Phosphinic acid derivatives with metallopeptidase inhibitory activity

• US 5,739,123 A
• Filed: 11/27/1996
• Issued: 04/14/1998
• Est. Priority Date: 06/21/1994
• Status: Expired due to Fees

• Current Assignee: Zambon Group SPA (GEFIM SRL)
• Original Assignee: Zambon Group SPA (GEFIM SRL)
• Inventors: Norcini, Gabriele, Morazzoni, Gabriele, Santangelo, Francesco, Botta, Daniela
• Primary Examiner(s): Shippen, Michael L.
• Application Number:
  US08/750,035
• Time in Patent Office: 503 Days
• Field of Search: 514/119, 562/15
• US Class Current: 514/119
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07F 9/301 Acyclic saturated acids which can have further substituents on alkyl

Abstract

Compounds of formula (I), ##STR1## wherein R is a biphenyl group optionally substituted, by one or more substituents, the same or different selected among halogen atoms, hydroxy groups, alkoxy, alkyl thioalkyl or alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C₁ -C₃ alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulphonyl groups, momo- or di-alkylamino groups having from 1 to 6 carbon atoms in the alkyl moiety, mono- or di-alkylamino-carbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety; R₁ is a hydrogen atom, a straight or branched C₁ -C₆ alkyl group or an arylalkyl group having from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl is a phenyl, a biphenyl, a napthyl or a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted with one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkoxy, alkyl, thioalkyl or alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C₁ -C₃ alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono- or di-alkylamino groups having from 1 to 6 carbon atoms in the alkyl moiety, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety; R₂ is a straight or branched C₁ -C₆ alkyl group, optionally containing one or more fluorine atoms or one or more --NH-- groups, an arylalkyl, an arylcarbonylaminoalkyl, an arylalkylcarbonylaminoalkyl or an arylaminocarbonylalkyl group having from 1 to 6 carbon atoms and optionally one or more --NH-- groups in the alkyl moiety, the aryl being optionally substituted by one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkoxy, alkyl, thioalkyl or alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C₁ -C₃ alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono-or di-alkylamino groups having from 1 to 6 carbon atoms in the alkyl moiety, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety; m is 0 or 1; X is a hydrogen or fluorine atom; the carbon atom marked with an asterisk is an asymmetric carbon atom; and their pharmaceutically acceptable salts, are described. The compounds of formula (I) are endowed with a mixed ACE-inhibitory and NEP-inhibitory activity and are useful in the treatment of cardiovascular diseases.

Claims

1. A compound of formula ##STR11## wherein R is a biphenyl group optionally substituted by one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkoxy, alkyl, thioalkyl or alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C₁ -C₃ alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono- or di-alkylamino groups having from 1 to 6 carbon atoms in the alkyl moiety, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety;

R₁ is a hydrogen atom, a straight or branched C₁ -C₆ alkyl group or an arylalkyl group having from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl is a phenyl, a biphenyl, a naphthyl or a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted with one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkoxy, alkyl, thioalkyl or alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C₁ -C₃ alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono- or di-alkylamino groups having from 1 to 6 carbon atoms in the alkyl moiety, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety;

R₂ is a straight or branched C₁ -C₆ alkyl group, optionally containing one or more fluorine atoms or one or more --NH-- groups, an arylalkyl, an arylcarbonylaminoalkyl, an arylalkylcarbonylaminoalkyl or an arylaminocarbonylalkyl group having from 1 to 6 carbon atoms and optionally one or more --NH-- groups in the alkyl moiety, the aryl being optionally substituted by one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkoxy, alkyl, thioalkyl or alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C₁ -C₃ alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono- or di-alkylamino groups having from 1 to 6 carbon atoms in the alkyl moiety, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety;

m is 0 or 1;

X is a hydrogen or fluorine atom;

the carbon atom marked with an asterisk is an asymmetric carbon atom;

and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein R is a biphenyl group optionally substituted with from 1 to 3 substituents, the same or different, selected among chlorine or fluorine atoms or hydroxy groups;

R₁ is a straight or branched C₁ -C₆ alkyl group or an arylalkyl group having from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl group is a phenyl or a bipheny;

R₂ is a straight or branched C₁ -C₆ alkyl, an arylcarbonylaminoalkyl, an arylalkylcarbonylaminoalkyl or an arylalkyl group having from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl group is a phenyl, m is 1 and X is hydrogen.

3. A compound according to claim 2 wherein R is a 4-biphenyl group;

R₁ is a straight or branched C₃ -C₆ alkyl group;

R₂ is an arylcarbonylaminoalkyl or an arylalkylcarbonylaminoalkyl group having from 1 to 3 carbon atoms in the alkyl moiety wherein the aryl group is a phenyl, m=1 and X=H.

4. A compound according to claim 1 in the form of a salt with an alkali metal selected among sodium, lithium and potassium.

5. A process for the preparation of a compound of formula I according to claim 1 which comprises the reaction between a compound of formula ##STR12## wherein R₁, R₂, m and X have the meanings reported in claim 1 and Y represents a protective group selected among a C₁ -C₄ alkyl, a phenyl or a phenylalkyl group having from 1 to 4 carbon atoms in the alkyl moiety;

and a biphenylalanine derivative of formula ##STR13## wherein R has the meanings reported in claim 1.

6. A process for the preparation of a compound of formula I wherein m=1 and X=H according to claim I which comprises the reaction between a compound of formula ##STR14## wherein R₂ has the meanings reported in claim 1 and Y represents a protective group selected among a C₁ -C₄ alkyl, a phenyl or a phenylalkyl group having from 1 to 4 carbon atoms in the alkyl moiety;

and a compound of formula ##STR15## wherein R and R₁ have the meanings reported in claim 1.

7. A pharmaceutical composition containing a therapeutically effective amount of a compound of formula I according to claim 1 in admixture with a carrier for pharmaceutical use.

8. A pharmaceutical composition according to claim 7 for the treatment of cardiovascular diseases.