GB2051781A - Oxoamino acid derivatives - Google Patents

Oxoamino acid derivatives Download PDF

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GB2051781A
GB2051781A GB8014359A GB8014359A GB2051781A GB 2051781 A GB2051781 A GB 2051781A GB 8014359 A GB8014359 A GB 8014359A GB 8014359 A GB8014359 A GB 8014359A GB 2051781 A GB2051781 A GB 2051781A
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acid
oxoamino
hydrogen atom
methylpropanoyl
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Ono Pharmaceutical Co Ltd
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Priority claimed from JP5423979A external-priority patent/JPS55147257A/en
Priority claimed from JP9320579A external-priority patent/JPS5618959A/en
Priority claimed from JP9489079A external-priority patent/JPS5620579A/en
Priority claimed from JP12882679A external-priority patent/JPS5653670A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The oxoamino acid derivatives of the general formula: <IMAGE> [wherein A represents a single bond, or a methylene (i.e. -CH2-), ethylene (i.e. -CH2CH2-) or methylmethylene (i.e.@CHCH3) group, B represents a single bond, or a methylene group, X represents a methylene group, or an oxygen or sulphur atom, or a group @NR0 (in which R0 represents a hydrogen atom, or a lower alkyl group, or a tetrahydropyran-2-yl group), R represents a hydrogen atom, or a lower alkyl group, R1 represents a hydrogen atom, or a lower alkanoyl group, or a benzoyl group, and R2 represents a hydrogen atom, or a lower alkyl group unsubstituted or substituted by one group -SR1 (in which R1 is as hereinbefore defined), with the proviso that the ring is a 5-or 6-membered ring, and with the proviso that, when R2 represents a lower alkyl group substituted by one group -SR1, both R1 are the same], and, when R represents a hydrogen atom, non-toxic salts thereof, possess an inhibitory activity on angiotensin converting enzyme, and are useful as antihypertensives.

Description

SPECIFICATION Oxoamino acid derivatives This invention relates to new oxoamino acid derivatives, to processes for their preparation, and to pharmaceutical compositions containing them as active ingredients.
More particularly, it relates oxoamino acid derivatives of the general formula:
[wherein A represents a single bond, or a methylene (i.e. -CH2-), ethylene (i.e. -CH2CH2-), or methylmethylene (i.e. CHCH3) group, B represents a single bond, or a methylene group, X represents a methylene group, or an oxygen or sulphur atom, or a group NRo (in which Ro represents a hydrogen atom, or a lower alkyl group, or a tetrahydropyran-2-yl group), R represents a hydrogen atom, or a lower alkyl group, R1 represents a hydrogen atom, or a lower alkanoyl group, or a benzoyl group, and R2 represents a hydrogen atom, or a lower alkyl group unsubstituted or substituted by one group -SR1 (in which R1 is as hereinbefore defined), with the proviso that the ring is a 5- or 6-membered ring, and with the proviso that, when R2 represents a lower alkyl group substituted by one group -SR1, both R1 are the same], and, when R represents a hydrogen atom, non-toxic salts thereof, which possess an inhibitory activity on angiotensin converting enzyme, and thus are useful as antihypertensives.
The term "a lower alkyl group" used in this specification means a straight- or branched-chain alkyl group containing from 1 to 5 carbon atoms, i.e. methyl, ethyl, propyl, butyl, pentyl, and their isomers.
The term "a lower alkanoyl group" used in this specification means a straight- or branched-chain alkanoyl group containing from 2 to 5 carbon atoms, e.g. acetyl, propanoyl, butyryl, or isobutyryl.
Preferably R is hydrogen, methyl or tert-butyl, more preferred R is hydrogen or tert-butyl, most preferred R is hydrogen. Preferably R1 is hydrogen or acetyl, more preferred R1 is hydrogen. Preferably R2 is methyl, ethyl, acetylthiomethyl or mercaptomethyl, more preferred R2 is methyl. Preferably Ro is hydrogen, or a lower alkyl group, more preferred Rio its hydrogen or tert-butyl. Preferably the ring is a group of the formula:
(wherein R7 is a hydrogen atom or a lower alkyl group) more preferred the ring is a group of formula A1, A2, A4, A6 or A7, most preferred the ring is a group of formula A1.
As will be apparent to those in the art, the compounds of the present invention depicted in general formula I have at least one center of chirality being at the carton atom attached to the group COOR. Still further centers of chirality may occur when R2 represents a lower alkyl group unsubstituted or substituted by one group -SR1 (except for R2 being a group -CH2SR1), or, when A represents a methylmethylene group.
Accordingly, the compounds of the present invention are concerned with all isomers or mixtures thereof.
Preferably the configuration of the carbon atom attached to the group R2 is in S-configuration. Preferably the cyclicamino acid is in L-form.
Widespread investigations have been carried out in order to discover inter alia new cyclicamino acid derivatives possessing an inhibitory activity on angiotensin converting enzyme. As a result of extensive research and experimentation, it has been found that by introducing an oxo group and a mercaptopropanoyl group into a cyclicamino acid, the pharmaceutical properties of the known cyclicamino acids [cf.
Biochemistry, 16r25), 5484 (1977)1 are enhanced.
According to a feature of the present invention, the oxoamino acid derivatives of general formula I, wherein R1 represents a lower alkanoyl group or a benzoyl group, Ro is other than a hydrogen atom, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula::
[wherein F3 represents a lower alkanoyl group, or a benzoyl group, R4 represents a hydrogen atom, or a lower alkyl group unsubstituted or substituted by one group -SR3 (in which F3 is as hereinbefore defined), X1 represents a methylene group, or an oxygen or sulphur atom, or a group NRs (in which Rs represents a lower alkyl group, or a tetrahydropran-2-yl group), and the other symbols are as hereinbefore defined], are prepared by reaction of a compound of the general formula:
(wherein the various symbols are as hereinbefore defined) with an activated derivative of a compound of the general formula::
(wherein the various symbols are as hereinbefore defined) in the presence of a base, e.g. an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an alkali metal carbonate such as sodium carbonate or potassium carbonate, or an alkali metal hydride such as sodium hydride or potassium hydride, or an organic base such as triethylamine or pyridine, in an inert solvent, e.g. water, methylene chloride, diethyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, benzene, toluene, dioxane, N,N-dimethylformamide, hexamethylphosphoramide, or a mixture of two or more of them, at ambient temperature or, if desired, with heating or cooling.
Examples of the activated derivative of compounds of general formula Ill are an acid halide such as an acid chloride or bromide, an acid anhydride, a mixed acid anhydride with an alkylcarbonate or an inorganic halide (e.g. thionyl chloride, phosphorus oxychloride or phosphorus trichloride), an activated ester (e.g.
p-nitrophenyl ester or polychlorophenyl ester), and an activated ester with N,N'-dicyclohexylcarbodiimide, and they are well known, or may easily be prepared by methods known per se. By the term "methods known perse" as used in this specification is meant methods heretofore used or described in the chemical literature.
The compounds of general formula II are well known, or may easily be prepared by methods known per se.
For example, the compounds of general formula II, wherein A represents a methylene group, B represents a single bond, X1 represents a group NRs, (in which F5 represents a lower alkyl group, or a tetrahydropyran-2-yl group), and R is as hereinbefore defined, i.e. compounds of the general formula:
(wherein R and Rs are as herein before defined) are prepared by the series of reactions depicted schematicåíly below in Scheme A, wherein CBZ represents a benzyloxycarbonyl group, and the other symbols are as hereinbefore defined.
SCIFEME A
Referring to Scheme A, the conversion [a] may be carried out (1), when Rs is a lower alkyl group, by the methods as described in "Compendium of Organic Synthetic Methods", Volume 1 (1971), 2 (1974) and 3 (1977), Section 97, John Wiley & Sons, Inc. (USA), or (2), when Rs is a tetrahydropyran-2-yl group, by using 2,3-dihydropyran in the presence of a condensing agent, e.g. p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, trifluoroacetic acid, trifluoroboran-etherate, phosphorus oxychloride or camphorsulphonic acid, in an inert organic solvent, e.g. methylene chloride, chloroform or diethyl ether, at a temperature from ambient to -30 C.
The conversion [b] may be carried out by using palladium on carbon in methanol at room temperature under an atmosphere of hydrogen.
The starting materials of general formula V are prepared as described in Bull. Chem. Soc. Japan, 41, 2748 (1968).
The oxoamino acid derivatives of general formula I, wherein R1 represents a hydrogen atom, Ro is other than a hydrogen atom, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula:
[wherein F6 represents a hydrogen atom, or a lower alkyl group unsubstituted or substituted by one group -SH, and the other symbols are as hereinbefore defined], are prepared by hydrolysis of a compound of general formula IA under basic conditions.
The hydrolysis under basic conditions may be carried out in the presence of a base, for example an alkali metal, e.g. sodium or potassium, hydroxide or carbonate, ammonia, or an amine such as hydrazine, 2-mercaptoethylamine or ethanolamine, in an inert solvent, e.g. water, methanol, ethanol, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, or a mixture of two or more of them, at ambient temperature or, if desired, with heating or cooling. Advantageously the reaction may be carried out under an atmosphere of an inert gas such as argon or nitrogen (i) with ammonia in aqueous tetrahydrofuran or methanol, or (ii) with 2-mercaptoethylamine in acetonitrile at ambient temperature.
The oxoamino acid derivatives of general formula I, wherein R represents a hydrogen atom, Ro is other than a tetrahydropyran-2-yl group, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula:
[wherein X2 represents a methylene group, or an oxygen or sulphur atom, or a group= NR7 (in which R7 represents a hydrogen atom, or a lower alkyl group), and the other symbols are as hereinbefore defined] are prepared by reaction of a compound of general formula IA or IB, wherein R represents a lower alkyl group, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula:
(wherein F8 represents a lower alkyl group, preferably a tert-butyl group, and the other symbols are as hereinbefore defined) under acidic conditions.
The reaction under acidic conditions may be carried out by using an inorganic acid such as hydrochloric acid, hydrobromic acid or perchloric acid, or an organic acid such as trifluoroacetic acid, trifluoromethanesulphonic acid or p-toluenesulphonic acid in the absence or presence of an inert solvent, e.g. water, methanol, ethanol, benzene, diethyl ether, tetrahydrofuran, acetic acid, anisole, or a mixture of two or more of them, in the presence or absence of ethanethiol at ambient temperature or, if desired, with heating or cooling. Advantageously, when F8 represents a tert-butyl group, the reaction may be carried out by using trifluoroacetic acid in anisole at room temperature.
The oxoamino acid derivatives of general formula I, wherein the various symbols are as hereinbefore defined, are prepared by oxidation of a compound of the general formula:
(wherein the various symbols are as hereinbefore defined).
The oxidation for the conversion of a secondary hydroxy group to a ketone group is well known, for example the methods described in the Chemical Society of Japan, "Shinjikken Kagaku Kohza", Volume 15 (1976), Maruzen (Japan). For example the oxidation may easily be carried out by the oxidation with chromic acid.
The oxidation may be carried out by using an oxidizing reagent, e.g. chromium trioxide, bichromic acid salt, chromic acid salt, chromyl chloride, chromic acid ester, pyridinium chlorochromate, Collins reagent or Jones reagent (1) under acidic conditions utilizing acetic acid or sulphuric acid, (2) under basic conditions utilizing pyridine, or (3) under neutral conditions utilizing benzene ortoluene, if desired, in the presence of an inert solvent such as water, methylene chloride, diethyl ether, acetone, or N,N-dimethylformamide, at ambient temperature or, if desired, with heating or cooling.
The compounds of general formula VII are well known, [cf. United States Patent Specification Nos.
4046889, 4105776 and 4154840, and British Patent Publication Specification No. 2010675A], or may easily be prepared by means heretofore mentioned for the preparation of compounds of general formula IA.
When the carbon atom attached to the group F2 (wherein R2 is other than a hydrogen atom or the group -CH2-s-R1, R1 being as herein before defined) is an asymmetric carbon atom, the racemate of general formula I or III may be separated by optical resolution with a known resolving reagent such as cinchonidine, quinine, cinchonine, quinidine or dicyclohexylamine in an inert solvent such as acetonitrile, methanol, ethanol, chloroform; diethyl ether, benzene, glycerol or acetone at ambient temperature or, if desired, with heating or cooling, followed by desalting in manner known perse to give each optical isomers of general formula I or ill.
Esters of general formula I, wherein R represents a lower alkyl group, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula:
(wherein Rg represents a lower alkyl group, and the other symbols are as hereinbefore defined) are prepared by esterification of a corresponding acid of general formula I, wherein R represents a hydrogen atom, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula:
(wherein the various symbols are as hereinbefore defined) by methods known per se, for example by using a diazoalkane, e.g. diazomethane, diazoethane, diazopropane, diazobutane or diazopentane.
Acids of general formula I, wherein R represents a hydrogen atom, may, if desired, be converted by methods known perse into salts. Preferably, the salts are non-toxic salts. By the term 'non-toxic salts', as used in this specification, is meant salts the cations of which are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmacological properties of the compounds of general formula I are not vitiated by side-effects ascribable to those cations. Preferably the salts are water-soluble. Suitable non-toxic salts include the alkali metal, e.g. sodium or potassium, salts, the alkaline earth metal, e.g. calcium or magnesium, salts and ammonium salts, and pharmaceutically acceptable (i.e.
non-toxic) amine salts. Amines suitable for forming such salts with carboxylic acid are well known and include, for example, amines derived in theory by the replacement of one or more of the hydrogen atoms of ammonia by groups, which may be the same or different when more than one hydrogen atom is replaced, selected from, for example, alkyl groups containing from 1 to 6 carbon atoms and hydroxyalkyl groups containing 2 or 3 carbon atoms.Suitable non-toxic amine salts are, for example, tetra-alkylammonium salts such as tetramethylammonium salts, and other organic amine salts such as methylamine salts, ethylamine salts, isopropylamine salts, tert-butylamine salts, dimethylamine salts, diethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts, dicyclohexylamine salts, methylhexylamine salts, pyridine salts or pyrrolidine salts.
Salts may be prepared from the acids of general formula I, wherein R represents a hydrogen atom, by methods known per se, for example, by reaction of stoichiometric quantities of an acid of general formula I and an appropriate base, e.g. an alkali metal or alkaline earth metal hydroxide or carbonate, ammonium hydroxide, ammonia or an organic amine, in a suitable solvent. The salts may be isolated by lyophilisation of the solution, or, if sufficiently insoluble in the reaction medium, by filtration, if necessary after removal of part of the solvent.
The compounds of the present invention of general formula land non-toxic salts thereof possess an inhibitory activity on angiotensin converting enzyme for the conversion of angiotensin I, which is produced from angiotensinogen with enzyme renin, to hypertensive angiotensin land thus are useful for treatment of angiotensin-induced hypertension [cf. the Lancet, 755(1977)].
The compounds of the present invention of general formula I and non-toxic salts thereof obviously inhibit exogenously-angiotensin I-induced pressor (exogenous angiotensin I converts into angiotensin II in rats to produce pressor) in normotensive anesthetized rats (cf. Table 1), and do not inhibit exogenously-angiotensin Il-induced pressor.
For example, inhibitory effects of the compounds of the present invention on angiotensin 1(1000 ttgikg, i.v.)-induced pressor response in anesthetized rats are shown in Table 1, and the concentration of the compounds of the present invention required to produced a 50% inhibitory activity (IC50) on angiotensin converting enzyme with Hippuryl-L-Histidyl-L-Leucine as a substrate, which was determined according to the method as described in Biochem. Pharmcol., 20, 1637(1971) are shown in Table 1 as IC50.
TABLE 1 IC80 doses inhibiton (%) compounds (nM) litgkg,i.v.) 2 5 10 20 30 60(min.) 300 (n=3) 71.2 55.8 34.4 9.8 6.7 0 100 (n=3) 55.1 44.1 34.8 18.5 14.8 15.0 E8 6.4 30(n=4) 37.0 24.4 15.8 15.8 9.1 10 (n=4) 9.3 7.9 5.6 4.7 300 (n=3) 73.8 68.9 57.4 32.8 26.2 19.1 100 (n=4) 62.8 48.6 31.7 19.1 12.6 5.5 30 8(a) 3.6 30 (=4) 44.5 34.1 16.8 11.6 2.3 10 (n=4) 16.7 12.6 7.6 +0.6 100 (n=3) 42.2 42.2 34.8 33.3 20.7 12.6 E 8(c) 6.6 30 (n=3) 44.4 40.7 30.0 23.6 8.6 0 10 (n=4) 17.2 7.6 2.5 1.3 0.6 100 (n=3) 49.5 25.7 8.7 2.4 0.5 E 9(a) 6.4 30 (n=3) 30.4 8.2 0 10 (n=3) 20.0 7.5 5.0 4.0 300 (n=3) 51.1 47.2 16.0 0 E 9(b) 20 100 (n=3) 45.5 9.2 3.0 3.0 30 (n=3) 24.8 5.0 0 E 8 :2S-1 -(3-Mercapto-2RS-methylpropanoyl)pyroglutamic acid.
E 8(a):2S-1-(3-Mercapto-2S-methylpropanoyl)pyroglutamic acid.
E 8(c) :2S-1 -(3-Mercapto-2S-methylpropanoyl -4-oxoproline.
E 9(a) :3-(3-Mercapto-2S-methylpropanoyl)-2-oxazolidone-4S-carboxylic acid.
E 9(b) :3-(3-Mercapto-2S-methylpropanoyl)-2oxothiazolidine-4R-carboxylic acid.
Thus, the compounds of the present invention of general formula I and non-toxic salts thereof are useful for the alleviation of the angiotensin dependent hypertension in mammals. They are preferably administered orally, but parenteral route such as subcutaneously, intramuscularly, intravenously or intraabdominally may also be employed.
The compounds of the present invention of general formula I and non-toxic salts thereof can be utilized to treat for the hypertension by formulating in compositions such as tablets, capsules, granules, powders, syrups or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.
For this purpose a compound of the present invention of general formula I or a non-toxic salt thereof or a their mixture can be compounded with pharmaceutically acceptable adjuvants such as vehicles, carriers, binders, stabilizers or flavors.
In the human adult, a daily dose for oral administration is generally from 0.1 to 100 mg/kg body weight, preferably from 1 to 50 mg/kg body weight. A daily dose for parenteral administration is generally from 0.05 to 50 mg/kg body weight, preferably from 0.1 to 10 mg/kg body weight. The dose may be administered once, preferably two to four times separately.
Preferred oxoamino acid derivatives of the present invention are as follows: 1 -(3-merca pto-2-methyl propanoyl)pyrog I utamic acid, 1-(3-mercapto-2-ethylpropanoyl)pyroglutamic acid, i-(3-mercapto-2-mercaptomethylpropanoyl)pyrog lutamic acid, 1 -(3-mercapto-2-methylpropanoyl)-4-oxoproline, 1 -(3-mercapto-2-ethyl propanoyl )-4-oxoproline, 1-(3-mercapto-2-mercaptomethylpropanoyl)-4-oxoproline, 1 -(3-mercapto-2-methylpropanoyl )-2-piperidone-6-carboxylic acid, 1 -(3-mercapto-2-ethyl propanoyl )-2-piperidone-6-ca rboxylic acid, 1-(3-mercapto-2-mercaptomethylpropanoyl)-2-piperidone-6-carboxylic acid, 3-(3-mercapto-2-methyl propanoyl )-2-oxazolidone-4-ca rboxylic-acid, 3-(3-mercapto-2-ethyl propanoyl)-2-oxazo lidone-4-carboxyl ic acid, 3-(3-mercapto-2-mercaptomethylpropanoyl)-2-oxazolidone-4-carboxylic acid, 3-(3-mercapto-2-methylpropanoyl)-5-methyl-2-oxazolidone-4-carboxylic acid, 3-(3-mercapto-2-ethylpropanoyl)-5-methyl-2-oxazolidone-4-carboxylic acid, 3-(3-mercapto-2-mercaptomethylpropanoyl)-5-methyl-2-oxazolidone-4-carboxylic acid, 3-(3-mercapto-2-methyl propanoyl )-2-oxothiazolidine-4-carboxylic acid, 3-(3-mercapto-2-ethylpropanoyl)-2-oxothiazolidine-4-carboxylic acid, 3-(3-mercapto-2-mercaptomethylpropanoyl)-2-oxothiazolidine-4-carboxylic acid, 1-(3-mercapto-2-methylpropanoyl)-2-oxoimidazolidine-5-carboxylic acid, 1 -(3-merca pto-2-ethyl propanoyl )-2-oxoimidazolidine-5-carboxylic acid, 1-(3-mercapto-2-mercaptomethylpropanoyl)-2-oxOimidazolidine-5-carboxylic acid, 1 -(3-mercapto-2-methyl propanoyl)-3-tert-butyl-2-oxoimidazolidine-5-carboxylic acid, 1 -(3-mercapto-2-ethylpropanoyl)-3-tert-butyl-2-oxoimidazolidine-5-carboxylic acid, 1-(3-mercapto-2-mercaptomethylpropanoyl)-3-tert-butyl-2-oXoimidazolidine-5-carboxylic acid, the corresponding acetylthio derivatives, and esters and non-toxic salts thereof.
Particularly preferred oxoamino acid derivatives of the present invention are the acetylthio derivatives: 2S-1 -(3-acetylthio-2RS-methylpropanoyl)pyroglutamic acid tert-butyl ester, 2S-1 -(2-acetylthiomethyl-3acetylthiopropanoyl )pyroglutamic acid tert-butyl ester, 3-(3-acetylthio-2S-methyl propanoyl)-2-oxazolidone- 4R-carboxylic acid tert-butyl ester, 3-(3-acetylth io-2S-methyl propa noyl)-2-oxothiazol idine-4R-ca rboxylic acid tert-butyl ester, 1 -(3-acetylthio-2S-methylpropanoyl)-2-piperidone-6RS-carboxylic acid tert-butyl ester, 3-(3 acetylthio-2S-methylpropanoyl)-5S-methyl-2-oxazolidone-4S-carboxylic acid tert-butyl ester, 1 -(3-acetylthio- 2S-methylpropanoyl)-3-tert-butyl-2-oxoimidazolidine-5S-carboxylic acid tert-butyl ester, 1 -(3-acetylthio-2S- methylpropanoyl)-3-(tetrahydropyran-2-yl)-2-oxoimidazolidine-5RS-carboxylic acid tert-butyl ester, 2S-1 -(3- acetylthio-2RS-methylpropanoyl)-4-oxoproline, 2S-1 -(3-acetylthio-2RS-methyl propanoyl Ipyroglutamic acid, 2S-1 -(2-acetylthiomethyl-3-acetylthiopropanoyl)pyroglutamic acid, 3-(3-acetylthio-2S-methylpropanoyl)-2- oxazolidone-4S-carboxylic acid,3-(3-acetylthio-2S-methylpropanoyl)-2-oxothiazolidine-4R-carboxylic acid, 1-(3-acetylthio-2S-methylpropanoyl)-2-piperidone-6RS-carboxylic acid, 1 -(3-acetylthio-2S- methylpropanoyl)-2-oxoimidazolidine-5RS-carboxylic acid, 1 -(3-acetylthio-2S-methyl propanoyl)3-tert- butyl-2-oxoimidazolidine-5S-carboxylic acid, 2S-1 -(3-acetylthio-2S-methylpropanoyl)pyroglutamic acid, 2S- 1 -(3-acetylthio-2S-methylpropanoyl)-4-oxoproline; the esters:: 2S-1-(3-acetylthio-2RS- methylpropanoyl)pyroglutamic acid tert-butyl ester, 2S-1 -(2-acetylthiomethyl-3 acetylthiopropanoyl )pyroglutamic acid tert-butyl ester, 3-(3-acetylthio-2S-methylpropanoyl)-2-oxazolidone- 4S-carboxylic acid tert-butyl ester, 3-(3-acetylthio-2S-methylpropanoyl )-2-oxothiazolidine-4R-ca rboxylic acid tert-butyl ester, 1-(3-acetylthio-2S-methylpropanoyl)-2-piperidone 6RS-carboxylic acid tert-butyl ester, 3-(3 acetylthio-2S-methyl pro pa noyl )-5S-methyl-2-oxazol idone-4S-carboxylic acid tert-butyl ester, I -(3-acetylthio- 2S-methylpropanoyl)-3-tert-butyl-2-oxoimidazolidine-5S-carboxylic acid tert-butyl ester,1-(3-acetylthio-2S- methylpropanoyl)-3-(tetrahydropyran-2-yl)-2-oxoimidazolidine-5RS-carboxylic acid tert-butyl ester, 3-(3 mercapto-2S-methylpropanoyl)-2-oxazolidone-4S-carboxylic acid tert-butyl ester, 3-(3-mercapto-2Smethylpropanoyl)-2-oxothiazol idine-4R-carboxyl ic acid tert-butyl ester, 3-(3-mercapto-2S-methylpropanoyl)- 5S-methyl-2-oxazolidone-4S-carboxylic acid tert-butyl ester; and the acids: 2S-1-(3-acetylthio-2RS methylpropanoyl)-4-oXoproline,2S-1-(3-acdetylthio-2RS-methylpropanoyl)-pyroglutamic acid, 2S-1-(2acetylthiomethyl-3-acetylthiopropanoyl)-pyroglutamic acid, 3-(3-acetylthio-2S-methylpropanoyl)-2- oxazolidone-4S-ca rboxylic acid, 3-(3-acetylthio-2S-methyl propa noyl)-2-oxothiazol idine-4R-carboxylic acid, 1 -(3-acetylthio-2S-methylpropa noyl )-2-piperidone-6RS-carboxylic acid, 1 -(3-acetylthio-2S methyl propanoyl )-2-oxoi midazol idi ne-5RS-carboxylic acid, 1 -(3-acetylthio.2S-methyl propanoyl)-3-tert- butyl-2-oxoimidazolidine-5S-carboxylic acid, 2S-1 -(3-acetylthio-2S-methylpropanoyl)pyroglutamic acid, 2S- 1 -(3-acetylthio-2S-methylpropanoyl)-4-oxoproline, 2S-1 -(3-mercapto-2RS-methylpropanoyl)pyroglutamic acid, 2S-1 -(3-mercapto-2S-methylpropanoyl)pyroglutamic acid, 2S-1 -(2-mercaptomethyl-3- mercaptopropanoyl)pyroglutamic acid,2S-1-(3-mercapto-2S-methylpropanoyl)-4-oXoproline,1-(3- mercapto-2S-methyl propa noyl )-3-tert-butyl-2-oxoim idazolidi ne-5S-carboxylic acid,3-(3-mercapto-2S- methylpropanoyl)-2-oxazolidone-4S-carboxylic acid, 3-(3-mercapto-2S-methylpropanoyl)-2-oxothiazolidine4R-carboxylic acid, 1 -(3-mercapto-2S-methylpropanoyl)-2-piperidone-6RS-carboxylic acid, 1 -(3-mercapto 2S-methylpropanoyl)-2-oxoimidazolidine-5RS-carboxylic acid, 3-(3-mercapto-2S-methylpropanoyl)-5S- methyl-2-oxazolidone-4S-carboxylic acid and non-toxic salts thereof.
The following Reference Examples and Examples illustrate the present invention. In the Reference Examples and Examples, 'IR', 'NMR' and 'MS' represent respectively 'Infrared absorption spectrum', 'Nuclear magnetic resonance spectrum' and 'Mass spectrum'. Where solvent ratios are specified in chromatographic separations, the ratios are by volume. Except when specified otherwise, infrared spectra are recorded by the liquid film method, and nuclear magnetic resonance spectra are recorded in deuterochloroform (CDC13) solution.
REFERENCE EXAMPLE 1 3-A cetylthio-2S-meth ylpropanoic acid A solution of 512 g of dl-3-acetylthio-2-methylpropanoic acid and 929 g of cinchonidine in 5 liters of acetonitrile was allowed to stand overnight at 0 C. Crystalline precipitate was filtered off, and dried to give 610 g of crystals. The crystals were dissolved in 1.5 liters of acetonitrile with heating, and were allowed to stand overnight at 0 C to give 450 g of crystals. Once more the crystals were dissolved in 1.2 liters of acetonitrile with heating, and were allowed to stand overnight at 0 C to give 424 g of crystals.They were dissolved in 300 ml of 4N hydrochloric acid, extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous sodium sulphate, and then concentrated under reduced pressure. The residue was separated by distillation in vacuo to give 76 g of the title compound as the fraction of boiling point being 128-131"C(2.6 mmHg).
Optical rotation: [cr]8= -33.3" (c=1.089, ethanol).
REFERENCE EXAMPLE 2 l-Benzyloxycarbon y/-2-oxoimidazolidine-5S-carboxylic acid tert-butyl ester A mixture of 4.890 g of 1 -benzyloxycarbonyl-2-oxoimidazolidine-5S-carboxylic acid [prepared as described in Bull. Chem. Soc. Japn, 41,2748(1968)], 17.5 ml of isobutene, a catalytic amount of conc. sulphuric acid and 100 ml of methylene chloride was reacted at 40"C for 20 hours in an autoclave. The reaction mixture was filtered, and the filtrate was diluted with methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (3:2) as eluent to give 2.504 g of the title compound.
Optical rotation: [t]D0= -90.1- (c=0.784, methanol).
NMR(CD30D solution): b =7.2(5H,s), 6.45(1 H,bs), 5.1 5(2H,s), 4.7-4.4(1 H,m(, 3.9-3.1 (2H,m), 1 .40(9H,s).
MS: m.'e=320(M+).
The following compound was prepared with an excess of isobutene by the same procedure as described above.
(a) 1 -Benzyloxycarbonyl-3-tert-butyl-2-oxoimidazolidine-5S-carboxylic acid tert-butyl ester Optical rotation: [t]r2)4= -52.57 (c=1.033, methanol).
NMR: h=7.2(5H,s), 5.15(2H,s), 4.4(1 H,bs), 4.0-3.1 (2H,m), 1 .34(9H,s).
MS: m/e=376(M+).
REFERENCE EXAMPLE 3 1-Benzyloxycarbon yl-3-(tetrah yd ro pyran-2-yl)-2-oxoimidazolidine-5S-carboxylic acid tert-b utyl ester A mixture of 2.504 g of the compound (prepared as described in Reference Example 2), 2.2 ml of 2,3-dihydropyran, a catalytic amount of p-toluenesulphonic acid, and 30 ml of methylene chloride was stirred at room temperature for 15 minutes. The reaction mixture was quenched with pyridine, and concentrated under reduced pressure. The residue purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 2.203 g of the title compound.
MS: m/e=404(Mt).
REFERENCE EXAMPLE 4 3-(Tetrahydrop yran-2-yIJ-2-oxoimidazolidine-5S-carboxylic acid tert-butyl ester Under an atmosphere of hydrogen, a mixture of 2.1 g of the compound (prepared as described in Reference Example 3), 600 mg of 10% palladium on carbon, and 30 ml of methanol was stirred at room temperature for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluentto give 809 mg of the title compound.
NMR: ò=5.5-5.3(1 H,bs), 5.1 -4.8(1 H,m), 4.3-3.5(5H,m), 2.0-1 .5(6H,bs), 1 .48(9H.s).
The following compound was prepared from the compound [prepared as described in Reference Example 2(a)] by the same procedure as described above.
(a) 3-Tert-butyl-2-oxoimidazolidine-5S-carboxylic acid tert-butyl ester NMR: b=3.97(1 H,dd, J=7 and 8 Hz), 4.04-3.40(2H,m), 1 .48(9H,s), 1 .35(9H,s).
MS: mle=242(M+).
Optical rotation: [ct]r20= +8.66 (c=0.679, methanol).
EXAMPLE 1 2S- l-(3-Acetylthio-2RS-meth ylpropano yI)pyroglutamic acid tert-butyl ester To a solution of 914 mg of ZL-pyrog lutamic acid tert-butyl ester in 16 ml of an hydrous tetrahydrofuran were added 180 mg of sodium hydride (content 63%) a little at a time with cooling in an ice bath. After stirring for 20 minutes, the mixture was stirred with a solution of 891 mg of 3-acetylthio-2RSmethylpropanoyl chloride (prepared by reaction of 3-acetylthio-2RS-methylpropanoic acid with thionyl chloride in an hydrous benzene at room temperature for 20 hours, followed by concentration under reduced pressure) in 8 ml of tetrahydrofuran for 1.5 hours with cooling in an ice bath, and then at room temperature for 2 hours.The reaction mixture was diluted with 100 ml of ethyl acetate, washed with water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (2:1) as eluent to give 1.13 g of the title compound.
Optical rotation. [ct]020= -48.2 (c=0.70, methanol).
MS: m/e=329(M+).
IR: v=1745,1695 cm-'.
NMR: b=4.70-4.50(1H), 4.2-3.7(1 H), 3.25-3.05(2H), 2.32 and 2.30(3H), 1.48 and 1.46(9H), 1.29-1.19(3H).
The following compounds were prepared by the same procedure as described above.
(a) 2S-1 -(2-Acetylthiomethyl-3-acetylthiopropanoyl)pyroglutamic acid tert-butyl ester from Lpyroglutamic acid tert-butyl ester and 2-acetylthiomethyl-3-acetylthiopropanoyl chloride.
NMR: 6'=4.7-3.9(2H,m), 3.6-3.0(4H,m), 3.0-2.5(2H,bs), 2.33(3H,s), 2.30(3H,s), 2.5-1 .9(2H,bs), 1 .40(9H,s).
MS: m/e=403(M+).
(b) 3-(3-Acetylthio-2S-methylpropanoyl)-2-oxazolidone-4S-carboxylic acid tert-butyl ester from 2oxazolidone-4S-carboxylic acid tert-butyl ester and 3-acetylthio-2S-methylpropanoyl chloride [prepared by reaction of the acid (prepared as described in Reference Example 1) with thionyl chloride in anhydrous benzene at room temperature for 20 hours, followed by concentration under reduced pressured.
NMR: 6=4.9-4.1 (3H), 4.1-3.6(1 H), 3.2-3.0(2H), 2.27(3H,s), 1 .50(9H,s), 1.30(3H,d, J=7 Hz).
MS: mle=331(M').
(c) 3-(3-Acetylthio-2S-methylpropanoyl)-2-oxothiazolidine-4R-carboxylic acid tert-butyl ester from 2oxothiazolidine-4R-carboxylic acid tert-butyl ester and 3-acetylthio-2S-methylpropanoyl chloride.
NMR: b=4.95(1 H,dd, J=9.2 Hz), 4.0-3.0(5H,m), 2.30(3H,s), 1 .40(9H,s), 1 .20(3H,d, J=8.0 Hz).
MS: mi'e=347(M+).
(d) 1 1(3-Acetylthio-2S-methylpropanoyl)-2-piperidone-6RS-carboxylic acid tert-butyl ester from 2piperidone-6RS-carboxylic acid tert-butyl ester and 3-acetylthio-2S-methylpropanoyl chloride.
MS: mte=343(M+).
(e) 3-(3-Acetylthio-2S-methyl propanoyl)-5S-methyl-2-oxazolidone-4S-carboxylic acid tert-butyl ester from 5S-methyl-2-oxazolidone-4S-carboxylic acid tert-butyl ester and 3-acetylthio-2S-methylpropanoyl chloride.
NMR: h=4.7-4.2(2H,m), 4.2-3.6(1H,m), 3.3-3.0(2H,m), 2.3(3H,s), 1.8-1.2 (1 5H,m).
(f) 1 -(3-Acetylthio-2S-methylpropanoyl)-3-tert-butyl-2-oxoimidazolidine-5S-carboxylic acid tert-butyl ester from the product of Reference Example 4(a) and 3-acetylthio-2S-methylpropanoyl chloride.
NMR: 6=4.6-4.2(1 H,bs), 4.2-3.0(5H,m), 2.2513H,s), 1 .45(9H,s), I .36(9H,s) 1 .25(3H,d, J =7 Hz).
MS: m/e=386(M+).
(9) 1 - (3-Acetylthio-2S-methylpropanoyl)-3-(tetrahydropyran-2-yl)-2-oxoimidazolidine-5RS-carboxylic acid tert-butyl ester from the product of Reference Example 4 and 3-acetylthio-2S-methylpropanoyl chloride.
MS: m/e=414(M+).
EXAMPLE 2 2S- l-(3-A cetylthio-2RS-methylpropano yJ)-4-oxoprollne To a solution of 7.60 g of 2S-1-(3-acetylthio-2RS-methylpropanoyl)-4-hydroxyproline in 450 ml of acetone were added dropwise 61 ml of the Jones reagent (16.3 g of chromium trioxide and 14.0 ml of conc. sulphuric acid were mixed, and water was added to make a volume of 61 ml) with cooling in an ice-bath over a period of 15 minutes. After stirring for one hour at that temperature, the mixture was quenched with 20 ml of isopropanol. The chromium residue was filtered off, and the acetone solution was concentrated under reduced pressure. The residue was diluted with one liter of ethyl acetate, washed with water, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel using a mixture of chloroform, methanol and acetic acid (60:3:1) as eluent to give 5.15 g of the title compound.
Optical rotation. [a]032 -43.9' (c=1.62, methanol).
MS: m/e=273 (M+).
IR: v=1770,1690,1640cm-1.
NMR: 6=4.90-5.20(1 H), 3.90-4.30(2H), 2.33(3H,s), 1.23(3H,d, J=7.0 Hz).
EXAMPLE 3 2S- l-(3-A cetylthio-2RS-meth ylpropano yI)-4-oxoproline To a solution of 3.87 g of L-4-oxoproline in 30 ml of 1 N sodium hydroxide were added dropwise 5.42 g of 3-acetylthio-2RS-methylpropanoyl chloride and 15 ml of 2N sodium hydroxide over a period of 15 minutes with cooling in an ice-bath, and the mixture was stirred with cooling in an ice-bath for 15 minutes, and then at room temperature for 3 hours. The reaction mixture was acidified with 2 ml of conc. hydrochloric acid and 1 N hydrochloric acid, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulphate, and then concentrated under reduced pressure to give 8.5 g of the crude product. The product was purified by column chromatography on silica gel using a mixture of chloroform, methanol and acetic acid (60:3:1) as eluent to give 7.6 g of the title compound.
The data of optical rotation, MS, IR and NMR were the same as the product of Example 2.
EXAMPLE 4 2S- l-(3-A cetylthio-2RS-meth ylpropanoyl)p yroglutamic acid A solution of 990 mg of the ester (prepared as described in Example 1) in 5 ml of anisole was stirred with 10 ml of trifluoroacetic acid at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give 830 mg of the title compound.
NMR: 6=4.85-4.46(1 H), 4.05-3.80(1 H), 3.25-3.05(2H), 2.31 (3H,s), 1.25 (3H,d).
MS: m/e=273(M+).
The following compounds were prepared from the corresponding esters by the same procedure as described above. The products of (a), (b), (c), (d), (e) and (f) were purified by column chromatography on silica gel using a mixture of chloroform, tetrahydrofuran and acetic acid (100:10:1) as eluent, and the reaction (b) was carried out in the presence of ethanethiol.
(a) 2s-1 -(2-Acetylthiomethyl-3-acetylthiopropanoyl)pyroglutamic acid from the ester of Example 1(a).
NMR: b=9.0(1 H,s), 4.85-4.50(1 H,bs), 4.30-3.90(1 H,bs), 3.60-3.10(4H,m), 2.90-2.50(2H,bs), 2.35(6H,s).
MS: m/e=347(Mt).
(b) 3- (3-Acetylthio-2S-methyl propaoyl)-2-oxazolidone-4s-carboxylic acid from the ester of Example (b).
MS: m/e=275(Mt).
(c) 3- (3-Acetylthio-2S-mthylpropanoyl)-2-oxothiazolidine-4R-carboxylic acid from the ester of Example 1(c).
MS: m/e=291(M+).
(d) 1 -(3-Acetylthio-2S-methylpropanoyl )-2-piperidone-6RS-carboxylic acid from the ester of Example 1(d).
MS: míe=287(M+).
(e) 1 -(3-Acetylthio-2S-methylpropanoyl)-2-oxoimidazolidine-5RS-carboxylic acid from the ester of Example 1(g).
NMR: b=9.9(1H,bs). 6.8(1H,bs), 5.0-4.7(1 H,bs), 4.1 -3.4(3H,m), 3.3-3.0 (2H,m), 2.3(3H,s), 1.27 and 1.23(2H,dd, J =7 Hz).
MS: mie=274(M').
(f) 1 -(3-Acetylthio-2S-methylpropanoyl)-3-tert-butyl-2-oxoimidazolidine-5S-carboxylic acid from the ester of Example 1(f).
NMR: (h=9.9(1 H,bs), 4.65(1 H,dd, J=10 and 6 Hz), 4.3-3.0(5H,m), 3.2(3H,s), 1.45(9H,s), 1.25(3H,d, J=7 Hz).
MS: mie=330(M').
EXAMPLE 5 2S- l-(3-A cetylthio-2s-methylpropano yl)p yroglutamic acid dicyclohexylamine salt To a solution of 103 mg of the 2RS compound (prepared as described in Example 4) in 0.7 ml of acetonitrile were added 0.075 ml of dicyclohexylamine. Crystalline precipitate was recrystallized from acetonitrile to give 70 mg of the title compound.
Melting point: 185-187 C.
Optical rotation: I(o2O= -72.6 (c=0.46, methanol).
The following compound was prepared by the same procedure as described above.
(a) 2s-1 -(3-Acetylthio-2S-methylpropanoyl)-4-oxoproline dicyclohexylamine salt from the product of Example 2 or 3.
Melting point: 156-158 C.
Optical rotation: I(]021= -31.7- (c=0.706. methanol).
EXAMPLE 6 2S- 1- (3-A cetylthio-2S-meth ylpropano yl)p yroglutamic acid 347 mg of the salt (prepared as described in Example 5) were dissolved in water, acidified with 0.5N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of chloroform. tetrahydrofuran and acetic acid (10:2:11 as eluentto give 217 mg of the title compound.
Optical rotation: I(']D= -100 (c=1.65, methanol).
IR:v=1750,1690cm ~'.
NMR: b=4.76(1H,dd,J=8 and 4 4Hz). 4.05-3.75(1 H.m). 3.3-3.0(2H.m), 2.31 l3H,s).1.2413H.d. J=7.0 Hz).
MS: mle=273(M-).
The following compound was prepared by the same procedure as described above.
(a) 2S-1-(3-Acetylthio-2S-methylpropanoyl)-4-oxoproline from the salt of Example 5(a).
Optical rotation: [(t]24= -72.8- (c=1.82, methanol).
NMR: h=5.20-4.90(1H), 3.32-2.90(2H), 3.3-2.615H). 2.34(3H.s), 1.23 (3H.d. J=7.0 Hz).
MS: m e=273(M-).
EXAMPLE 7 3-(3-Mercap to-2S-m eth ylpropano yl)-2-oxazolid one-4S-carboxylic acid tert-butyl ester Under an atomosphere of argon. a solution of 349 mg of the acetylthio compound [prepared as described in Example 1(b)] in 5 ml of acetonitrile was stirred with 85 mg of 2-mercaptoethylamine at room temperature for 4 hours, and concentrated under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (5:1) as eluentto give 221 mg of the title compound.
NMR: (5=4.9-4.1(3H), 4.1 -3.6(1H), 3.15-2.15(1H). 1.40(9H,s), 1.25 (3H,d, 5=7 Hz).
MS: m e=289IM).
The following compounds were prepared from the corresponding acetylthio compounds by the same procedure as described above.
(a) 3-(3-Mercapto-2S-methylpropanoyi)-2-oxothiazolidine-4R-carboxylic acid tert-butyl ester from the acetylthio compound of Example 1(c).
NMR: b=4.95(1 H,dd, J=9 and 2 Hz), 3.9-2.2(5H,m), 1.40(9H,s), 1.20 (3H.d, J=8 Hz).
MS: me=305(M-).
(b) 3- (3-Mercapto-2S-methyI propanoyl)-5S-methyl-2-oxazolidone-4S-carboxylic acid tert-butyl ester from the acetylthio compound of Example 1(e).
NMR: 6=4.8-4.3(2H,m), 4.2-3.6(1H,m). 3.3-2.0(2H,m), 1.8-1.2(15H,m).
MS: me=303(M-).
EXAMPLE 8 2S- 1-(3-Mercapto-2RS-methylpropanoyl)pyroglutamic acid Under an atmosphere of nitrogen, a solution of 315 mg of the acetylthio compound (prepared as described in Example 4) in 3 ml of tetrahydrofuran was stirred with 0.29 ml of 300, aqueous ammonia at room temperature for 30 minutes. The reaction mixture was acidified with acetic acid. extracted with ehtyl acetate, and the extract was dried over anhydrous sodium sulphate, and then concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel using a mixture of chloroform, tetrahydrofuran and acetic acid (20:2:1) as eluent to give 163 mg of the title compound.
Optical rotation: [a]020 -61.5- (c=1.18, methanol).
IR(KBrtablet): v=1745, 1690cm1.
NMR: h=9.55(1H), 4.95-4.70(1H), 4.05-3.70(1H), 3.1 -2.0(6H), 1.65-1.40(1H). 1.25(3H.d).
MS: me=231(M-).
The following compounds were prepared from the corresponding acetylthio compounds by the same procedure as described above.
(a) 2S-1-(3-Mercapto-2S-methylpropanoyl)pyroglutamic acid from the acetylthio compound of Example 6.
Optical rotation: [&alpha;]D20= -113.6" (c=0.550, methanol).
IR: v=1750,1695 cm-1.
NMR: h=8.78(1H),4.83(1 H,dd, J =8.5 and 4Hz), 4.10-3.70(1H,m), 3.0-2.0 (6H), 1.52(1 H,t, J=9.0 Hz), 1.24(3H,d, J=6.5 Hz).
MS: m/e=231(M+).
(b) 2S-1 -(2-mercaptomethyl-3-mercaptopropanoyl)pyroglutamic acid from the acetylthio compound of Example 4(a).
Optical rotation: [a]o27= -60.3 (c=1.700, methanol).
IR: v=3200, 2550, 1740, 1690cm1.
NMR: #=9.29(1H,bs),4.85(1 H,dd, J=9 and 4Hz), 4.06(1 H,q, J=6.5 Hz),3.4-2.0(8H,m),1.57(1H,5, J=9 Hz), 1.53(1H,t,J=9 Hz).
MS: m/e=263(M+).
(c) 2S-1-(3-Mercapto-2S-methylpropanoyl)-4-oxoproline from the acetylthio compound of Example 6(a).
Optical rotation: [&alpha;]23D= -47.0 (c=0.706, methanol.
IR: v=1770, 1690, 1640 cmi'.
MS: m'e=231(M).
(d) 1-(3-Mercapto-2S-methylpropanoyl)-3-tert-butyl-2-oxoimidazolidine-5S-carboxylic acid from the acetylthio compound of Example 4(f).
Optical rotation: [&alpha;]D22= -85.8" (c=1.900, methanol).
Melting point: 124-125 C.
IR(KBrtablet): #=3600-2400, 1740, 1670 cm-1.
NMR: b=9.2-9.0(1 H,bs),4.9-4.6(1 H,m) 4.2-3.4(3H,m), 3.1-2.4(2H,m), 1.43(9H,s), 1.25(3H,d, J=7 Hz).
MS: mle=288(M).
EXAMPLE 9 The following compounds were prepared from the corresponding acetylthio compounds by the same procedure as described in Example 7.
(a) 3-(3-Mercapto-2S-methylpropanoyl)-2-oxazolidone-4S-carboxylic acid from the actylthio compound of Example 4(b).
Optical rotation: [a]027= -154.4 (c=0.580, methanol).
Melting point: 101-102"c.
IR(KBrtablet): v=3500-3000, 2700, 1800, 1740, 1690 cm~1.
NMR(CD3OD solution): b=4.97(1 H,dd, J=9 and 4Hz), 4.64(1 H,t, J=9 Hz), 4.39(1 H,dd, J=9 and 4Hz), 4.1-3.7(1H,m), H,m),3.0-2.4(3H,m),1.27(3H,d, J=6.5 Hz).
MS: mie=233(M).
(b) 3-(3-Mercapto-2S-methylpropanoyl)-2-oxothiazolidine-4R-carboxylic acid from the acetylthio compound of Example 4(c).
Optical rotation: [&alpha;]D26= -191.8 (c=1.000, methanol).
IR: v=3200, 2550, 1740, 1680 cm-.
NMR: h=9.58(1H,bs). 5.00(1 H,dd, J=9 and 2Hz), 4.0-3.3(3H,m), 3.05-2.40 (2H,m), 1.03(1H,t, J=9 Hz), 1.25(3H,d, J=8 Hz).
MS: m/e=249(M+).
(c) 1 -(3-Mercapto-2S-methylpropanoyl)-2-piperidone-6RS-carboxylic acid from the acetylthio compound of Example 4(d).
Optical rotation: [&alpha;]D28= -44.4 (c=0.73, methanol).
IR: v=3600-2400, 1720-1680, 1450, 1370 cm-1.
NMR: 6=8.87(lH,s), 5.20-4.85(1 H,m), 4.20-3.60(1 H,m), 1.60-1.34(1 H,m), 1.35-1.20(3H,m).
MS: mle=245(M).
(d) 1 -(3-Mercapto-2S-methylpropanoyl)-2-oxoimidazolidine-5RS-carboxylic acid from the acetylthio compound of Example 4(e).
Optical rotation: [&alpha;]D24 -45.69- (c=0.51, methanol).
IR: v=3600-2300, 1740, 1690, 1410 cam-.
NMR(CD30D solution): a=4.95-4.70(1H,bs),4.0-3.3(3H,m),3.2-2.5(2H,m),1.28 and 1.25(3H,dd, J=7 Hz).
MS: m/e=217(M).
EXAMPLE 10 3- (3-Mercap to-2S-meth ylpropano yl-2-oxazolidone-4S-carboxylic acid Under an atmosphere of argon, a solution of 289 mg of the ester compound (prepared as described in Example 7) in 2 ml of anisole was stirred with 310 mg of ethanethiol and 4 ml of trifluoroacetic acid at room temperature for one hour. After concentration under reduced pressure, the residue was purified by column chromatography on silica gel using a mixture of chloroform, tetrahydrofuran and acetic acid (100:10:1) as eluentto give 114 mg of the title compound.
The data of optical rotation, melting point, IF, NMR and MS were the same as the product of Example 9(a).
The following compounds were prepared from the corresponding ester compounds by the same procedure as described above.
(a) 3-(3-Mercapto-2S-methylpropanoyl)-2-oxothiazolidine-4R-carboxylic acid from the ester compound of Example 7(a).
The data of optical rotation, IR, NMR and MS were the same as the product of Example 9(b).
(b) 3- (3-Mercapto-2S-methylpropanoyl)-5S-methyl-2-oxazolidone-4S-carboxylic acid from the ester compound of Example 7(b).
Optical rotation: [(t]D6= -72.6" (c=1.00, methanol).
IR: v=3200, 2600, 1790, 1700 cm-'.
NMR: 6=7.8(2H,s), 4.8-4.5(2H,m), 4.1-3.75(1 H,bs), 3.1 -2.3(2H,m), 1.60 (3H,d, J=6 Hz), 1.57(1 H,t, J=8.5 Hz), 1.29(2H,d, J=8 Hz).
MS: m/e=247(M+).
EXAMPLE 11 25 3-Mercapto-25-methylpropanoylJ-40xoproline dicyciohexylamine salt) To a solution of 5.04 9 of the oxoproline compound [prepared as described in Example 8(c)] in 20 ml of acetone was added 4.38 ml of dicyclohexylamine with cooling in an ice bath. The crystalline precipitate was filtered off, washed with a mixture of ethyl acetate and acetonitrile (1:1), and dried in vacuo to give 4.83 g of the title compound.
Optical rotation: kt]D4= -9.27" (c=0.928, methanol).
Melting point: 171 175CC (decomposed).
EXAMPLE 12 Preparation of tablets One thousand tablets were prepared from following compounds in manner described below, each tablet containing 100 mg of 2S-1 -(3-mercapto-2S-methylpropanoyl)pyroglutamic acid.
25-1 -(3-mercapto-2S-methylpropanoyl)pyrog lutamic acid 100 g corn starch 50 g gelatin 7.5g avicel 25g magnesium stearate 2.5 9 2S-1-(3-Mercapto-2S-methylpropanoyl)pyroglutamic acid, corn atarch and an aqueous gelatin solution were mixed, dried, and ground to microfine powders. The powders were admixed with avicel and granular magnesium stearate, compressed to 1000 tablets, each tablet containing 100 mg of the active substance.
By proceeding as described above, but replacing the 2S-1 -(3-mercapto-2S-methylpropanoyl )pyroglutamic acid by 2S-1 -(3-mercapto-2Sl-methylpropanoyl)-4-oxoproline, 3-(3-mercapto-2S-methylpropanoyl)-2- oxazolidone-4S-carboxylic acid, 3-(3-mercapto-2S-methylpropanoyl )-2-oxothiazolidine-4R-carboxylic acid or 1 -(3-mercapto-2S-methyl propanoyl)-3-tert-butyl-2-oxoimidazolidine-5S-carboxylic acid, there were obtained one thousand tablets, respectively, each tablet containing 100 mg of the active ingredient.

Claims (67)

1. An oxoamino acid derivative ofthe general formula:
[wherein A represents a single bond, or a methylene (i.e. -CH2-), ethylene (i.e. -CH2CH2-), or methylmethylene (i.e. CHCH3) group, B represents a single bond, or a methylene group, X represents a methylene group, or an oxygen or sulphur atom, or a group NRo (in which Ro represents a hydrogen atom, or a lower alkyl group, or a tetrahydropyran-2-yl group), R represents a hydrogen atom, or a lower alkyl group, R' represents a hydrogen atom, or a lower alkanoyl group, or a benzoyl group, and R2 represents a hydrogen atom, or a lower alkyl group unsubstituted or substituted by one group -SR1 (in which R1 is as hereinbefore defined), with the proviso that the ring is a 5-or 6-membered ring, and with the proviso that, when F2 represents a lower alkyl group substituted by one group -SR1, both R, are the same), and, when R represents a hydrogen atom, a non-toxic salt thereof.
2. An oxoamino acid derivative according to claim 1 wherein A represents a methylene group, B represents a single bond, X represents a methylene group, R2 represents a hydrogen atom, or a lower alkyl group, and R and R, are as defined in claim land, when R represents a hydrogen atom, a non-toxic salt thereof.
3. An oxoamino acid derivative according to claim 1 wherein A represents a single bond, B represents a methylene group, X represents a methylene group, R2 represents a hydrogen atom, or a lower alkyl group, and R and R1 are as defined in claim 1, ad, when R represents a hydrogen atom, a non-toxic salt thereof.
4. An oxoamino acid derivative according to claim 1 wherein A represents a methylene group, B represents a single bond, X represents an oxygen atom, R2 represents a hydrogen atom, or a lower alkyl group, and Rand R, are as defined in claim 1, and, when R represents a hydrogen atom, a non-toxic salt thereof.
5. An oxoamino acid derivative according to claim 1 wherein A represents a methylene group, B represents a single bond, X represents a sulphur atom, R2 represents a hydrogen atom, or a lower alkyl group, and Rand R1 are as defined in claim 1, and, when R represents a hydrogen atom, a non-toxic salt thereof.
6. An oxoamino acid derivative according to claim 1 wherein the ring is a group of the formula:
(wherein R7 is a hydrogen atom or a lower alkyl group)
7. An oxoamino acid derivative according to claim 1 or 6 wherein the ring is a group of formula A1, A7, AS,, A8 or A7 depicted in claim 6.
8. An oxoamino acid derivative according to claim 1, 6 or7 wherein R-( represents a hydrogen atom, or a tert-butyl group.
9. An oxoamino acid derivative according to claim 1, 6,7 or 8 wherein R7 represents a methyl, ethyl, acetylthiomethyl or mercaptomethyl group, and R1 represents a hydrogen atom, or an acetyl group.
10. An oxoamino acid derivative according to any one of the preceding claims wherein R7 represents a methyl group.
11. An oxoamino acid derivative according to any one of the preceding claims wherein R1 represents a hydrogen atom, or an acetyl group.
12. An oxoamino acid derivative according to any one ofthe preceding claims wherein R1 represents a hydrogen atom.
13. An oxoamino acid derivative according to any one of the preceding claims wherein R represents a hydrogen atom, or a tert-butyl group.
14. An oxoamino acid derivative according to any one of the preceding claims wherein R represents a hydrogen atom.
15. An oxoamino acid derivative according to any one of the preceding claims wherein the carbon atom attached to the group Rg is in S-configuration.
16. An oxoamino acid derivative according to any one of the preceding claims wherein the cyclicamino acid is in L-form.
17. 2S-1-(3-Acetylthio-2RS-methylpropanoyl)-4-oxoproline.
18. 2S-1-(3-Acetylthio-2RS-methylpropanoyl)pyroglutamic acid.
19. 2S-1 -(2-Acetylthiomethyl-3-acetylthiopropano )pyroglutamic acid.
20. 3-(3-Acetylthio-2S-methylpropanoyl)-2-oxazolidone-4S-carboxylic acid.
21. 3-(3-Acetylthio-2S-methylpropanoyl)-2-oxothiazolidine-4R-carboxylic acid.
22. 1 -l3-Acetylthio-2S-methylpropa noyl l-2-piperidone-6RS-carboxylic acid.
23. 1-(3-Acetylthio-2S-methylpropanoyl)-2-oxoimidazolidine-5RS-carboxylic acid.
24. 1-(3-Acetylthio-2S-methylpropanoyl)-3-tert-butyl-2-oXo-imidazolidine-5S-carboxylic acid.
25. 2S-1 -(3-Acetylthio-2S-methyl propanoyl)pyrog I utamic acid.
26. 2S-1 -(3-Acetylthio-2S-methyl propanoyl)-4-oxoproline.
27. 2S-1 -(3-Mercapto-2RS-methylpropanoyl)pyroglutamic acid.
28. 2S-1 -(3-Mercapto-2S-methylpropanoyl )pyroglutamic acid.
29. 2S-1 -(2-Mercaptomethyl-3-mercaptopropanoyl)pyroglutamic acid.
30. 2S-1-(3-Mercapto-2S-methylpropanoyl}-4-oxoproline.
31. 1 -(3-Mercapto-2S-methylpropanoyl )-3-tert-butyl-2-oxo-imidazol idine-5S-carboxylic acid.
32. 3-(3-Mercapto-2S-methylpropa noyl )-2-oxazolidone-4S-carboxylic acid.
33. 3-(3-Mercapto-2S-methylpropanoyl )-2-oxothiazolidine-4R-carboxylic acid.
34. 1 -(3-Mercapto-2S-methylpropanoyl )-2-piperidone-6RS-carboxylic acid.
35. 1 -(3-Mercapto-2S-methylpropanoyl )-2-oxoimidazolidine-5RS-carboxylic acid.
36. 3-(3-Mercapto-2S-methyl propanoyl )-5S-methyi-2-oxazol idone-4S-carboxyl ic acid.
37. 2S-1 -(3-Acetylthio-2RS-methyl propanoyl)pyroglutamic acid tert-butyl ester.
38. 2S-1 -(2-Acetylthiomethyl-3-acetylthiopropanoyl)pyroglutamic acid tert-butyl ester.
39. 3-(3-Acetylthio-2S-methyl propanoyl )-2-oxazolidone-4S-carboxyl ic acid tert-butyl ester.
40. 3-(3-Acetylthio-2S-methylpropanoyl)-2-oxothiazolidine-4R-carboxylic acid tert-butyl ester.
41. 1 -(3-Acetylthio-2S-methyl propanoyl )-2-piperidone-6RS-carboxylic acid tert-butyl ester.
42. 3-(3-Acetylthio-2S-methyl propa noyl)-5S-methyl-2-oxazolidone-4S-carboxylic acid tert-butyl ester.
43. 1 -(3-Acetylthio-2S-methylpropa noyl)-3-tert-butyl-2-oxoimidazol idene-55-carboxylic acid tert-butyl ester.
44. 1 -(3-Acetylthio-2S-methylpropanoyl )-3-(tetrahydropyran-2-yl )-2-oxoim idazol idi ne-5RS-carboxylic acid tert-butyl ester.
45. 3-(3-Mercapto-2S-methylpropanoyl)-2-oxazolidone-4S-carboxylic acid tert-butyl ester.
46. 3-(3-Mercapto-2S-methyl propa noyl )-2-oxothiazol idine-4R-carboxyl ic acid tert-butyl ester.
47. 3-(3-Mercapto-2S-methylpropanoyl )-5S-methyl-2-oxazolidone-4S-carboxyl ic acid tert-butyl ester.
48. A non-toxic salt of an oxoamino acid derivative as claimed in any one of claims 1 to 36.
49. A process for the preparation of an oxoamino acid derivative of the general formula:
[wherein R3 represents a lower alkanoyl group, or a benzoyl group, R4 represents a hydrogen atom, or a lower alkyl group unsubstituted or substituted by one group -SR3 (in which F3 is as hereinbefore defined), X1 represents a methylene group, or an oxygen or sulphur atom, or a group NR8 (in which Rg represents a lower alkyl group, or a tetrahydropyran-2-yl group), and the other symbols are as defined in claim 1], which comprises the reaction of a compound of the general formula:
(wherein X1 is as hereinbefore defined, and the other symbols are as defined in claim 1 (with an activated derivative of a compound of the general formula: : R4 R3-S-CH2-CH-COOH (Ill) (wherein R3 and R4 are as hereinbefore defined) in the presence of a base.
50. A process according to claim 49 in which the base is an alkali metal hydroxide, carbonate or hydride, ortriethylamine or pyridine.
51. A process for the preparation of an oxoamino acid derivative of the general formula:
(wherein R6 represents a hydrogen atom, or a lower alkyt group unsubstituted or substituted by one group -SH, X1 is as defined in claim 49, and the other symbols are as defined in claim 1), which comprises the hydrolysis of a compound of general formula lAdepicted-in claim 49 under basic conditions.
52. A process according to claim 51 in which the hydrolysis under basic conditions is carried out in the presence of an alkali metal hydroxide or carbonate, or ammonia, or hydrazine, 2-mercapto-ethylamine or ethanolamine.
53. A process for the preparation of an oxoamino acid derivative of the general formula:
[wherein X2 represents a methylene group, or an oxygen or sulphur atom, or a group NR7 (in which R7 represents a hydrogen atom, or a lower alkyl group), and the other symbols are as defined in claim 1], which comprises the reaction of a compound of the general formula:
(wherein F8 represents a lower alkyl group, X1 is as defined in claim 49, and the other symbols are as defined in claim 1) under acidic conditions.
54. A process according to claim 53 in which F8 represents a tert-butyl group.
55. A process according to claim 53 or 54 in which the reaction under acidic conditions is carried out by using hydrochloric acid, hydrobromic acid, perchloric acid, trifluoroacetic acid, trifluoromethanesulphonic acid orp-toluenesulphonic acid.
56. A process for the preparation of an oxoamino acid derivative of general formula I depicted in claim 1, wherein the various symbols are as defined in claim 1, which comprises the oxidation of a compound of the general formula:
(wherein the various symbols are as defined in claim 1).
57. A process for the preparation of an oxoamino acid derivative of general formula I depicted in claim 1, wherein R represents a lower alkyl group, which comprises the esterification by methods known perse of a corresponding oxoamino acid derivative, wherein R represents a hydrogen atom.
58. A process according to any one of claims 49 to 56 followed by the step of converting by methods known perse a resulting oxoamino acid derivative of general formula I, wherein R represents a hydrogen atom, and the other symbols are as defined in claim 1, into a non-toxic salt thereof.
59. A process for the preparation of an oxoamino acid derivative of general formula I substantially as hereinbefore described.
60. A process for the preparation of an oxoamino acid derivative of general formula I substantially as hereinbefore described in any one of Examples 1 to 5 and 7 to 11.
61. An oxoamino acid derivative of general formula I and, when R represents a hydrogen atom, a non-toxic salt thereof, when prepared by the process claimed in any one of claims 49 to 60.
62. A pharmaceutical composition, which comprises as active ingredient, at least one oxoamino acid derivative as claimed in any one of claims 1 to 47 and 61, or, when R represents a hydrogen atom, a non-toxic salt thereof, in association with a pharmaceutical carrier or coating.
63. A pharmaceutical composition according to claim 62, which comprises, as active ingredient, at least one oxoamino acid derivative as claimed in any one of claims 17 to 47, or a non-toxic salt of an oxoamino acid derivative claimed in any one of claims 17 to 36, in association with a pharmaceutical carrier or coating.
64. A pharmaceutical composition according to claim 62 or 63 substantially as hereinbefore described.
65. A pharmaceutical composition according to claim 62 or 63 substantially as hereinbefore described in Example 12.
66. An axoamino acid derivative or a non-toxic salt thereof, as claimed in any one of claims 1 to 48 and 61 for use in the treatment of hypertension.
67. A daily dose for pareteral administration to a human adult comprising 0.05 to 50 mg/kg body weight of an oxoamino acid derivative or non-toxic salt thereof, as claimed in any one of claims 1 to 48 and 61.
GB8014359A 1979-05-04 1980-05-01 Oxoamino acid derivatives Expired GB2051781B (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP5423979A JPS55147257A (en) 1979-05-04 1979-05-04 Pyroglutamic acid derivative, its preparation and pharmaceutical composition containing it as effective component
JP9320579A JPS5618959A (en) 1979-07-24 1979-07-24 4-oxoproline derivative, its preparation, and pharmaceutical composition containing the same
JP9489079A JPS5620579A (en) 1979-07-27 1979-07-27 2-oxazolidone-4-carboxylic acid derivative, its preparation, and drug composition comprising the same as active constituent
JP12882679A JPS5653670A (en) 1979-10-08 1979-10-08 2-oxothiazolidine-4-carboxylic acid derivative, its preparation, and pharmaceutical composition containing said compound as effective component

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GB2051781B GB2051781B (en) 1983-03-09

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US4816466A (en) * 1984-12-21 1989-03-28 Takeda Chemical Industries, Ltd. Piperidine derivatives

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JPS5788165A (en) * 1980-11-21 1982-06-01 Tanabe Seiyaku Co Ltd 2-oxoimidazolidine-4-carboxylic acid derivative and its preparation

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US4046889A (en) * 1976-02-13 1977-09-06 E. R. Squibb & Sons, Inc. Azetidine-2-carboxylic acid derivatives
US4129566A (en) * 1978-02-15 1978-12-12 E. R. Squibb & Sons, Inc. Derivatives of dehydrocyclicimino acids
CA1132985A (en) * 1978-12-22 1982-10-05 John Krapcho Ketal and thioketal derivatives of mercaptoacyl prolines

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Publication number Priority date Publication date Assignee Title
US4816466A (en) * 1984-12-21 1989-03-28 Takeda Chemical Industries, Ltd. Piperidine derivatives
US4954625A (en) * 1984-12-21 1990-09-04 Takeda Chemical Industries, Ltd. Piperidine derivatives, their production and use

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