EP0075334A2
Expired / Lapsed
EP
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Pharmaceutical compounds, and preparation, formulations and use thereof
Assignee: Wellcome Foundation Ltd
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Filing: 1982-09-24
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Granted: —
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Expires: 2002-09-24
Abstract
Abstract Compounds of the general formula wheren Ph is a phenyl group which is optionally substituted by one or more substituents selected from halo (i.e. fluoro, chloro, bromo or iodo), C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, nitro, sulphonyl, aminosulphonyl, trihalomethyl, carboxy, C 1-4 alkoxycarbonyl, amido, C 1-4 alky(amido C 1-4 alkoxy, C 2-4 alkenyl, cyano, aminomethyl or methylsulphonyl; R' und R b , which may be the same or different, each represents a hydrogen or alkali metal (eg. sodium or lithium) atom or a C 1-4 (eg. ethyl) group; m is 0 or 1; Y is a group of formula: or a group of formula: where R' is hydrogen or methyl; R 2 is alkyl of 1 to 3 carbon atoms or is methylthiomethyl; and Z is -OR 3 or -NR 4 R s where R 3 , R 4 and R 5 are each hydrogen or alkyl of 1 to 4 carbon atoms (ie. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl) and R 3 can further be phenylalkyl having 1 to 3 carbon atoms in the alkylene moiety thereof, or phenyl; and basic salts thereof. These compounds have an advantageous enkephalinase inhibitor activity which renders the compounds useful in medical therapy, eg. to prolong and/or potentiate in a mammal, the effects of endogenous or exogenous enkephalins. The latter includes synthetic enkephalin analogues.
Inventors
- 👤 Samuel Wilkinson
- 👤 Roger Wrigglesworth
- 👤 George William Hardy
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-08 07:36
CPC Classifications
C; C07; C07F; C07F9/00; C07F9/02; C07F9/28; C07F9/38; C07F9/3804; C07F9/3808; C07F9/40; C07F9/4003; C07F9/4006
Claims Analysis
Total Claims: 18
Claim 1
Independent Claim
194 words
1) Compounds of the general formula wherein Ph is a phenyl group which is optionally substituted by one or more substituents selected from halo (ie. fluoro, chloro, bromo or iodo), C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, nitro, sulphonyl, aminosulphonyl, trihalomethyl, carboxy, C 1-4 alkoxycarbonyl, amido, C 1-4 alkylamido, C 1-4 alkoxy, C 2-4 alkenyl, cyano, aminomethyl or methylsulphonyl; R and R b , which may be the same or different, each represents a hydrogen or alkali metal atom such as sodium or lithium, or a C 1-4 alkyl group; m is 0 or 1; Y is a group of formula: or a group of formula: where R 1 is hydrogen or methyl; R 2 is alkyl of 1 to 3 carbon atoms or is methylthiomethyl; and Z is - OR 3 or - NR 4 R 5 where R 3 , R 4 and R 5 are each hydrogen or alkyl of I to 4 carbon atoms (ie. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl) and R 3 can further be phenylalkyl having 1 to 3 carbon atoms in the alkylene moiety thereof, or phenyl; and basic salts thereof.
Claim 2
Dependent Claim
194 words
1) Compounds of the general formula wherein Ph is a phenyl group which is optionally substituted by one or more substituents selected from halo (ie. fluoro, chloro, bromo or iodo), C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, nitro, sulphonyl, aminosulphonyl, trihalomethyl, carboxy, C 1-4 alkoxycarbonyl, amido, C 1-4 alkylamido, C 1-4 alkoxy, C 2-4 alkenyl, cyano, aminomethyl or methylsulphonyl; R and R b , which may be the same or different, each represents a hydrogen or alkali metal atom such as sodium or lithium, or a C 1-4 alkyl group; m is 0 or 1; Y is a group of formula: or a group of formula: where R 1 is hydrogen or methyl; R 2 is alkyl of 1 to 3 carbon atoms or is methylthiomethyl; and Z is - OR 3 or - NR 4 R 5 where R 3 , R 4 and R 5 are each hydrogen or alkyl of I to 4 carbon atoms (ie. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl) and R 3 can further be phenylalkyl having 1 to 3 carbon atoms in the alkylene moiety thereof, or phenyl; and basic salts thereof.
Claim 3
Dependent Claim
26 words
2) Compounds as claimed in claim 1, wherein Ph is unsubstituted phenyl or phenyl substituted by iso-propyl, methoxy, nitro or bromo (eg. in the 4 position).
Claim 4
Dependent Claim
23 words
3) Compounds as claimed in any of claims 1-3, wherein Y is a group of formula (in either the D- or L- configuration).
Claim 5
Dependent Claim
25 words
4) Compounds as claimed in any of claims 1 and 2, wherein Y is a group of formula (in either the D- or L- configuration).
Claim 6
Dependent Claim
18 words
5) Compounds as claimed in any of claims 1 and 2, wherein Y is a group of formula
Claim 7
Dependent Claim
28 words
6) Compounds as claimed in any of claims 1-5, wherein Z is -OR 3 , where R is an ethyl, methyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl group.
Claim 8
Dependent Claim
19 words
7) Compounds as claimed in any of claims 1-5, wherein Z is -OR 3 , where R is hydrogen.
Claim 9
Dependent Claim
88 words
8) A compound selectexd from:- N-[2-(dihydroxyphosphinyl)-3-(4-methoxyphenyl)propionyl]-L-leucine and basic salts thereof; either diastereoisomer (or a mixture in any proportion thereof) of N-[2-(dihydroxyphosphinyl)-3-phenylpropionyl]-L-leucine ethyl ester and basic salts thereof; either (or a mixture in any proportion thereof) of N-[2-(dihydroxyphosphinyl)-3-phenylpionyl]-L-leucine trilithium salt; N-[-3-(4-bromophenyl)-2-dihydroxyphosphinylpropionyl]-L-leucine and basic salts thereof; N-[3-(4-bromophenyl)-2-dihydroxyphosphinylpropionyl]-L-leucine monosodium salt; N-[2-dihydroxyphosphinyl-3-(4-isoprogylphenyl)propionyl]-L-leucine and basic salts thereof; N-[2-dihydroxyphosphinyl-3-(4-isoproxylphenyl)propionyll-L-leucine disodium salt; either diastereoisomer (or a mixture in any proportion thereof) of N-[2-benzyl-3-(dihydroxyphosphinyl)propionyl]-L-leucine ethyl ester, and basic salts thereof; and either diastereoisomer (or a mixture in any proportion thereof) of N-[2-benzyl-3-(dihydroxyphosphinyl)propionyl]leucine and basic salts thereof.
Claim 10
Dependent Claim
88 words
8) A compound selectexd from:- N-[2-(dihydroxyphosphinyl)-3-(4-methoxyphenyl)propionyl]-L-leucine and basic salts thereof; either diastereoisomer (or a mixture in any proportion thereof) of N-[2-(dihydroxyphosphinyl)-3-phenylpropionyl]-L-leucine ethyl ester and basic salts thereof; either (or a mixture in any proportion thereof) of N-[2-(dihydroxyphosphinyl)-3-phenylpionyl]-L-leucine trilithium salt; N-[-3-(4-bromophenyl)-2-dihydroxyphosphinylpropionyl]-L-leucine and basic salts thereof; N-[3-(4-bromophenyl)-2-dihydroxyphosphinylpropionyl]-L-leucine monosodium salt; N-[2-dihydroxyphosphinyl-3-(4-isoprogylphenyl)propionyl]-L-leucine and basic salts thereof; N-[2-dihydroxyphosphinyl-3-(4-isoproxylphenyl)propionyll-L-leucine disodium salt; either diastereoisomer (or a mixture in any proportion thereof) of N-[2-benzyl-3-(dihydroxyphosphinyl)propionyl]-L-leucine ethyl ester, and basic salts thereof; and either diastereoisomer (or a mixture in any proportion thereof) of N-[2-benzyl-3-(dihydroxyphosphinyl)propionyl]leucine and basic salts thereof.
Claim 11
Dependent Claim
139 words
9) A process for the preparation of compounds of formula (I)(as defined in claim 1) or a basic salt thereof, which comprises reacting a compound of formula wherein a b R a , R b , m and Ph are as defined in claim 1; Q is carboxy or a functional equivalent thereof; and Q 1 and Q 2 are both hydrogen or together form a bond) with a compound of formula (wherein Y is as defined in formula (I) and Z is a group Z as defined in formula (I) or a functionally protected derivative thereof) followed (when Q 1 and Q 2 together form a bond) by selective reduction of the said bond and, as appropriate, by deprotection of the product and conversion of the product into the compound of formula (I) or a basic salt thereof.
Claim 12
Dependent Claim
211 words
10) Pharmaceutical formulations comprising, as active ingredient, at least one compound of formula wherein Ph is a phenyl group which is optionally substituted by one or more substituents selected from halo (ie. fluoro, chloro, bromo or iodo), C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, nitro, sulphonyl, aminosulphonyl, trihalomethyl, carboxy, C 1-4 alkoxycarbonyl, amido, C l-4 alkylamido, C 1-4 alkoxy, C 2-4 alkenyl, cyano, aminomethyl or methylsulphonyl; R a and R b , which may be the same or different, each represents a hydrogen or alkali metal atom or a C 1-4 alkyl group; m is 0 or 1; Y is a group of formula: or a group of formula: where R is hydrogen or methyl; R 2 is alkyl of 1 to 3 carbon atoms or is methylthiomethyl; and Z is -OR 3 or -NR 4 R 5 where R , R 4 and R are each hydrogen or alkyl of 1 to 4 carbon atoms (ie. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl) and R 3 can further be phenylalkyl having 1 to 3 carbon atoms in the alkylene moiety thereof, or phenyl; and physiologically acceptable basic salts thereof, together with one or more pharmaceutically acceptable carriers therefor and, optionally, one or more other therapeutic ingredients.
Claim 13
Dependent Claim
211 words
10) Pharmaceutical formulations comprising, as active ingredient, at least one compound of formula wherein Ph is a phenyl group which is optionally substituted by one or more substituents selected from halo (ie. fluoro, chloro, bromo or iodo), C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, nitro, sulphonyl, aminosulphonyl, trihalomethyl, carboxy, C 1-4 alkoxycarbonyl, amido, C l-4 alkylamido, C 1-4 alkoxy, C 2-4 alkenyl, cyano, aminomethyl or methylsulphonyl; R a and R b , which may be the same or different, each represents a hydrogen or alkali metal atom or a C 1-4 alkyl group; m is 0 or 1; Y is a group of formula: or a group of formula: where R is hydrogen or methyl; R 2 is alkyl of 1 to 3 carbon atoms or is methylthiomethyl; and Z is -OR 3 or -NR 4 R 5 where R , R 4 and R are each hydrogen or alkyl of 1 to 4 carbon atoms (ie. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl) and R 3 can further be phenylalkyl having 1 to 3 carbon atoms in the alkylene moiety thereof, or phenyl; and physiologically acceptable basic salts thereof, together with one or more pharmaceutically acceptable carriers therefor and, optionally, one or more other therapeutic ingredients.
Claim 14
Dependent Claim
30 words
(1) Compound of Formula (I), as defined in claim 1, and pharmacologically and pharmaceutically acceptable basic salts thereof, for use in the therapeutic treatment of a mammal such as man.
Claim 15
Dependent Claim
36 words
12) Compounds of formula (I), as defined in claim 1, and pharmacologically and pharmaceutically acceptable basic salts thereof, for use in the prolongation and/or potentiation in a mammal of the effects of endogenous or exogenous enkephalins.
Claim 16
Dependent Claim
30 words
13) Compounds of formula (1), as defined in claim 1, and pharmacologically and pharmaceutically acceptable basic salts thereof, for use in the prophylaxis and/or treatment of convulsions in a mammal.
Claim 17
Dependent Claim
30 words
14) Compounds of formula (I), as defined in claim 1, and pharmacologically and pharmaceutically acceptable basic salts thereof, for use in the prophylaxis and/or treatment of anxiety in a mammal.
Claim 18
Dependent Claim
39 words
15) Compounds of formula (I), as defined in claim 1, and pharmacologically and pharmaceutically acceptable basic salts thereof, for use in the prophylaxis and/or treatment of a condition of a mammal, where an improvement in cardio-pulmonary function is indicated.
References Cited (Backward Citations)
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