WO1997000239A1 - Medicament contre l'angine contenant un derive nitroxy comme ingredient actif - Google Patents

Medicament contre l'angine contenant un derive nitroxy comme ingredient actif Download PDF

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Publication number
WO1997000239A1
WO1997000239A1 PCT/JP1996/001625 JP9601625W WO9700239A1 WO 1997000239 A1 WO1997000239 A1 WO 1997000239A1 JP 9601625 W JP9601625 W JP 9601625W WO 9700239 A1 WO9700239 A1 WO 9700239A1
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Prior art keywords
acceptable salt
group
pharmacologically acceptable
derivative
hydrogen atom
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PCT/JP1996/001625
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English (en)
Japanese (ja)
Inventor
Sadao Ishihara
Fujio Saito
Yasuo Ohhata
Shigeki Miyake
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Sankyo Company, Limited
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Priority to AU60164/96A priority Critical patent/AU6016496A/en
Publication of WO1997000239A1 publication Critical patent/WO1997000239A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/16—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by an inorganic acid or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • C07C233/16—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 singly-bound oxygen atoms
    • C07C233/17—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 singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—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 singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the present invention relates to a composition for preventing or treating angina pectoris comprising a nitroxy derivative or a pharmacologically acceptable salt thereof as an active ingredient, and a medicament for preventing or treating angina pectoris comprising the same as an active ingredient.
  • Prevention or treatment of angina pectoris using their use for the manufacture or their pharmacologically effective amount to warm-blooded animals, or optically active dithroxy with excellent collateral vasodilatory and antianginal effects The present invention relates to a derivative or a pharmacologically acceptable salt thereof, or a composition for preventing or treating angina pectoris, comprising the active ingredient.
  • nitroglycerin is most frequently used clinically as a treatment for cardiovascular diseases, especially angina.
  • This drug has the disadvantage that it is susceptible to the first-pass effect and its duration of action is short. Side effects include headaches, dizziness, and tachycardia due to decreased blood pressure.
  • clinically ineffective first-pass drugs and highly persistent angina pectoris treatments have been proposed.
  • nitroxy derivative having an antianginal effect for example, the following compound A is known (Japanese Patent Application Laid-Open No. 2-207707). Also, as an intermediate for the synthesis of a compound having an anti-anginal effect, many nitroxy derivatives are known [for example, Chemical-Abstract, Vol. 41, p. 3868, 1947: Chem. Abst., 41 Chem. Abst., 58, 12372 (1964), etc.], 3868 (1947), JP-B-146873, Chemical Abstract, Vol. 58, p. 12372, 1964: Chem. Abst., 58, 12372 (1964). CONHCH 2 CH 2 ON02
  • the present inventors have synthesized compounds having a series of nitroxy moieties for many years and have studied their pharmacological actions. As a result, the present inventors have found that a specific nitroxy derivative has an excellent collateral vasodilatory action, its action is persistent, and that it has few side effects and is useful as a therapeutic agent for angina pectoris. Was completed.
  • the present invention relates to a composition for preventing or treating angina pectoris comprising a nitroxy derivative or a pharmacologically acceptable salt thereof as an active ingredient, and a composition for producing a medicament for preventing or treating angina pectoris.
  • a pharmacologically acceptable salt or a composition comprising the same as an active ingredient for preventing or treating angina pectoris.
  • the nitroxy derivative as the active ingredient of the present invention has a general formula
  • R 1 represents a hydrogen atom or a C 1 -C 6 alkyl group
  • A is a C 2 -C 8 alkylene group or a C 2 -alkylene group substituted with a C 2 -C 5 alkylene (however, the alkylene of the substituent is a C 2 alkylene group To the same carbon atom. ).
  • optically active nitroxy derivative of the present invention has the general formula
  • R 1 is as defined above,
  • R 2 represents a C 6 alkyl group
  • n 1 or 2.
  • R 1 C, - C 6 Arukanoiru group is, for example, formyl, Asechiru, propionitrile, cycloalkenyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, be a hexa mail group to suitably, C, - C 5 Arukanoiru group And more preferably a C 2 -C 3 alkyl group, particularly preferably an acetyl group.
  • the C 2 -C 8 alkylene group of A is, for example, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 1-methylethylene, 1-ethylethylene, 1-propylethylene, 1-isopropylethylene, 1-butylethylene. , 1-isobutylethylene, 1-pentylethylene, 1-isopentylethylene, 1-hexylethylene, 1-isohexylethylene, 1,1-dimethylethylene group, and preferably, ethylene, Rimethylene, tetramethylene, 1-methylethylene, 1-ethylethylene, 1-propylethylene, 1-r-sopropylethylene, 1-butylethylene, 1-isobutylethylene or 1,1-dimethylethylene group.
  • ethylene 1-methylethylene, 1-ethylethylene, 1-propyl Ethylene, 1 one isopropylethylene, 1-butyl Ethylene, 1-isobutylethylene or 1,1-dimethylethylene group, and even more preferably, 1-methylethylene, 1-ethylethylene, 1-propylethylene, 1-isopropylethylene, 1-butylethylene or 1-isobutylene. And more preferably or more preferably 1-methylethylene, 1-port propylene, 1-butylethylene or 1- (sobutylethylene, particularly preferably 1-methylethylene It is.
  • C 2 substituted by C 5 alkylene - - C 2 of Alpha C 4 alkylene group for example, 1, 1-ethylene-ethylene group, 1, 1-ethylene trimethylene group, 1, 1-E Ji Ren tetramethylene group , 1,1-trimethyleneethylene, 1,1-tetramethyleneethylene, 1,1-pentamethyleneethylene, and preferably 1,1-ethyleneethylene, 1,1-ethylenetrimethylene.
  • a 1,1-trimethyleneethylene group, a 1,1-tetramethyleneethylene group or a 1,1-pentamethyleneethylene group and more preferably, a 1.1-ethyleneethylene group, —
  • the d-Ce alkyl group for R 2 can be, for example, a methyl, ethyl, propyl, isopropyl, butyl, S-butyl, t-butyl, isobutyl, pentyl, hexyl group; c 4 alkyl group, more preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl group, even more preferably methyl, propyl, butyl or isobutyl group, particularly preferably methyl Group.
  • n is preferably 1.
  • the compounds having the general formulas (I) and (II) can be converted into pharmacologically acceptable salts, if necessary.
  • Such salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, Salts with carboxylic acids such as malic acid, benzoic acid, methanesulfo 9700239
  • It may be a salt with sulfonic acid such as acetic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, or a salt with an acidic amino acid such as glutamic acid or aspartic acid. Salt.
  • sulfonic acid such as acetic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid
  • an acidic amino acid such as glutamic acid or aspartic acid. Salt.
  • the present invention also includes hydrates of the compound (I) or a salt thereof, and when the compound (I) has an asymmetric carbon in the molecule, includes a racemic form and an optically active compound, Ii) or a hydrate of the salt thereof.
  • a force C 2 - C 5 alkylene substituted C 2 - C 4 compounds is an alkylene group and A is C 2 -C 8 alkylene group, R 1 is Compounds that are C, -C 6 alkanoyl groups are new compounds.
  • R 1 is Compounds that are C, -C 6 alkanoyl groups are new compounds.
  • R 1 force A compound which is a hydrogen atom or a C 2 -C 3 alkanoyl group
  • R 1 force a compound that is a hydrogen atom or an acetyl group
  • R 1 force s', a compound that is a hydrogen atom
  • 1,1,1-ethyleneethylene, 1,1-ethylenetrimethylene, 1,1-trimethyleneethylene, 1,1-tetramethyleneethylene or 1,1-pentamethyleneethylene group 1,1-dimethylethylene
  • R 1 is selected from the group consisting of (1)-(4)
  • A is selected from the group consisting of (5)-(9), and these are arbitrarily combined is also preferable. Can be given.
  • R 1 >>, hydrogen atom or C, — C 5 alkanoyl group
  • R 1 is a hydrogen atom or a C 2 -C 3 alkanoyl group
  • R 1 force is a hydrogen atom or an acetyl group
  • a force Compounds that are 1-methylethylene, 1-propylethylene, 1-butylethylene or 1-isobutylethylene group or
  • R 1 force is a hydrogen atom
  • A is a compound in which A is a 1-methylethylene group.
  • R 1 forces a hydrogen atom or C, the compound is an C 5 Arukanoiru group,
  • R 1 force A compound which is a hydrogen atom or a C 2 -C 3 alkanoyl group
  • R 1 force a compound which is a hydrogen atom or an acetyl group
  • R 1 is a compound which is a hydrogen atom
  • R 2 force s', a compound which is a C, -C 4 alkyl group
  • R 2 force A compound which is a methyl, propyl, butyl or isobutyl group
  • R 1 is selected from the group consisting of (15)-(18)
  • R 2 is selected from the group consisting of (19)-(22)
  • n is selected from (23), and these are arbitrarily combined. Also preferred are compounds that have been subjected to, for example, the following.
  • R 1 is a hydrogen atom or a C 5 alkanoyl group
  • R 2 is a C, -C 4 alkyl group
  • R 1 a hydrogen atom or a C 2 -C 3 alkanoyl group
  • R 2 a methyl, ethyl, propyl, isopropyl, butyl or isopropyl group;
  • R 1 is a hydrogen atom or an acetyl group
  • R 2 is a methyl, propyl, butyl or isobutyl group
  • R 1 is a hydrogen atom or an acetyl group
  • Compound No. 1-10 a compound of 1,1-dimethyl-2-nitroxicetilamine and Compound No. 1-11: 1,1-ethylene-12-2-troxicetilamine.
  • the compound having the general formula (I) of the present invention may be a known compound [Chemical-Abstract, vol. 41, p. 3868, 1947: Chem. Abst., 41, 3868 (1947); -146873, Chemical 'Abstract, Vol. 58, p. 12372, 1964: Chem. Abst., 58, 12372 (1964), etc.], or the following method.
  • R 1 and A have the same meaning as described above, R 3 represents a hydrogen atom or a protecting group for an amino group, and A ′ represents a C, -C 7 alkylene group or C 2 —C s represents a C 2 -C 3 alkylene group substituted with an alkylene.
  • Amino groups may, for example, t-butoxycarbonyl group, methoxybenzyl old alkoxycarbonyl, C, one C 4 ⁇ Turkey alkoxybenzylacetic O alkoxycarbonyl group such as ethoxy benzyl old alkoxycarbonyl group, Kuroruasechiru, bromoacetyl, ® chromatography It may be a halogenoacetyl group such as a doacetyl group, preferably a t-butoxycarbonyl group or a P-methoxybenzyloxycarbonyl group, and particularly preferably a t-butoxycarbonyl group.
  • Method A is a method for producing compound (I).
  • Step A1 is a step for producing a compound having the general formula (IV), and This is achieved by protecting the amino group of the compound having the general formula (III).
  • reaction for protecting the amino group is carried out according to a well-known method in the field of synthetic organic chemistry.
  • compound ( ⁇ ) can be prepared by di-t-butyl-carbonate; t-butyl-chlorocarbonate or the like.
  • Bases used are, for example, organic amines such as tritylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, sodium bicarbonate, metal bicarbonate such as bicarbonate lime, It can be an alkali metal carbonate such as sodium carbonate or carbonated lime, preferably an alkali metal bicarbonate or an organic amine.
  • the inert solvent used is not particularly limited as long as it does not participate in the reaction.
  • examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene, dichloromethane, 1,2-dichloroethane, and tetrachloromethane.
  • Halogenated hydrocarbons such as carbon chloride, ethers such as ether, tetrahydrofuran and dioxane, water, and a mixed solvent of water and the above organic solvent may be used.
  • benzene with di-butyl ether it is a mixed solvent of ethers or water and ethers.
  • compound ( ⁇ ) with halogenocarbonate or acetyl chloride hydrocarbon Or ethers.
  • the reaction temperature varies depending on the type of the starting compound ( ⁇ ) and the solvent, but is usually from ⁇ 20 ° C. to 100 ° C., preferably from 0 ° C. to 50 ° C.
  • the reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours, and preferably 30 minutes to 20 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering the precipitated crystals or adding water, extracting with a water-immiscible organic solvent such as ethyl acetate, drying, and distilling off the extraction solvent. If necessary, it can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.
  • Step A2 is a step of producing a compound having the general formula (V), wherein the compound (IV) or a reactive derivative thereof (for example, a C 4 alkyl ester or an acid chloride, an acid bromide, an acid Such an acid halide, preferably a methyl ester, an ethyl ester or an acid chloride) is achieved, and the reaction is carried out in an inert solvent in the presence of a reducing agent.
  • the compound (IV) or a reactive derivative thereof for example, a C 4 alkyl ester or an acid chloride, an acid bromide, an acid
  • an acid halide preferably a methyl ester, an ethyl ester or an acid chloride
  • the reducing agent used is, for example, hydrogen borohydride alkali metal salts such as sodium borohydride, potassium borohydride, lithium borohydride, calcium borohydride, hydrogen hydride such as lithium aluminum hydride And preferably lithium aluminum hydride.
  • the inert solvent used is not particularly limited as long as it does not participate in the reaction.
  • examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene, ether, tetrahydrofuran, and dioxane.
  • ethers are preferred, and ethers (particularly, tetrahydrofuran) are preferred.
  • the reaction temperature varies depending on the type of the starting compound (IV), the reducing agent, the solvent, and the like, but is usually from 20 ° C to 100 ° C, preferably from 10 ° C to 50 ° C. C.
  • the reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours, and preferably 30 minutes to 16 hours.
  • compound (V) can be produced by protecting the amino group of a known amino monoalcohol compound in the same manner as in the above-mentioned Step A1.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, filtering out the precipitated crystals or adding water and adding water such as ethyl acetate. It can be obtained by extracting with an immiscible organic solvent, drying and distilling off the extraction solvent.If necessary, it can be further purified by a conventional method, for example, recrystallization, column chromatography, etc. it can. ' ⁇
  • the step A3 is a step for producing a compound having the general formula (I), in which the compound (V) is subjected to double-dropping, if necessary, the protecting group of the amino group is removed, and further, if necessary, the compound is acylated. Achieved by
  • the nitration reaction is achieved by reacting compound (V) with a diuretic agent in an inert solvent, preferably in the presence of a base.
  • the nitrating agent used can be, for example, fuming nitric acid, nitrocollidium tetrafluoroborane, thiocyanyl chloride nitric acid, thiocyanyl nitric acid, nitronium tetrahydrofuran, and preferably nitrocollidium tetrabutyl nitrate.
  • the inert solvent used is not particularly limited as long as it does not participate in the reaction.
  • examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene, dichloromethane, 1,2-dichloroethane, and tetrachloromethane.
  • Halogen hydrocarbons such as carbon chloride, ethers such as ether, tetrahydrofuran, dioxane, ketones such as acetone, nitriles such as acetate nitrile, N, N Amides such as dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide, preferably halogen. Hydrocarbons, ethers, nitriles, amides or sulfoxides.
  • the reaction temperature varies depending on the type of the raw material compound (V), the nitrating agent, the solvent, and the like, but is usually from 20 ° C to 80 ° C, and preferably from 0 ° C to 50 ° C. .
  • the reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 24 hours, preferably 1 hour to 10 hours.
  • the target substance for the nitration reaction is collected from the reaction mixture according to a conventional method.
  • it can be obtained by distilling off the extraction solvent or adding water, extracting with an aqueous immiscible organic solvent such as ethyl acetate, drying, and then distilling off the extraction solvent. It can be further purified by a method such as recrystallization and column chromatography.
  • the reaction for removing the protecting group of the amino group depends on the type of the protecting group, but is carried out by a method usually used in the field of organic synthetic chemistry.
  • the protecting group of the amino group is t-butoxycarbonyl group or d-C4 alkoxybenzyloxycarbonyl group
  • the corresponding compound is converted into an inert solvent (for example, hexane, cyclohexane, benzene, toluene, xylene, etc.).
  • Acid e.g., hydrocarbons, halogen hydrocarbons such as dichloromethane, 1,2-dichloroethane, carbon tetrachloride or ethers such as ether, tetrahydrofuran and dioxane, preferably ethers).
  • Hydrogen halides such as hydrogen chloride, hydrogen bromide and hydrogen iodide; mineral acids such as hydrochloric acid, nitric acid, hydrobromic acid and sulfuric acid; or acetic acid, formic acid, oxalic acid, methanesulfonic acid and paratoluenesulfonic acid Organic acids, such as trifluoroacetic acid, trifluoromethanesulfonic acid, preferably halogenated water And particularly preferably hydrogen chloride) at 30 C to 80 C (preferably 0 C to 50 C) for 30 minutes to 10 hours (preferably 1 hour to 5 hours) The reaction removes the protecting group.
  • mineral acids such as hydrochloric acid, nitric acid, hydrobromic acid and sulfuric acid
  • acetic acid formic acid, oxalic acid, methanesulfonic acid and paratoluenesulfonic acid
  • Organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid, preferably
  • the protecting group for the amino group is a halogenacetyl group
  • the corresponding compound is converted into an inert solvent (for example, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, Amides such as hexamethylphosphoramide or sulfoxides such as dimethylsulfoxide, preferably amides), at a temperature of 120 ° C. to 80 ° C. (preferably 0 ° C. ° C to 50 ° C)
  • the protecting group is removed by reacting the mixture for 1 minute to 10 hours (preferably 1 hour to 5 hours).
  • the target compound for the reaction for removing the protecting group for the amino group is collected from the reaction mixture according to a conventional method.
  • it can be obtained by filtering the precipitated crystals or adding water, extracting with a water-immiscible organic solvent such as ethyl acetate, drying, and distilling off the extraction solvent. If necessary, it can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.
  • the acylation reaction is carried out by reacting the corresponding amine compound or an acid addition salt thereof (eg, a mineral acid salt such as hydrochloride, nitrate, sulfate) with a general formula
  • PTa represents a d—C 6 alkanoyl group.
  • a reactive derivative thereof (acid halides, mixed acid anhydrides or active esters), for example, an acid halide method, a mixed acid anhydride method, an active ester method or a condensation method.
  • compound (VI) except when FTa is a formyl group
  • a halogenating agent for example, thiocyanyl chloride, oxalic acid chloride, pentachloride ichlin, etc.
  • the base used is, for example, organic amines such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, sodium bicarbonate, metal bicarbonate such as bicarbonate rim, It may be an alkali metal carbonate such as sodium carbonate or carbonated carbonate, preferably organic amine.
  • organic amines such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, sodium bicarbonate, metal bicarbonate such as bicarbonate rim, It may be an alkali metal carbonate such as sodium carbonate or carbonated carbonate, preferably organic amine.
  • the inert solvent used is not particularly limited as long as it does not participate in the reaction.
  • hydrocarbons such as hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, and tetrachloromethane
  • Halogenated carbon such as carbon chloride Hydrides, ethers, ethers such as tetrahydrofuran, dioxane, ketones such as acetone, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone
  • amides such as hexamethylphosphoramide, and sulfoxides such as dimethyl sulfoxide, and are preferably hydrocarbons, halogenated hydrocarbons, ethers or amides.
  • the reaction temperature varies depending on the type of the starting material compound and the solvent, etc.
  • the reaction between the halogenating agent and the compound (VI) and the reaction between the acid halide and the corresponding amine compound or the acid addition salt thereof are usually at ⁇ 20 ° C.
  • the reaction between the halogenating agent and the compound (VI) is preferably from ⁇ 10 to 50 ° C., and the amine compound corresponding to the acid halide or the acid addition salt thereof Is crc to 1 oo ° c.
  • the reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours, and preferably 30 minutes to 16 hours.
  • the reaction for preparing the mixed acid anhydride is chlorocarbonate Echiru, carbonate d like chloroformate isobutyl - C 4 alkyl halide; di like GETS chill cyanophosphate - d - C 4 alkyl Xia Roh phosphate; or Jifue two
  • the reaction is carried out by reacting a compound (VI) with a diarylphosphoryl azide such as diphosphoryl azide, di (p-l-nitrophenyl) phosphoryl azide or dinaphthyl phosphoryl azide, preferably in an inert solvent. Performed in the presence of a base.
  • the base and inert solvent used are the same as those used in the above-mentioned acid halide method.
  • the reaction temperature varies depending on the type of the starting compound and the solvent, but is usually from 20 to 50 ° C, preferably from 0 to 30 ° C. Temperature More different forces are typically between 15 minutes and 24 hours, preferably between 30 minutes and 16 hours.
  • the reaction of the mixed acid anhydride or formic acid with the acid anhydride of acetic acid and the corresponding amine compound or an acid addition salt thereof is preferably carried out in an inert solvent in the presence or absence of a base.
  • the base and the inert solvent used are the same as those used in the above-mentioned acid halide method.
  • the reaction temperature varies depending on the type of the raw material mixture, the type of the solvent, and the like, and is usually from 120 ° C to 100 ° C, preferably from 110 ° C to 50 ° C
  • the reaction time varies depending on the reaction temperature and the like, but is usually from 15 minutes to 24 hours, preferably from 30 minutes to 16 hours.
  • the compound ( ⁇ ) is converted into an active esterifying agent (for example, N-hydroxysuccinimide, N-hydroxybenzoate) in the presence of a condensing agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazole, etc.).
  • an active esterifying agent for example, N-hydroxysuccinimide, N-hydroxybenzoate
  • a condensing agent for example, dicyclohexylcarbodiimide, carbonyldiimidazole, etc.
  • the reaction for producing the active ester is preferably carried out in an inert solvent, and the inert solvent used is the same as that used in the above-mentioned acid halide method.
  • the reaction temperature varies depending on the raw material mixture, the type of the solvent, and the like.
  • the active esterification reaction it is usually ⁇ 20 ° C. to 50 ° C., and preferably ⁇ 10 ° C. to 30 ° C. C
  • the reaction between the active ester compound and the corresponding amine compound or its acid addition salt is performed at a temperature of from 120 ° C. to 50 ° C., preferably from 10 ° C. to 30 ° C. C
  • the reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours, preferably 30 minutes to 16 hours for both reactions.
  • the condensation method is equivalent to compound (VI) in the presence of a condensing agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazole, 1- (N, N-dimethylaminopropyl) _3-ethylcarbodiimide hydrochloride, etc.)
  • a condensing agent for example, dicyclohexylcarbodiimide, carbonyldiimidazole, 1- (N, N-dimethylaminopropyl) _3-ethylcarbodiimide hydrochloride, etc.
  • the target compound of each reaction is collected from the reaction mixture according to a conventional method.
  • it can be obtained by filtering the precipitated crystals or adding water, extracting with a water-immiscible organic solvent such as ethyl acetate, drying, and distilling off the extraction solvent. If necessary, it can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.
  • the starting compound (III) for Method A is known or is easily produced according to a known method or a method similar thereto [for example, Vilsutine, Vol. 14, p. 194, 1951: Beil., 14, 194]. (1951), Vailshutein, Vol. 14, p. 299,
  • the compound having the general formula (II) of the present invention is easily produced according to the following method.
  • R 1 , R 2 , R 3 and ⁇ have the same meanings as described above.
  • the step B1 is a step for producing a compound having the general formula (VIII), which is optionally achieved by protecting the amino group of the compound having the general formula (VII). It is performed in the same manner as the process.
  • the step B2 is a step of producing a compound having the general formula (IX), and the compound (VIII) or a reactive derivative thereof (for example, C 1, C 4 alkyl ester or acid chloride, acid promide, This is achieved by reducing an acid halide such as acid oxide, preferably methyl ester, ethyl ester or acid chloride), and this step is performed in the same manner as the above-mentioned step A2.
  • Step B3 is a step of preparing a compound having the general formula (II), wherein the compound (IX) is subjected to double troche, if necessary, the protecting group for the amino group is removed, and if necessary, the compound is further acylated. This step is performed, and is performed in the same manner as the A3 step.
  • the starting compound (VII) in Method B is known or It is easily prepared according to a similar method [eg, Virciutane, Vol. 14, p. 194, 1951: Beil., 14, 194 (1951), Virciutane, Vol. 14, p. 299, 1951: Beil. , 14, 299 (1951), Beirciutane, Vol. 14, p. 526, 1951: Beil., 14, 526 (1951), etc.].
  • the compound (I) or pharmacologically acceptable salt or compound ( ⁇ ) or pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, has excellent collateral vasodilatory activity and low toxicity. It has no side effects such as headache, dizziness, tachycardia or adverse effects on the digestive system, liver, bones, etc., and has no first-pass effect. Is useful as a therapeutic agent).
  • Compound (II) has excellent storage stability and is easy to handle.
  • the compound (I) or a pharmacologically acceptable salt thereof, which is the active ingredient of the present invention, or the compound (II) or a pharmacologically acceptable salt thereof of the present invention is used as a therapeutic or preventive agent for angina pectoris, , Itself or an appropriate pharmacologically acceptable excipient, mixed with a diluent, etc., orally with tablets, capsules, granules, powders or syrups or parenterally with injections, etc. Can be administered.
  • These preparations may contain excipients (eg, lactose, sucrose, glucose, mannitol, sugar derivatives such as sorbitol; corn starch, potato starch, ⁇ -starch, dextrin, starch such as carboxymethyl starch).
  • excipients eg, lactose, sucrose, glucose, mannitol, sugar derivatives such as sorbitol; corn starch, potato starch, ⁇ -starch, dextrin, starch such as carboxymethyl starch).
  • Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally cross-linked carboxymethylcellulose sodium; gum arabic; dextran; Silicic acid, synthetic aluminum silicate Gum, silicate derivatives such as magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate), binding Agents (eg, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; magrogol, etc.), disintegrants (eg, the above-mentioned excipients: croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, etc.) Luxes such as chemically modified starch, cellulose derivatives, etc., lubricants (eg, talc;
  • the dosage varies depending on symptoms, age, etc.
  • the lower limit is 1 mg (preferably 5 mg) and the upper limit is 100 mg (preferably 300 mg) per dose.
  • the lower limit of 0.1 mg (preferably 0.5 mg) and the upper limit of 100 mg (preferably 50 mg) per dose may be 1 to 100 mg / day for adults. It is recommended to administer it 6 times according to symptoms.
  • nitronitetrafluoroboron is suspended in 200 ml of anhydrous sodium nitrile, and 17.5 ml of 2,4,6-collidine is suspended in a nitrogen stream at -5 ° C to 0 ° C. The mixture was stirred for 30 minutes. 10. 70 g of N-t-butoxycarbonyl-L-alaninol was added to the above solution, and the mixture was stirred at room temperature for 1 hour and 20 minutes. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, insolubles were filtered off, and the solvent was distilled off.
  • Collateral vasodilator effect by intravenous administration A beagle dog (male) weighing 9-13 kg was anesthetized by intravenous injection of pentovalpital 3 Omg / Kg, and the experiment was performed under artificial respiration.
  • a polyethylene force neur Atom venous catheter 2F was inserted retrograde into one branch of the left thyroid artery.
  • the left carotid artery upstream of this pressure measurement site was occluded for one minute with arterial clement, and the pressure immediately before occlusion (P) and the decrease in peripheral pressure ( ⁇ ) were measured.
  • test drug was administered from the polyethylene forceps inserted into the hip vein, and the left carotid artery was occluded again at 5, 15, 30, 45, and 6 minutes, and the pressure immediately before the occlusion was observed. (P,) and the decrease in peripheral pressure ( ⁇ ,) were measured.

Abstract

L'invention concerne une composition pout traiter ou empêcher l'angine de poitrine, qui comprend comme ingrédient actif un dérivé nitroxy ayant la formule générale (I): R1NH - A - ONO¿2?, ou un sel de celui-ci acceptable sur le plan pharmaceutique. Dans cette formule, R?1¿ représente un hydrogène ou un alcanoyle en C¿1-6? et A représente un alkylène en C2-8 ou un alkylène en C2-4 substitué par des alkylènes en C2-5, à condition que les substituants alkylène se fixent au même atome de carbone du groupe alkylène en C2-4. Le dérivé nitroxy en question et les sels de celui-ci acceptables sur le plan pharmaceutique sont très efficaces contre l'angine et sont donc utiles comme remèdes préventifs ou curatifs contre l'angine de poitrine.
PCT/JP1996/001625 1995-06-14 1996-06-14 Medicament contre l'angine contenant un derive nitroxy comme ingredient actif WO1997000239A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60164/96A AU6016496A (en) 1995-06-14 1996-06-14 Antianginal drug comprising nitroxy derivative as active ingredient

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP14664195 1995-06-14
JP7/146641 1995-06-14

Publications (1)

Publication Number Publication Date
WO1997000239A1 true WO1997000239A1 (fr) 1997-01-03

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WO (1) WO1997000239A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54122235A (en) * 1978-02-09 1979-09-21 Merck Patent Gmbh 11aryloxyy33nitratoalkylaminoo22propanol and its manufacture
JPS6136259A (ja) * 1984-07-18 1986-02-20 ベーリンガー・マンハイム・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング 新規オキシインドール‐誘導体、その製法及びこれを含有する心蔵及び循環系疾病の治療及び予防剤
JPH01146873A (ja) * 1987-12-03 1989-06-08 Hokuriku Seiyaku Co Ltd 硝酸エステル誘導体
JPH02169558A (ja) * 1988-10-22 1990-06-29 Boehringer Mannheim Gmbh 心臓および循環器疾患の治療薬および新規ニトロキシアルキルアミン誘導体
WO1993015057A1 (fr) * 1992-01-28 1993-08-05 Kirin Beer Kabushiki Kaisha Compose de pyridinecarboximidamide et son utilisation
JPH05213910A (ja) * 1991-03-27 1993-08-24 Sankyo Co Ltd チアまたはオキサゾリジノン誘導体
WO1994021631A1 (fr) * 1993-03-22 1994-09-29 Nippon Kayaku Kabushiki Kaisha Derives de chromane et utilisation de ces derives
JPH07258212A (ja) * 1991-02-25 1995-10-09 Sankyo Co Ltd ピロリジノン誘導体

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54122235A (en) * 1978-02-09 1979-09-21 Merck Patent Gmbh 11aryloxyy33nitratoalkylaminoo22propanol and its manufacture
JPS6136259A (ja) * 1984-07-18 1986-02-20 ベーリンガー・マンハイム・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング 新規オキシインドール‐誘導体、その製法及びこれを含有する心蔵及び循環系疾病の治療及び予防剤
JPH01146873A (ja) * 1987-12-03 1989-06-08 Hokuriku Seiyaku Co Ltd 硝酸エステル誘導体
JPH02169558A (ja) * 1988-10-22 1990-06-29 Boehringer Mannheim Gmbh 心臓および循環器疾患の治療薬および新規ニトロキシアルキルアミン誘導体
JPH07258212A (ja) * 1991-02-25 1995-10-09 Sankyo Co Ltd ピロリジノン誘導体
JPH05213910A (ja) * 1991-03-27 1993-08-24 Sankyo Co Ltd チアまたはオキサゾリジノン誘導体
WO1993015057A1 (fr) * 1992-01-28 1993-08-05 Kirin Beer Kabushiki Kaisha Compose de pyridinecarboximidamide et son utilisation
WO1994021631A1 (fr) * 1993-03-22 1994-09-29 Nippon Kayaku Kabushiki Kaisha Derives de chromane et utilisation de ces derives

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