium hydride: for example, lithium amide, lithium diisopropyl amide, lithium pistrimethylsilyl amide and the like.
  • Titanium amides such as methyllithium, butyllithium, and tert-butyllithium: metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide: sodium hydroxide, hydroxylation power Metal hydroxides such as lithium and lithium hydroxide.
  • the amount of the base to be used is generally 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the starting alkylating agent 5.
  • the reaction temperature is usually —100 ° C. to the boiling point of the solvent used in the reaction, preferably —80 ° C. to 100 ° C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 30 minutes. ⁇ 24 hours.
  • the step of producing the target compound [ ⁇ ] from the compound represented by the general formula is usually carried out by reacting the compound represented by the general formula 6 in an inert solvent such as methanol, ethanol, benzene, ethyl ether, and tetrahydrofuran.
  • the imine compound represented by the general formula Z may be used in an amount of 1 mole to excess mole, preferably 1 to 2 moles, preferably 1 to 2 moles, to form an imine in advance, followed by reduction to reduce the imine compound. it can.
  • the reaction temperature in the process of forming the imine is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from room temperature to 100 ° C., and the reaction time is generally from 5 minutes to 48 hours, preferably 30 minutes. ⁇ 24 hours.
  • the reaction solution may be used as it is in the reduction reaction in the next step, or the reaction solution may be distilled off, or the imine compound may be isolated using a conventional separation means, and subjected to the subsequent reduction reaction. I can do it.
  • a gold hydride complex such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, or the like is used, or a catalytic reduction using, for example, a palladium-carbon catalyst, a Raney nickel catalyst, or the like is performed. be able to.
  • the amount of the reducing agent is 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the imine.
  • a solvent may be used as appropriate, for example, alcohols such as methanol and ethanol; for example, dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethyloxetane, dioxane, tetrahydrofuran.
  • Ether solvents such as pentane, hexane, heptane and cyclohexane; and inert solvents such as aromatic hydrocarbons such as benzene and toluene, or mixed solvents thereof. It is.
  • the reaction temperature is usually from 0 ° C. to room temperature, and the reaction time is usually from 1 hour to 6 hours.
  • an alkyl derivative represented by the general formula 5 is acted on a nitrile or carboxylic acid derivative represented by the general formula II to produce an alkyl derivative in advance, and then the alkyl derivative is prepared.
  • the reaction at this time can be carried out under the same conditions as in the above-mentioned production method A, and therefore, the reaction conditions and the like can all be used as they are in the production method A.
  • the target compound [ ⁇ ] has the general formula Can be produced by reacting a compound represented by the formula (1) with a reducing agent such as a hydrogenated metal complex to produce an alcohol compound, and then reacting the alcohol compound with an amine compound represented by the general formula Z.
  • a reducing agent such as a hydrogenated metal complex
  • the above reaction step will be specifically described below with reference to suitable reaction conditions and the like.
  • the step of reducing the compound represented by the general formula 6 to the alcohol 8 is usually performed in an inert solvent that does not adversely affect the reaction, for example, sodium borohydride, diisobutylaluminum hydride, lithium hydride.
  • This can be performed by force using a metal hydride complex such as aluminum, tri-sec-butyllithium borohydride (L-selectride TM), or catalytic reduction using, for example, a palladium-carbon catalyst or a Raney-nickel catalyst. it can.
  • the amount of the reducing agent used is usually The amount is from 1 mol to an excess, preferably from 1 to 5 mol, per 1 mol of the compound represented by the general formula 6.
  • the inert solvent used in this reaction can be appropriately selected depending on the type of the reducing agent.
  • the reducing agent is sodium borohydride
  • alcohols such as methanol and ethanol
  • ethers such as dimethoxetane, dioxane, tetrahydrofuran, and diglyme
  • non-protons such as dimethylformamide and dimethylacetamide
  • an inert solvent such as a polar solvent or water, or a mixed solvent thereof is used, and alcohols such as methanol and ethanol are particularly preferable.
  • ethers such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethyloxetane, dioxane, tetrahydrofuran, and diglyme; for example, pentane, hexane, heptane, cyclohexane, and the like
  • Aliphatic hydrocarbons for example, aromatic hydrocarbons such as benzene and toluene; and inert solvents such as methylene chloride or mixed solvents thereof, and toluene and methylene chloride are particularly preferred.
  • ethers such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethyloxetane, dioxane, tetrahydrofuran, diglyme; Aliphatic hydrocarbons such as pentane, hexane, heptane, and cyclohexane; inert solvents such as aromatic hydrocarbons such as benzene and toluene; and mixed solvents thereof are used. Lahydrofuran and the like are preferred.
  • alcohols such as methanol and ethanol are preferable as the solvent.
  • reaction temperature and reaction time vary depending on the stability of the ketone body 6 as a raw material, the susceptibility of the reduction reaction, the type of the reducing agent and the type of the solvent, etc., but the reaction temperature is usually -80 °. C to 100 ° C, preferably -70 ° C to 40 ° C, and the reaction time is usually 5 minutes to 2 days, preferably 30 minutes to 24 hours.
  • a sulfonating agent such as, for example, methansulfonyl chloride is acted on the alcohol compound represented by the general formula 8 in the presence of a base.
  • the reaction for introducing a leaving group is usually carried out in an inert solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran, ethyl acetate or the like in an amount of 1 mol to excess mol, preferably 1 to 1 mol, per 1 mol of the alcohol.
  • the reaction can be carried out by reacting 2 mol of a sulfonating agent and a base such as triethylamine, or by using 1 mol to an excess mol, preferably 1 to 5 mol of a halogenating agent.
  • the reaction temperature is usually from -70 ° C to the boiling point of the solvent used in the reaction, preferably from 20 ° C to 80 ° C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours. Time.
  • the step of allowing the amine compound Z to act on the compound after introduction of the leaving group obtained in the above reaction is usually carried out in an inert solvent such as methylene chloride, chloroform, benzene, ethyl ether, tetrahydrofuran or the like.
  • the reaction can be carried out using 1 to 50 moles, preferably 1 to 50 moles, of the amine compound Z based on 1 mole of the starting compound having a leaving group.
  • this reaction can be carried out in the presence of another base different from the amine compound represented by the general formula Z, if necessary.
  • the base examples include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and the like, or triethylamine, N-ethyldiisopropylpropylamine, pyridine, and the like. And organic bases such as ⁇ , ⁇ -dimethylaniline.
  • inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and the like, or triethylamine, N-ethyldiisopropylpropylamine, pyridine, and the like.
  • organic bases such as ⁇ , ⁇ -dimethylaniline.
  • the amount of the base to be used is generally 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the starting compound.
  • the reaction temperature is usually from 50 ° C to 150 ° C, preferably from -20 ° C to 100 ° C, and the reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
  • the target compound [ ⁇ ] is The alcohol derivative represented by the general formula 8 is reacted with azodicarboxylic acid acetyl ester, triphenylphosphine and phthalimid (or hydrazic acid or diphenylphosphoric azide) or in the presence of a base such as triethylamine.
  • phthalimid or sodium azide
  • a base After reacting with a sulfonylating agent such as methanesulfonyl chloride, phthalimid (or sodium azide) is reacted in the presence of a base to produce a protected phthalimid (or azide) of the amine form.
  • Hydrazine or reducing agent
  • the amine group is removed (or the azide group is reduced) to produce an amide represented by the general formula, and finally, the compound is treated with the compound represented by the general formula, and then reduced to produce can do.
  • reaction step will be specifically described below with reference to suitable reaction conditions and the like.
  • various synthetic methods and reaction conditions well known in organic synthetic chemistry for converting an alcohol to an amine can be used.
  • a so-called Mitsunobu reaction is carried out using azodicarboxylic acid getyl ester, triflatin phosphine and phthalimid (or hydrazoic acid or difunyuryl phosphate azide), or in the presence of a base such as triethylamine.
  • a sulfonylating agent such as methanesulfonyl and the like
  • phthalimid or sodium azide
  • the resulting phthalimid is treated with hydrazine ( Or reduction).
  • the above reaction is usually carried out in an inert solvent which does not participate in the reaction.
  • the inert solvent include tetrahydrofuran, dimethoxyethane, benzene, toluene and the like in the Mitsunobu reaction, and phthalimid after sulfonylation.
  • Or sodium azide for example, methylene chloride, chloroform, tetrahydrofuran, benzene, ethyl acetate, dimethylformamide, etc.
  • alcohols such as methanol and ethanol are suitable.
  • ethers such as ethyl ether and tetrahydrofuran are used, and when phosphine is reduced using trifenylphosphine and the like, hydrated tetrahydrofuran is used.
  • alcohols such as methanol and ethanol are preferable.
  • the amount of the reagent to be used is, for example, 1 mole of the alcohol compound as a raw material in the above-mentioned Mitsunobu reaction, based on ezodicarboxylic acid getyl ester, triphenyl phosphine and phthalimid (or hydrazoic acid or diphenylphosphoric acid azide). Is 1 mol to excess mol, preferably 1 to 5 mol, respectively.
  • a sulfonylating agent such as methanesulfonyl chloride is added to 1 mole of the alcohol 8
  • 1 mol to excess mol preferably 1 to 2 mol
  • the base such as triethylamine used in this case is 1 mol to excess mol, preferably 1 to 2 mol, per 1 mol of sulfonylating agent.
  • 1 mol to excess mol preferably 1 to 5 mol of phthalimid is used per 1 mol of the sulfonylating agent.
  • bases or sodium azide are used.
  • the base used together with phthalimide is preferably sodium carbonate, potassium carbonate, or the like.
  • the sodium salt or potassium salt of phthalimid can be used as it is.
  • the hydrazine is used in an amount of 1 mol to excess mol, preferably 1 to 10 mol, per 1 mol of the phthalimid compound as a raw material compound, and the azide metal hydride
  • the reducing agent is used in an amount of 1 mol to excess mol, preferably 1 to 2 mol, per 1 mol of the azide.
  • the reaction temperature is usually -7 (TC to 100 ° C, preferably 1 to 20 ° C to 50 ° C, and the reaction time is usually 5 to 48 hours, preferably 30 minutes.
  • the reaction temperature is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from room temperature to 100 ° C.
  • the reaction time is usually In the reaction for reducing an azide form to an amine form, when a metal hydride complex is used as a reducing agent, the reaction temperature is usually--48 hours, preferably 30 minutes-24 hours.
  • the reaction time is usually 5 minutes to 48 hours, is preferred properly from 10 minutes to 10 hours, also Torifuyuni as a reducing agent
  • the reaction temperature is usually from room temperature to the solution used for the reaction. To the boiling point of the medium, it is preferably from 30 ° C. to 100 ° C., and the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours.
  • the reaction temperature is usually 0 to 100 ° C, preferably room temperature to 50 ° C, and the reaction time is generally 10 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • a compound represented by the general formula 9 is reacted with 1 mol to an excess mol, preferably 1 to 2 mol, of 1 mol of the compound represented by the general formula 9 to form an imine in advance. It can be manufactured later by reducing it.
  • This step can be carried out in the same manner as in the step of producing the target compound [ ⁇ ] from the compound represented by the general formula in the above-mentioned production method A, and therefore, the same method can be used for the reaction conditions and the like.
  • the compound represented by the general formula can be produced by using a commercially available product, or by appropriately combining a method described in Reference Example, a known method, or a method analogous thereto as needed.
  • R pl represents a hydroxyl-protecting group
  • the target compound [VI] is first represented by the general formula [!]
  • an alkylating agent represented by the general formula U to act on a ketone represented by the general formula:
  • a reducing agent such as a metal hydride complex to form an alcohol
  • acetyldicarboxylate acetyl ester triphenylphosphine and phthalimid (or hydrazoic acid or diphenylphosphoric acid adjuvant) are obtained.
  • a sulfonating agent such as methanesulfonyl chloride in the presence of a base such as triethylamine
  • phthalimid or sodium azide
  • Ahmin body A phthalimid protected form (or azide form) of ⁇ is produced, followed by the action of hydrazine (or a reducing agent) to remove the phthalimide group (or to reduce the azide group), and represented by the general formula]
  • a compound represented by the general formula [1] is produced by reacting the compound with a compound represented by the general formula 1Q, and then reduced to a compound represented by the general formula [11].
  • the protecting group represented by Rpl is selectively removed to obtain a compound represented by the general formula.
  • General formula by introducing a leaving group into ⁇ !
  • the compound represented by ⁇ is obtained, the compound can be produced by finally allowing the compound to act with triunilylphosphine, trimethyl phosphite, triethyl phosphite, or the like.
  • Examples of the hydroxyl-protecting group represented by IT include the hydroxyl-protecting groups described in the above Production Method 1.
  • the step of producing the compound represented by the general formula from the ketone body represented by the general formula includes the step of producing the compound represented by the general formula from the ketone body represented by the general formula in the above-mentioned production method A.
  • the same conditions can be applied to the reaction conditions and the like.
  • the step of producing the compound represented by the general formula from the amine compound represented by ⁇ includes the step of producing the compound represented by the general formula [II] from the amine compound represented by the general formula by the above-mentioned production method c. Can be done in a similar way and therefore anti Similar conditions can be applied to the response conditions and the like.
  • the general formula from the compound represented by general formula 11! In the process of producing the compound represented by ⁇ , the reaction between the compound represented by the general formula and the carboxylic acid represented by the general formula [in] or a reactive derivative thereof is carried out by the general formula
  • the reaction can be carried out in the same manner as in the reaction of the compound represented by [II] with the carboxylic acid represented by the general formula [ ⁇ ] or a reactive derivative thereof, and therefore, the same conditions apply to the reaction conditions and the like. it can.
  • the protecting group represented by R p ′ In the step of selectively removing the protecting group represented by R p ′ from the compound obtained by the above reaction, various methods are appropriately selected depending on the type and properties of the protecting group. That is, by utilizing the difference in stability between R pl and another protecting group with respect to acid, base or reduction, the protecting group can be selectively removed by a conventional means such as acid, base or reduction. . Specific conditions for these reactions include, for example, methods described in known literature [Protective Groups in Organic Synthesis, 1.W.7 Lean (TWGreene), John Wiley & Sons (1981)].
  • the step of producing a compound represented by the general formula] by introducing a leaving group into the compound represented by the general formula includes, for example, a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, or oxychloride. Phosphorus, phosphorus tribromide, oxalyl chloride, phosgene, etc. are used as the sulfonating agent using, for example, methyl sulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride and the like.
  • the reaction can be carried out in the same manner as the method for introducing a leaving group into the represented compound, and therefore, the same conditions can be applied to the reaction conditions and the like.
  • the step of producing the desired compound [VI] from the compound represented by ⁇ is performed by reacting the compound represented by the general formula with triphenylphosphine, trimethyl phosphite, or triethyl phosphite. be able to.
  • triphenylphosphine trimethyl phosphite, or triethyl phosphite.
  • trif-Xnylphosphine when trif-Xnylphosphine is allowed to act, it is usually carried out in an inert solvent which does not participate in the reaction.
  • the inert solvent toluene, xylene and the like are preferable.
  • the amount of triphenylphosphine used is usually 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the compound.
  • the reaction temperature is usually from 80 ° C to 150 ° C, usually from room temperature to the boiling point of the solvent used in the reaction, and the reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 24 hours.
  • the reaction is usually carried out in an inert solvent not involved in the reaction, or more preferably, in excess of trimethyl phosphite or excess.
  • Triethyl phosphite is used as a solvent and reactant.
  • the reaction temperature is usually from 80 ° C to 150 ° C, usually from room temperature to the boiling point of the solvent used in the reaction, and the reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 24 hours.
  • the compound represented by the general formula (1) can be produced by using a commercially available product, a method described in Reference Examples, a known method, or a method analogous thereto, if necessary, in an appropriate combination.
  • R p2 and R p3 are the same or different and each represents a methyl group, an ethyl group, or an ethylene group together with R p2 and R p3 ;
  • the target compound [VIII] is obtained by first reacting a ketone represented by the general formula with an alkylating agent represented by the general formula II to obtain a compound represented by the general formula After reacting the compound with a reducing agent such as a metal hydride complex to form an alcohol, azodicarboxylic acid getyl ester, triphenylphosphine and phthalimid (or hydrazoic acid or diphenylphosphoric acid azide) are reacted. Or a sulfonating agent such as methylsulfonyl chloride in the presence of a base such as triethylamine, and then phthalimid (or sodium azide) in the presence of a base to react with the amine.
  • a reducing agent such as a metal hydride complex
  • azodicarboxylic acid getyl ester triphenylphosphine and phthalimid (or hydrazoic acid or diphenylphosphoric acid azide) are reacted.
  • a protected product (or azide) of ⁇ is prepared, followed by the action of hydrazine (or a reducing agent) to remove the phthalimide group (or to reduce the azide group) to give the general formula!
  • An amine represented by ⁇ is produced, and the compound ⁇ has a general formula!
  • the compound is reduced to a compound represented by the general formula ⁇ , and after reacting the compound ⁇ with the carboxylic acid represented by the general formula [in] or a reactive derivative thereof, , R p2 and R p3 can be produced by selectively removing the protecting groups.
  • the removal of these protecting groups is preferably carried out in a solvent such as aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran and the like in the presence of an acid such as hydrochloric acid, sulfuric acid and p-toluenesulfonic acid.
  • a solvent such as aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran and the like in the presence of an acid such as hydrochloric acid, sulfuric acid and p-toluenesulfonic acid.
  • the reaction temperature is usually-20 ° C to 100 ° C, preferably 0 ° C to 50 ° C, and the reaction time is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • the respective steps from the production of the target compound [VIII] from the ketone compound represented by the general formula 4 include the conversion of the ketone compound represented by the general formula 4 into the general formula!
  • the reaction can be performed in the same manner as in each step of producing the compound represented by ⁇ , and therefore, the same reaction conditions and the like as those in the corresponding steps can be applied.
  • the compound represented by the general formula 17 may be a commercially available product or a method described in Reference Example. Alternatively, it can be produced by appropriately combining known methods or methods equivalent thereto as necessary.
  • FT represents a protecting group for a hydroxyl group when W ′ is an oxygen atom; a protecting group for a mercapto group when W 1 is a sulfur atom;, I Ar 3 ⁇ , (Cy-,
  • W has', Z, R 3P, R 4P, R 5, R 6, R 7p, R 8P, R 9p, R '0p, R' lp, x, y, and z and R p as defined above ]
  • the target compound [ ⁇ ] is first obtained by reacting a ketone compound represented by the general formula with an alkylating agent represented by the general formula to obtain a compound represented by the general formula:
  • a reducing agent such as a metal hydride complex to form an alcohol
  • azodicarboxylic acid getyl ester, triphenylphosphine and phthalimid (or hydrazoic acid or diphenylphosphoric acid azide) are reacted, or
  • a sulfonylating agent such as methanesulfonyl chloride is allowed to act in the presence of a base such as triethylamine, and then phthalimid (or sodium azide) is actuated in the presence of a base to protect the amine in the presence of phthalimid.
  • R w is a hydroxyl-protecting group
  • examples of the hydroxyl-protecting group include the hydroxyl-protecting groups described in the above Production Method 1.
  • the protective group for an IT-capable mercapto group the protective group for a hydroxyl group described in the above-mentioned Production Method 1 can be applied as the protective group for the mercapto group.
  • the respective steps from the production of the target compound [XII] from the ketone compound represented by the general formula are represented by the general formula!
  • the reaction can be performed in the same manner as in each step of producing the compound represented by ⁇ , and therefore, the same reaction conditions and the like as those in the corresponding steps can be applied.
  • the target compound [X] can be produced by introducing a leaving group into the compound represented by the general formula [XII-a].
  • This step can be performed by a method similar to the method of introducing a leaving group into the compound represented by the general formula in the above-mentioned Production Method D, and therefore, the same reaction conditions and the like can be applied.
  • n, T, R lp and R 2p have the above-mentioned meaning] is a method for producing a compound represented by the general formula [VI] from a compound represented by the general formula in Production Method D According to the general formula [XIII]
  • n, ZR lp and R 2P have the above-mentioned meaning].
  • the compound represented by the general formula [ ⁇ ] can be produced by appropriately combining the power of a commercially available product, the method described in Reference Examples, a known method, or a method analogous thereto, as necessary.
  • R a and R e same or different, a lower alkyl group:
  • R b denotes a tert- Petit group, a benzyl group, Benzuhi drill group or trityl group]
  • Production method H is a synthesis method for producing a carboxylic acid derivative represented by the general formula [III-a] among the compounds represented by the general formula [III].
  • the target carboxylic acid derivative [III-a] is obtained by hydrolyzing a lower alkyl ester derivative of D- or L- or meso-tartaric acid represented by the general formula into a corresponding monocarboxylic acid derivative, After introducing the protecting group Rb of the laboxyl group which can be easily removed, the dibromomalonic acid derivative represented by the general formula ⁇ is reacted in the presence of a base to form a cyclic compound ⁇ . It can be produced by removing the protecting group R ′ ′′ of the group.
  • the protecting group R u or carboxyl group for example a methyl group, Echiru group And the like.
  • the carboxyl-protecting group Rb is preferably a group which can be easily removed under mild conditions such as weak acidity or catalytic reduction such as tert-butyl, benzyl, benzhydryl or trityl. ,.
  • the monohydrolysis reaction of the ester represented by the general formula is usually performed in an inert solvent such as tetrahydrofuran, methanol, ethanol or the like or a mixed solvent thereof with water, for example, sodium hydroxide,
  • an inert solvent such as tetrahydrofuran, methanol, ethanol or the like or a mixed solvent thereof with water, for example, sodium hydroxide
  • the reaction can be carried out by reacting the base with 1 mol to a small excess, preferably 1 to 1.5 mol, per 1 mol of the compound represented by the general formula.
  • the reaction temperature is -100 ° C to 100 ° C, preferably 0 ° C to 50 ° C, and the reaction time is generally 5 minutes to 48 hours, preferably 8 hours to 24 hours.
  • the step of introducing the protecting group Rb into the monocarboxylic acid derivative obtained above is usually carried out in an inert solvent that does not adversely influence the reaction, for example, diphenyl diazomethane, ⁇ , ⁇ ′-diisopropyl monoamine.
  • an inert solvent that does not adversely influence the reaction
  • diphenyl diazomethane ⁇ , ⁇ ′-diisopropyl monoamine.
  • —Venzyl isopera ⁇ , ⁇ ′—diisopropyl-1-0-tert-butyl isoperrea, etc.
  • an amount of 1 mol to excess mol preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula.
  • inert solvent for example, methanol, ethanol, tetrahydrofuran, dioxane, acetone, dimethylformamide, methylene chloride, chloroform, ethyl acetate and the like can be used.
  • the reaction temperature is usually from room temperature to the boiling point of the solvent used in the reaction, and the reaction time is usually from 5 minutes to 7, preferably from 1 hour to 3 days.
  • the step of selectively removing the protecting group represented by R ′ ′′ from the compound obtained in the above step various methods are appropriately selected depending on the type and properties of the protecting group.
  • the difference in stability between R "and other protecting groups R- and FT with respect to acid, base or reduction is used.
  • the protecting group can then be selectively removed by conventional means such as hydrolysis or reduction with an acid or base. Specific methods for these reactions are described, for example, in the method described in the literature [Protective uroups in Organic Synthesis] TW Greene, John Wiley & Sons, Inc. (1981)] or an equivalent method can be used.
  • the compound represented by the general formula ⁇ can be produced by using a commercially available product, or by appropriately combining the methods described in Reference Examples, known methods, or methods analogous thereto as needed.
  • R ' p and R 2p have the above-mentioned meanings), R p "-W 1- (CH 2 ) P -1 (where p' represents an integer of 0 to 4; R M and W 'has the above meaning) or
  • R s is a hydrogen atom or a methyl group
  • R ′ is a lower alkyl group, an aryl group or a lower alkenyl group
  • R 3p , R 4P and R 5 have the above-mentioned meanings]
  • the production method I is a synthetic method for producing an optically active form ⁇ or of an alcohol form obtained as a reduction product of the general formula or the general formula II or, and according to the present production method, the objective optically active alcohol form and Reacts a racemic alcohol derivative represented by the general formula with a vinyl ester derivative represented by the general formula in the presence of lipase to separate the obtained optically active ester derivative and the optically active alcohol derivative. Thereafter, the optically active ester derivative ⁇ can be produced by hydrolyzing the ester group.
  • R ′ of the vinyl ester derivative represented by the general formula ⁇ i is, for example, a lower alkyl group such as a methyl group or an ethyl group; an aryl group such as a phenyl group or a naphthyl group; a benzyl group; An aralkyl group such as a phenylethyl group is preferred.
  • a methyl group that is, a case where the compound represented by the general formula ii is vinyl acetate or isopropenyl acetate is preferred.
  • optical resolution reaction using lipase is usually carried out in an inert solvent such as methylene chloride, chloroform, ethyl ether, tetrahydrofuran, benzene, tonolene, hexane, heptane, and acetonitrile, or a vinyl ester of the general formula ⁇ which is a raw material.
  • an inert solvent such as methylene chloride, chloroform, ethyl ether, tetrahydrofuran, benzene, tonolene, hexane, heptane, and acetonitrile, or a vinyl ester of the general formula ⁇ which is a raw material.
  • the derivative itself can be used as a solvent.
  • the amount of the vinyl ester derivative ⁇ _ to be used is generally 1 mol to a large excess mol, preferably 1 to 100 mol, relative to the starting compound, and the amount of the lipase, which is a catalyst, is It is 0.01 to 100% by weight, preferably 0.1 to 20%.
  • the type of lipase is Reno, derived from Pseudomonas sp.
  • Toyozyme LIP TM manufactured by Toyobo
  • Toyobo is preferable.
  • the above-mentioned enzyme reaction tends to be accelerated by being carried out in the presence of a base.
  • a base for example, an organic base such as triethylamine and diisopropylethylamine is preferable.
  • the amount of the base to be used is generally 0.01 mol to a small excess mol, preferably 0.1 to 1.5 mol, relative to the starting compound.
  • the reaction temperature is generally 0 ° C to 50 ° C, preferably room temperature to 40 ° C, and the reaction time is generally 30 minutes to 7 days, preferably 1 hour to 48 hours.
  • the hydrolysis of the ester represented by the general formula ⁇ can be carried out under acidic or basic conditions by a general method well known in organic synthetic chemistry.
  • R a is a lower alkyl group
  • R lla is a lower alkoxycarbonyl group, a lower alkyl group, a lower alkoxy group or an optionally protected hydroxyl group or a lower hydroxyalkyl group
  • R is a carboxyl group or a lower An alkyl group, a lower alkoxy group or a protected t, a hydroxyl group or a lower hydroxyalkyl group
  • R ′′ c is a diphenylmethyloxycarbonyl group, a lower alkyl group, a lower alkoxy group or a protected May be a hydroxyl group or a lower hydroxyalkyl group
  • Ph represents a phenyl group
  • the target compound [III-1] is a compound having a leaving group. Then, a nitrile derivative is produced by reacting the compound with sodium cyanide or sodium cyanide, and then the nitrile derivative is hydrolyzed under acidic or basic conditions. Still another target compound, a protected benzhydryl form of carboxylic acid [III-2], is produced by treating the carboxylic acid [III-1] obtained above with diphenyldiazomethane. You can do it.
  • the reaction of reacting a compound having a leaving group with a compound having a leaving group is usually carried out in an inert solvent such as methanol, ethanol, dimethylformamide or the like.
  • the reaction can be carried out using 1 mol to an excess mol, preferably 1 to 5 mol of potassium cyanide or sodium cyanide with respect to 1 mol of ⁇ .
  • the reaction temperature is usually from 0 ° C to the boiling point of the solvent used in the reaction, preferably from room temperature to 100 ° C, and the reaction time is generally from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours. .
  • the step of producing the target carboxylic acid [ ⁇ -1] by hydrolyzing the nitrile form ⁇ obtained above is usually carried out in an inert solvent that does not adversely affect the reaction, for example, hydrochloric acid, sulfuric acid or nitric acid. It can be carried out using an acid or using a base such as sodium hydroxide or potassium hydroxide.
  • Acids and bases are usually preferred in excess.
  • the inert solvent is preferably an alcohol such as methanol, ethanol, propanol, butanol, tert-butanol or water, or a mixed solvent thereof under any of acidic conditions and basic conditions.
  • the reaction temperature is usually up to the boiling point of the solvent used in the room temperature to the reaction, preferably 50 ° C ⁇ 150 e C, the reaction time is usually 30 minutes to 72 hours, preferably one hour is ⁇ 48 hours .
  • the step of treating the carboxylic acid [III-11] with diphenyldiazomethane to produce another protected compound, a benzhydryl-protected carboxylic acid [III-11], is usually performed by the following steps.
  • the reaction can be carried out using a limited amount of diphenyldiazomethane in an inert solvent that does not adversely influence the reaction.
  • This reaction can be viewed as a partial (selective) esterification reaction of two or three existing carboxylic acid [ ⁇ -1] carboxylic acid [ ⁇ -1] with diphenyldiazomethane. Therefore, diphenyldiazomethane is usually used in limited amounts for this purpose.
  • inert solvent used for the reaction examples include ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; aromatic hydrocarbons such as benzene and toluene; or Acetone, ethyl acetate and the like are preferred.
  • the reaction temperature is usually 0 ° C to 4 (TC, and the reaction time is usually 30 minutes to 24 hours.
  • the compound represented by the general formula ⁇ can be produced by using a commercially available product, or by appropriately combining the methods described in Reference Examples, known methods, or methods analogous thereto as needed.
  • PFT activity was measured by adding biotin to the N-terminus of a peptide corresponding to the C-terminal 7 amino acid residues of H-ras protein or K-rasB protein (biosylated Lys-Thr-Ser-Cys-Val). -lie-Met) as a prenyl acceptor and [ ⁇ ] -labeled funaresyl pyrophosphate (FPP) as a prenyl donor [Rice et al., Methods: A Companion to Methods in Enzymology. No. 3, pp. 241-245 (1990)].
  • the H-ras protein was expressed and purified in Escherichia coli [Gibbs et al., Proc. Natl. Acad. Sci .. 81: 5704-5708 (1984)].
  • H- ras protein PFT reaction solution volume was prenyl receptor is Ri 25 mu 1 der, its composition, 50mM Hepes pH7.5 / 50 M ZnCl 2 / 5mM MgCl 2 / 20mM KClZ5mM DTT / 0.6 M all-trans [ ⁇ ] -Farnesyl pyrophosphate 25 MH-ras protein ⁇
  • Rat brain-derived PFT Q-Sepharose fractionation
  • Biochin additional Lys - Thr - Ser- Cys - Val one lie - PFT reaction solution volume was prenyl receptor Met is 25 / a zl, its composition, 50 mM Tris-C1 PH7.5 / 50 fi M ZnCl 2 / 5mM MgCl 2 / 20mM KCl / lmM DTT / 0.2% n- old Kuchiru S- D-Darukobiranoshido /0.6 / M all-trans [3 H] - Faruneshirupi port phosphate /3.6 beta Micromax Biochin additional Lys - Thr one Ser one Cys -Val-He-Met / PFT (Q-Sepharose fraction) derived from rat brain. Reaction temperature was 37 ° C, thermal equilibration time was 10 minutes, and reaction time was 20 minutes.
  • the enzymatic reaction product using the H-ras protein as a prenyl receptor was analyzed by SDS-PAGE (sodium dodecyl sulfate Z polyacrylamide gel electrophoresis). And analyzed.
  • the [ 3 H] -labeled enzyme reaction product is boiled for 3 minutes in a buffer containing 2% SDSZ 50 mM Tris-Cl, pH 6.8 ZlO% sucrose Z5% 2-mercaptoethanol, and electrophoresed on a slab gel of 12% polyacrylamide. After electrophoresis, [ ⁇ ] -labeled H-ras protein was fluorographically enhanced with EN 3 HANCE TM (New England Nuclear Co., Ltd.), and then visualized by autoradiography [J. James) et al., Science, Vol. 260, No. 25, pp. 1937-1942 (1993)].
  • the measurement of PFT using the H-ras protein as a prenyl receptor could be analyzed by another more rapid method.
  • the prenyl group transfer reaction is initiated by the addition of [ 3 H] -FPP and a convenient time by the addition of 0.5 ml of 4% SDS. To stop. After further adding 0.5 ml of 30% trichloroacetic acid and mixing well, the reaction solution was left at 4 ° C. for 60 minutes to precipitate H-ras protein. The reaction solution was filtered under reduced pressure through a hotman GFZB filter.
  • the filter was washed 6 times with 2 ml of 6% trichloroacetic acid, mixed with 8 ml of scintillation cocktail (Clearsol 1 TM, manufactured by Narai Lightesque), and then counted on a Beckman TRI-CARB2500TR scintillation counter.
  • Chevron 1 TM manufactured by Narai Lightesque
  • the PFT activity could be measured using biotin-added Lys-Thr-Ser-Cys-Val-He-Met as a prenyl receptor.
  • Pyrotination Lys— Thr— Ser— Cys— Val— lie— Met is used as a prenyl acceptor, and the measurement mixture without prenyl donor is thermally equilibrated in advance.
  • stop at a convenient time by adding 0.2 ml of 2 mg Zml perforated serum albumin, / 2% sodium dodecyl sulfate / 150 mM NaCl. Add 0.02 ml of avidin agarose (Pierce) and shake for 30 minutes. Add biotin with [-]-farnesyl group added.
  • Lys-Thr-Ser-Cys-Val-lie-Met is sufficient for avidin agarose.
  • avidin agarose is washed 4 times with 1 ml of 2 mg Zml ⁇ serum albumin (BSA) / 4% sodium dodecyl sulfate 150 mM NaCl, and 1 ml of scintillation cocktail (Clearsol 1 TM, Nacalai Tesque, Inc.) And then counted with a Beckman TRI-CARB2500TR scintillation counter.
  • BSA serum albumin
  • scintillation cocktail Clearsol 1 TM, Nacalai Tesque, Inc.
  • Biotin-added Lys-Thr-Ser-Cys-Val-He-Met heptapeptide used as an artificial substrate is converted to Lys-Thr-Ser-Cys-Val-lie-Met peptide.
  • Applied Biosystems Model 431A After solid-phase synthesis using a peptide synthesizer, the ⁇ -amino terminus of Lys-Thr-Ser-Cys-Val-lie-Met heptapeptide as it remains on the resin is biotinylated with ⁇ -hydroxysuccinimidobiotin, It was separated from the resin and purified by reversed-phase high-performance liquid chromatography (HPLC).
  • the compound of the present invention was added to the PFT reaction system by adding dimethyl sulfoxide in advance to 1% volume (0.251) of the reaction solution.
  • Table 1 shows the 50% inhibitory concentration (IC 5 value) of the compound of the present invention against PFT activity. Table 1 50% inhibitory concentration for PFT activity
  • the inhibitory effect on Ras protein falnesylation in NIH3T3 cells into which the activated ras gene was incorporated was measured.
  • NIH3T3 cells into which the activated ras gene had been incorporated were spread on a culture plate, and after the culture 3, the compounds of the present invention were added at various concentrations during the culture. After culturing the cells for 24 hours according to the method described in Journal of Biological 'Chemistry (J. Biol. Chem.), Vol. 268, p. 18415 (1993), the cells were lysed and lysed from the plate. . After centrifugation at 12000 g for 5 minutes, the supernatant was used as a cell extract. SDS polyacrylamide gel electrophoresis of the cell extract was performed to separate the farnesylated Ras protein and the farnesylated Ras protein.
  • the protein on the gel was transferred to a nitrocellulose membrane and reacted with a Ras protein antibody as a probe (primary antibody reaction). After reacting with the anti-primary antibody and the peroxidase conjugate (secondary antibody), Ras protein was detected with a chemiluminescence enhancement kit. The percentage of Ras protein that was not phnaresylated was quantified using a densidometer and defined as the inhibitory activity.
  • Table 2 50% inhibitory concentration on Ras protein pharmacosylation
  • the compound of the present invention exhibits excellent antitumor activity as shown in the following pharmacological test examples.
  • Table 3 shows the therapeutic effect of the compound of the present invention on NIHZras cells.
  • Table 3 Effect of the compound of Example 4 on NIH / ras Dose 2 ), Inhibition rate of intraperitoneal growth "(mgZkgZ injection) Average (g): standard deviation (%)
  • Tumor inoculation 10 6 cells were inoculated into female Nu nude mice subcutaneously.
  • Tumor weight On day 7 after cell inoculation, a tumor was excised and weighed.
  • the compound of the present invention has an excellent protein-farnesyltransferase (PFT) inhibitory activity, for example, colon cancer, spleen cancer, myeloid leukemia, lung cancer, skin cancer, thyroid cancer, etc. Useful as an antitumor agent for cancer You.
  • PFT protein-farnesyltransferase
  • the protein-pharmacinyltransferase (PFT) inhibitor according to the present invention can suppress ras transfection and suppress reactivation of HIV genes integrated into host cells, and thus can be used as an anti-HIV agent. Useful.
  • the compound represented by the general formula [I] can be administered orally or parenterally, and formulated as a form suitable for such administration, and provided as an antitumor agent or anti-HIV agent Can be.
  • pharmaceutically acceptable additives can be added to the compound according to the administration form, and then administered after various preparations.
  • additives commonly used in the pharmaceutical field can be used as the additives at this time, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, Carboquin methyl cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, calcium phosphate anhydrous, citrate, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate Sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light gay anhydride, tanolek, vegetable oil, benzyl alcohol, gum arabic, propylene glycol Lumpur, polyalkylene glycol, cyclodextrin or hydroxycarboxylic professional buildings cyclodextrin.
  • gelatin lactose
  • sucrose sucrose
  • titanium oxide starch
  • Dosage forms formulated as a mixture with these additives include, for example, solid preparations such as tablets, capsules, granules, powders and suppositories; and liquid preparations such as syrups, elixirs and injections, etc. These can be prepared according to a usual method in the pharmaceutical field.
  • liquid preparations they may be dissolved or suspended in water or other appropriate medium before use.
  • it may be dissolved or suspended in a physiological saline solution or a glucose solution as necessary, and a buffer or a preservative may be added.
  • formulations may contain a compound of the present invention in a proportion of 1.0 to 100%, preferably 1.0 to 60% by weight of the total drug. These formulations may also contain other therapeutically effective compounds.
  • the dosage and frequency of administration vary depending on the sex, age, weight, degree of symptoms, the type and range of the intended therapeutic effect, etc. of the patient. In general, for oral administration, it is preferable to administer 0.01 to 20 mgZkg in 1 to several doses per adult, and for parenteral administration, it is preferable to administer 0.002 to 10 mgZkg in 1 to several doses. .
  • Other compounds that are therapeutically effective include, for example, agents that cause a reduction in pharmacophoric acid in vivo.
  • the drug that reduces pharmacophoric acid in vivo is not limited as long as it has the above effect and is a pharmaceutically acceptable drug.
  • Inhibitors are preferred, and among them, for example, hydroxymethyldaltharyl represented by mouth bath, simvastatin, pravastatin, flupastatin and the like described in Nature, Vol. 343, pp. 425-430 (1990), for example.
  • Drugs that inhibit the biosynthesis process of funaresyl pyrophosphate such as CoA reductase inhibitor or hydroxymethyl glutaryl CoA synthase inhibitor, etc., especially oral vasculin, simpastatin, pravastatin, fluvastin, etc. Hydroquinone methylglutaryl CoA reductase inhibitor is preferred.
  • composition of the compound of the present invention and the above-mentioned drug can be formulated as in the case of using the compound of the present invention as a single agent.
  • the drug and the drug that causes reduction of fumaricylphosphoric acid in vivo may be contained in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the whole drug.
  • the weight ratio of the protein-farnesyltransferase inhibitor to the agent that causes a decrease in phthalnesyl pyrophosphate in vivo may be 0.001: 1 to 1000: 1, but the weight ratio is particularly high. It is preferably 0.01: 1-100: 1.
  • Example 4 N- ⁇ (1R2R) —4,4-diethoxy-1 1-methyl-1-2- (3,4-methylenedioxyphenyl) butyl ⁇ used as a raw material in Example 4 ⁇ —2-naphthylmethylamine and / or (4S , 5S) — 1,3-Dioxolane 1,2,4,5-tetracarboxylic acid 2,2-Jetyl 5-methyl ester in place of the corresponding amine or carboxylic acid derivative L, Otherwise, the same reaction as in Example 4 was carried out to obtain the compounds of Examples 10 to 15.
  • the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. Subsequently, the residue was dissolved in 100 ml of dimethylformamide, 16.7 g of sodium azide was added, and the mixture was heated and stirred at 120 ° C for 1 hour. After allowing the reaction solution to cool to room temperature, ethyl ether and water were added for extraction. The organic layer was separated, washed with saturated saline, and then the solvent was distilled off under reduced pressure.
  • (2R3S) obtained in the above (2) —2-Acetoxy-5,5—Jetoxy 3- (3,4-Methylenedioxyphenyl) Obtained by the hydrolytic hydrolysis of pentane.
  • (2R.3S) 5.5—Dietokin-3- (3,4-Methylenedioxyphenyl)
  • pentan-1-ol in the same manner as in (3) and (4), N- ⁇ (1S.2S) -1,4,1-ethoxy-l-methyl-2- (3,4-methylenedioxyphenyl) ) Butyl ⁇ 1-2-naphthylmethylamine was obtained.
  • the compound of the present invention has an excellent inhibitory effect on protein-pharmacinyltransferase (PFT) and is useful as an antitumor agent or an anti-HIV agent.
  • PFT protein-pharmacinyltransferase

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Abstract

Cette invention concerne un composé correspondant à la formule générale (I) où Ar?1, Ar2 et Ar3¿ représentent chacun aryle ou hétéroaryle; Cy représente aryle, hétéroaryle ou alicyclique; Q représente soit -(CH¿2?)m-, m étant un nombre entier de 1 à 6, soit -(CH2)n-W-(CH2)p-, W représentant oxygène, soufre, vinylène, ou éthynylène, et n et p étant chacun un nombre entier de 0 à 3; R?1, R2, R3, R4, R6, R7, R8, R9 et R10¿ représentent chacun hydrogène ou similaire; R5 représente alkyle inférieur; R11 représente hydroxyle ou similaire; x et z sont chacun un nombre entier de 0 à 2; et y est égal à 0 ou 1. Cette invention concerne également les sels et les esters acceptables sur le plan pharmaceutique de ce composé, ainsi que des agents antinéoplasiques contenant ces éléments en tant que principe actif.
PCT/JP1996/003239 1995-11-07 1996-11-06 Derives cycliques d'acide amique WO1997017321A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998037070A1 (fr) * 1997-02-21 1998-08-27 Takeda Chemical Industries, Ltd. Composes a anneaux condenses, leur procede de production et leur utilisation
FR2780892A1 (fr) * 1998-07-08 2000-01-14 Sod Conseils Rech Applic Utilisation d'inhibiteurs de prenyltransferases pour preparer un medicament destine a traiter les pathologies qui resultent de la fixation membranaire de la proteine g heterotrimerique
US7550489B2 (en) 2002-03-12 2009-06-23 Merck & Co., Inc. Substituted pyridyoxy amides

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005169A1 (fr) * 1994-08-12 1996-02-22 Banyu Pharmaceutical Co., Ltd. Derive d'acide amique n,n-bisubstitue
WO1996005168A1 (fr) * 1994-08-11 1996-02-22 Banyu Pharmaceutical Co., Ltd. Derive d'amide substitue

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005168A1 (fr) * 1994-08-11 1996-02-22 Banyu Pharmaceutical Co., Ltd. Derive d'amide substitue
WO1996005169A1 (fr) * 1994-08-12 1996-02-22 Banyu Pharmaceutical Co., Ltd. Derive d'acide amique n,n-bisubstitue

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998037070A1 (fr) * 1997-02-21 1998-08-27 Takeda Chemical Industries, Ltd. Composes a anneaux condenses, leur procede de production et leur utilisation
US6420375B1 (en) 1997-02-21 2002-07-16 Takeda Chemical Industries, Ltd. Fused ring compounds, process for producing the same and use thereof
FR2780892A1 (fr) * 1998-07-08 2000-01-14 Sod Conseils Rech Applic Utilisation d'inhibiteurs de prenyltransferases pour preparer un medicament destine a traiter les pathologies qui resultent de la fixation membranaire de la proteine g heterotrimerique
WO2000002558A1 (fr) * 1998-07-08 2000-01-20 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Utilisation d'inhibiteurs de prenyltransferases pour preparer un medicament destine a traiter les pathologies qui resultent de la fixation membranaire de la proteine g heterotrimerique
US7550489B2 (en) 2002-03-12 2009-06-23 Merck & Co., Inc. Substituted pyridyoxy amides
US7816534B2 (en) 2002-03-12 2010-10-19 Merck Sharp & Dohme Corp. Substituted amides

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