Claims
- 1. A method of inhibiting the activity of enkephalinase and angiotensin convertase enzymes which comprises adding thereto an effective amount of an amino acid derivative corresponding to the general formula: ##STR52## wherein for the formula (Ia) R.sub.1 represents a biphenyl group or one of the following groups, ##STR53## wherein Z, X and n have the meanings defined below:
- ______________________________________Z Y n______________________________________O O 1O CH.sub.2 1CH.sub.2 CH.sub.2 1O O 2CH.sub.2 CH.sub.2 2or ##STR54##______________________________________
- wherein for the formula (Ib) R.sub.1 has the meaning defined herein above and can also be a phenyl group;
- wherein R'.sub.1 represents a hydrogen atom, a lower alkyl group, a phenyl group, a lower phenylalkylene group;
- R.sub.2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenylalkylene group, a lower hydroxyphenylalkylene group, a lower aminoalkylene group, a lower guanidinoalkylene group, a lower mercaptoalkylene group, a lower alkythio lower alkylene group, a lower imidazolylalkylene group, a lower indolyalkylene group, a lower carbamylalkylene group, a lower carboxylalkylene or one of the following groups: ##STR55## wherein Z', Y' and n have meanings defined below:
- ______________________________________Z' Y' n______________________________________O O 1O O 2O CH.sub.2 1CH.sub.2 CH.sub.2 1CH.sub.2 CH.sub.2 2______________________________________
- X designates the group responsible for chelating the zinc atom of the enzymes (enkephalinase and ACE) selected from the group consisting of a mercaptomethyl, hydroxamic acid, an N-carboxylalkyl of the formula ##STR56## wherein R.sub.3 represents a benzyl lower alkyl radical or lower alkoxy radical, or phosphorated derivatives of formula ##STR57##
- 2. A method of inhibiting the activity of enkephalinase and angiotensin convertase enzymes which comprises adding thereto an effective amount of an amino acid derivative corresponding to the general formula: ##STR58## wherein ##STR59## wherein Z and Y are O and n=1 or 2 R.sub.2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenylalkylene group, a lower hydroxyphenylalkylene group, a lower aminoalkylene group, a lower guanidinoalkylene group, a lower mercaptoalkylene group, a lower alkythio lower alkylene group, a lower imidazolylalkylene group, a lower indolyalkylene group, a lower carbamylalkylene group, a lower carboxylalkylene group or one of the following groups: ##STR60## wherein Z', Y' and n have the meanings defined below:
- ______________________________________Z' Y' n______________________________________O O 1O O 2O CH.sub.2 1CH.sub.2 CH.sub.2 1CH.sub.2 CH.sub.2 2______________________________________
- X designates the group responsible for chelating the zinc atom of the enzymes (enkephalinase and ACE) selected from the group consisting of a mercaptomethyl, hydroxamic acid, an N-carboxylalkyl of the formula ##STR61## wherein R.sub.3 represents a benzyl lower alkyl radical or lower alkoxy radical, or phosphorated derivatives of formula ##STR62##
- 3. A method according to claim 1 or 2, wherein the amino acid derivative is such as X represents the mercaptomethyl group.
- 4. A method according to claim 1, wherein the amino acid derivative is selected from the group consisting of:
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!glycine or its optically pure forms,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-alanine or its optically pure forms,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-2-aminobutyric acid,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-norvaline,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-norleucine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-leucine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-tryptophan,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-phenylalanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-tyrosine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-serine
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-methionine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(RS)-3-(3,methylenedioxy phenyl)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-ethylenedioxy phenyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-ethylenedioxy phenyl)propyl!-(S)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-phenoxy phenyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-phenoxy phenyl)propyl!-(S)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-phenyl phenyl)propyl!-glycine or its optically pure forms,
- N-(R)-�1-oxo-2-(mercaptomethyl)-3-(4-phenyl phenyl)propyl)!-(S)-alanine or its optically pure forms,
- N-(R)-�1-oxo-2-(mercaptomethyl)-3-(4-phenyl phenyl propyl!-(S)-leucine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(5'-indanyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(5'-indanyl) propyl!-(S)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3,(2'-3'-dihydro-5'-benzofuranyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-methoxy phenyl)propyl!-(S)-alanine,
- N-(S)-�1-oxo-2-(mercaptomethyl)-3-(4-methoxy phenyl)propyl!-glycine,
- N-(S)-�1-oxo-2-(mercaptomethyl)-3-(4-methoxy phenyl)propyl!-(S)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-ethoxy phenyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-ethoxy phenyl)propyl!-(S)-alanine,
- N-(E)-�1-oxo-2-(mercaptomethyl)-2-ene-3-phenyl propyl!-(S)-alanine,
- N-(E)-�1-oxo-2-(mercaptomethyl)-2-ene-3-phenyl propyl!-(S)-norvaline,
- N-(E)-�1-oxo-2-(mercaptomethyl)-2-ene-3-phenyl propyl!-(RS)-3,(3,4-methylenedioxy phenyl)-alanine,
- N-(Z)-�1-oxo-2-(mercaptomethyl)-2-ene-3-(3,4-methylenedioxy phenyl) propyl!-glycine,
- N-(N-(RS)-(1-carboxy pentyl)-(RS)-3-(3,4-methylenedioxy phenyl)alanyl!-glycine hydrochloride,
- N-(N-(RS)-(1-carboxy-2-phenyl ethyl)-(S)-phenylalanyl!-glycine hydrochloride,
- N-(N-(RS)-(1-carboxy-2-phenyl ethyl)-(RS)-3-(3,4-methylenedioxy phenyl)alanyl!-glycine hydrochloride,
- N-(RS)-�2-dihydroxyphosphinyl)-methyl-1 -oxo-3-(3,4-methylenedioxy,
- N-(RS)-�2-dihyroxyphosphinyl)-methyl-1-oxo-3-(3,4-methylenedioxy phenyl)propyl!(S)-alanine or its calcium monosalt.
- 5. A composition acting as mixed inhibitor of the enkephalinase and ACE enzymes which comprises an effective amount of an amino acid derivative corresponding to the general formula: ##STR63## wherein for the formula (Ia) R.sub.1 represents a biphenyl group or one of the following groups, ##STR64## wherein Z, Y and n have the meanings defined below:
- ______________________________________Z Y n______________________________________O O 1O CH.sub.2 1CH.sub.2 CH.sub.2 1O O 2CH.sub.2 CH.sub.2 2or ##STR65##______________________________________
- wherein for the formula (Ib) R.sub.1 has the meaning defined herein above and can also be a phenyl group;
- wherein R'.sub.1 represents a hydrogen atom, a lower alkyl group, a phenyl group, a lower phenyalkylene group;
- R.sub.2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenylalkylene group, a lower hydroxyphenylalkylene group, a lower aminoalkylene group, a lower guanidinoalkylene group, a lower mercaptoalkylene group, a lower alkythio lower alkylene group, a lower imidazolylalkylene group, a lower indolyalkylene group, a lower carbamylalkylene group, a lower carboxylalkylene group or one of the following groups: ##STR66## wherein Z', Y' and n meanings defined below:
- ______________________________________Z' Y' n______________________________________O O 1O O 2O CH.sub.2 1CH.sub.2 CH.sub.2 1CH.sub.2 CH.sub.2 2______________________________________
- X designates the group responsible for chelating the zinc atom of the enzymes (enkephalinase and ACE) selected from the group consisting of a mercaptomethyl, hydroxamic acid, an N-carboxylalkyl of the formula ##STR67## wherein R.sub.3 represents a benzyl lower alkyl radical or lower alkoxy radical phosphorated derivatives of formula ##STR68## provided that when in the formula (Ia) X is mercaptomethyl, hydroxamic acid or phosphorated derivatives of the formula given above and R.sub.2 is as defined above, R.sub.1 cannot be a phenyl group substituted by a hydroxyl radical,
- provided that when in the formula (Ia) X is mercaptomethyl and R.sub.2 is a lower alkylthio lower alkylene, R.sub.1 cannot be a phenyl group substituted by a lower alkoxy radical, a phenoxyphenyl group or a biphenyl group,
- provided that when in the formula (Ia) X is a hydroxamic acid group and R.sub.2 is a hydrogen atom, a lower alkyl group and a lower alkylthio lower alkylene group, R.sub.1 cannot be a phenyl group substituted by a lower alkoxy
- provided that when in the formula (Ib) X is a hydroxamic acid group or a phosphorated derivative of formula ##STR69## R.sub.2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenylalkylene group, a lower hydroxyphenylalkylene group, a lower mercaptoalkylene group, a lower alkylthio alkylene group and a lower imidazolylalkylene group, R.sub.1 cannot be a phenyl group or a phenyl substituted by a hydroxy radical.
- 6. A composition acting as mixed inhibitor of the enkephalinase and angiotensin convertase enzymes which comprises an effective amount of an amino acid derivative corresponding to the general formula: ##STR70## wherein ##STR71## wherein Z and Y are O and n=1 or 2 R.sub.2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenylalkylene group, a lower hydroxyphenylalkylene group, a lower aminoalkylene group, a lower guanidinoalkylene group, a lower mercaptoalkylene group, a lower imidazolylalkylene group, a lower indolyalkylene group, a lower carboxylalkylene group ##STR72## wherein Z', Y' and n have the meanings defined below:
- ______________________________________Z' Y' n______________________________________O O 1O O 2O CH.sub.2 1CH.sub.2 CH.sub.2 1CH.sub.2 CH.sub.2 2______________________________________
- X designates the group responsible for chelating the zinc atom of the enzymes (enkephalinase and ACE) selected from the group consisting of a mercaptomethyl, hydroxamic acid, an N-carboxylalkyl of the formula ##STR73## wherein R.sub.3 represents a benzyl lower alkyl radical or lower alkoxy radical, or phoshorated derivatives of formula ##STR74##
- 7. A composition according to claim 5 or 6, wherein the amino acid derivative is such as X represents the mercaptomethyl group.
- 8. A composition according to claim 5, wherein the amino acid derivative is selected from the group consisting of:
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!glycine or its optically pure forms,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-alanine or its pure forms,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-2-amino-butyric acid,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(5'-indanyl) propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(5'-indanyl) propyl!-(S)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(2',3'-dihydro-5'-benzofuranyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(2',3'-dihydro-5'-benzofuranyl), propyl!-(S)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-methoxy phenyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-methoxy phenyl)propyl!-(S)-alanine,
- N-(S)-�1-oxo-2-(mercaptomethyl)-3-(4-methoxy phenyl)propyl!-glycine,
- N-(S)-�1-oxo-2-(mercaptomethyl)-3-(4-methoxy phenyl)propyl!-(S)-alanine,
- N-(RS)-1-oxo-2-(mercaptomethyl)-3-(4-ethoxy phenyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-ethoxy phenyl)propyl!-(S)-alanine,
- N-(E)-�1-oxo-2-(mercaptomethyl)-2-ene-3-phenyl propyl!-(S)-alanine,
- N-(E)-�1-oxo-2-(mercaptomethyl)-2-ene-3-phenyl propyl!-(S)-norvaline,
- N-(E)-�1-oxo-2-(mercaptomethyl)-2-ene-3-phenyl propyl!-(S)-norleucine,
- N-(E)-�1-oxo-2-(mercaptomethyl)-2-ene-3-phenyl propyl!-(RS)-3-(3,4-methylenedioxy phenyl)-alanine,
- N-(Z)-�1-oxo-2-(mercaptomethyl)-2-ene-3-(3,4-methylenedioxy phenyl)propyl!-glycine,
- N-�N-(RS)-(1-carboxy pentyl)-(RS)-3-(3,4-methylenedioxy phenyl)alanyl!-glycine hydrochloride,
- N-�N-(RS)-(1-carboxy-2-phenyl ethyl)-(S)-phenylalanyl)-glycine hydrochloride,
- N-�N-(RS)-(1-carboxy-2-phenyl ethyl)-(RS)-3-(3,4-methylenedioxy phenyl)alanyl)-glycine hydrochloride,
- N-(RS)-�2-(dihydroxyphosphinyl)-methyl-1-oxo-3-(3,4-methylenedioxy phenyl propyl-(S)-alanine or its calcium monosalt,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-norvaline,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-norleucine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-leucine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-tryptophan,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-phenylalanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-tyrosine,
- N-(S)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-serine
- N-(S)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(S)-methionine,
- N-(S)-�1-oxo-2-(mercaptomethyl)-3-(3,4-methylenedioxy phenyl)propyl!-(RS)-3,4-methylenedioxy phenyl)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-ethylenedioxy phenyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(3,4-ethylenedioxy phenyl) propyl!-(S)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(2,3-methylenedioxy phenyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-phenoxy phenyl)propyl!-glycine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-phenoy phenyl)propyl!-(S)-alanine,
- N-(RS)-�1-oxo-2-(mercaptomethyl)-3-(4-phenyl phenyl)propyl!-glycine or its optically pure forms,
- N-(R)-�1-oxo-2-(mercaptomethyl)-3-(4-phenyl phenyl)propyl!-(S)-alanine or its optically pure forms,
- N-(R)-�1-oxo-2-(mercaptomethyl)-3-(4-phenyl phenyl)propyl!-(S)-leucine,
- N-(RS)-�2-(dihydroxyphosphinyl)-methyl-1-oxo-3-(3,4-methylenedioxy phenyl)propyl!glycine or it calcium monosalt,
- N-(RS)-�2-(dihydroxyphosphinyl)-methyl-1-oxo-3-(4-phenyl phenyl)propyl!-(S)-alanine or its calcium monosalt,
- N-(RS)-�2-dihydroxyphosphinyl)-methyl-1-oxo-3-(4-phenyl phenyl)propyl!-glycine or its calcium monosalt.
Priority Claims (1)
Number |
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8912142 |
Sep 1989 |
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Parent Case Info
This is a division of application Ser. No. 08/462,590 filed Jun. 5, 1995; U.S. Pat. No. 5,670,531; which is a division of Ser. No. 08/422,652 filed Apr. 14, 1995 U.S. Pat. No. 5,599,951; which is a continuation of Ser. No. 08/103,156 filed Aug. 9, 1993 abandoned; which is a continuation of Ser. No. 07/689,238 filed Jun. 13, 1991 abandoned; which is a 35 U.S.C. .sctn. 371 continuation of PCT/FR 90/00659 filed Sep. 14, 1990. abandoned
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Divisions (2)
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Parent |
462590 |
Jun 1995 |
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Parent |
422652 |
Apr 1995 |
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Continuations (2)
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103156 |
Aug 1993 |
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Parent |
689238 |
Jun 1991 |
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