Substituted .beta.-amino acid derivatives useful as platelet aggregation inhibitors

• US 5,703,125 A
• Filed: 05/31/1995
• Issued: 12/30/1997
• Est. Priority Date: 10/15/1991
• Status: Expired due to Term

• Current Assignee: Western Michigan University
• Original Assignee: Monsanto Company (Bayer AG), GD Searle LLC (Pfizer Inc.)
• Inventors: Rico, Joseph G., Bovy, Philippe R., Tjoeng, Foe S., Zablocki, Jeffery A., Rogers, Thomas E.
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): Vollano, Jean F.
• Application Number:
  US08/455,612
• Time in Patent Office: 944 Days
• Field of Search: 560/35, 562/440, 514/531, 514/539, 514/563
• US Class Current: 514/539
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07C 257/18 having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 311/46 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 317/50 at least one of the nitrogen atoms being part of any of the groups , X being a hetero atom, Y being any atom
• CPC Class Codes: C07F 7/081 comprising at least one atom selected from the elements N, O, halogen, S, Se or Te

Abstract

The invention relates to platelet aggregation inhibitors which are substituted beta amino acid derivatives of the formula: ##STR1## wherein Z, A, Z'"'"', Z", W, q, R¹ and R² are as defined in the specification.

Claims

1. A substituted β

amino acid derivative or a pharmaceutically acceptable salt thereof having the formula;

##STR97## wherein R¹ is selected from the group consisting of hydrogen, lower alkyl radicals, lower alkenyl radicals, aromatic hydrocarbon radicals, alicyclic hydrocarbon radicals, benzyl radicals, phenethyl radicals, wherein said radicals are optionally substituted with halogen, lower alkoxy, hydroxy and lower alkyl;

R² is an aromatic hydrocarbon radical, wherein said radical is optionally substituted with hydroxy, lower alkoxy, lower alkyl, halogen, nitro, cyano, azido, ureido, ureylene, carboxyl or carbonyl derivatives, trifluoromethyl, acyloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, trialkylsilyl, aminosulfonyl, dialkylamino, alkanoylamino, aroylamino, phenyl, naphthyl, or lower alkynyl which are optionally substituted with one or more of the following;

halogen, nitro, lower alkoxy, lower alkyl, trialkylsilyl, azide and phenyl;

A is selected from the group consisting of ethylene, lower alkenylene radicals, lower alkynylene radicals, and divalent alicyclic radicals, wherein said radicals are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, alkoxycarbonylalkyl, amino, alkylamino, dialkylamino, acylamino, alkylthio, sulfonyl, and aromatic hydrocarbons which are optionally substituted with halogen, nitro, lower alkoxy and lower alkyl;

W is selected from the group consisting of hydrogen, lower alkyl radicals, lower alkenyl radicals, lower alkynyl radicals, alicyclic hydrocarbon radicals and aromatic hydrocarbon radicals, wherein said radicals are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, amino, acyloxy, phenyl and naphthyl which may be optionally substituted with halogen, nitro, lower alkoxy, and lower alkyl;

Z, Z'"'"', Z" are independently selected from the group consisting of hydrogen, lower alkyl radicals, halogen, alkoxy, cyano, sulfonyl, carboxyl, alkoxycarbonyl, and hydroxyl radicals;

q is an integer from 0 to about 6; and

with the proviso that when A is trimethylene and q is 0 then R₂ is not a phenyl radical.

2. A substituted β

amino acid derivative as recited in claim 1 wherein;

R₁ is selected from hydrogen, lower alkyl radicals of 1 to about 6 carbon atoms, lower alkenyl radicals of 1 to about 6 carbon atoms, aromatic hydrocarbon radicals, alicyclic hydrocarbon radicals of 3 to about 6 carbon atoms, benzyl radicals, phenethyl radicals, wherein said radicals are optionally substituted with halogen, lower alkoxy, hydroxy and lower alkyl;

R₂ is an aromatic hydrocarbon radical, wherein said radical is optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, cyano, azido, ureido, ureylene, amino, trialkylsilyl, alkylsulfonyl, phenylsulfonyl, trifluoromethyl, acetoxy, acetylamino, benzoylamino, carbonyl, carboxyl derivatives, alkylsulfonyl amino, and phenylsulfonyl amino;

A is selected from ethylene, lower alkenylene radicals of 2 to about 6 carbon atoms, lower alkynylene radicals of 2 to about 4 carbon atoms, and divalent alicyclic hydrocarbon radicals of 3 to about 5 carbon atoms, wherein said radicals are optionally substituted with hydroxyl, lower alkoxy, halogen, alkylthio and amino;

W is selected from hydrogen, lower alkyl radicals of 1 to about 6 carbon atoms, lower alkenyl radicals of 2 to about 6 carbon atoms, alicyclic hydrocarbon radicals of 3 to about 6 carbon atoms, and aromatic hydrocarbon radicals of 6 to about 12 carbon atoms, wherein all of said radicals are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, amino, and acyloxy;

Z, Z'"'"', Z" are independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, sulfonyl, carboxyl, alkoxycarbonyalkyl, alkoxycarbonyl and lower alkyl radicals; and

q is an integer from 0 to about 6.

3. A substituted β

amino acid derivative as recited in claim 1 wherein;

R₁ is selected from hydrogen, lower alkyl radicals, lower alkenyl radicals, aromatic hydrocarbon radicals, alicyclic hydrocarbon radicals, benzyl radicals, phenethyl radicals, wherein all of said radicals are optionally substituted with halogen, lower alkoxy, hydroxy and lower alkyl;

R² is selected from phenol radicals, phenyl radicals, and naphthyl radicals wherein each radical may have one or more substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, carboxyl derivatives, nitro, cyano, azido, ureido, ureylene, alkylcarbonyloxy, hydroxyl, alkylamino, alkoxycarbonyl, trialkylsilyl, alkoxyimino, alkylsulfonyl, phenylsulfonyl, alkylsulfonyl amino, phenylsulfonyl amino and amino;

A is selected from ethylene, lower divalent cycloalkyl, and lower alkenylene radicals;

W is selected from the group consisting of hydrogen and lower alkyl radicals;

Z, Z'"'"', Z" are independently selected from the group consisting of halogen, hydrogen, lower alkoxy, alkoxycarbonyl, alkoxycarbonylmethyl, and lower alkyl radicals;

q is an integer from 0 to about 6.

4. A substituted β

amino acid derivatives as recited in claim 1 wherein;

R¹ is selected from hydrogen, lower alkyl radicals, benzyl radicals, and phenyl radicals;

R² is phenyl optionally substituted with carboxyl, alkoxycarbonyl, cyano, hydroxyaminocarbonyl, hydroxyl, ureido, alkoxymethylaminocarbonyl, halogen, acetoxy, alkoxy, methoxyimino, azido, trimethylsilyl, phenylsulfonyl, methylsulfonyl amino, phenylsulfonyl amino, phenyl and t-butyl;

A is selected from ethylene, lower divalent cycloalkyl and lower alkenylene radicals wherein said radicals can be optionally substituted with lower alkyl radicals;

W is selected from the group consisting of hydrogen and lower alkyl radicals;

Z, Z'"'"', Z" are independently selected from the group of hydrogen, methyl, ethyl, hydroxy, methoxy, chloro, fluoro, alkoxycarbonyl, and alkoxycarbonylmethyl;

q is an integer from 0 to about 4.

5. A substituted β

amino acid derivative as recited in claim 4 wherein "A" is selected from the group of vinylene, allylene, ethylidene, and ethylene radicals.

7. A pharmaceutical composition comprising at least one non-toxic pharmaceutically acceptable carrier and at least one compound according to claim 1.

8. A pharmaceutical composition as recited in claim 7 comprising at least one non-toxic pharmaceutically acceptable carrier and at least one compound according to claim 4, 5, or 6 together with said carrier.

9. A method of treating a mammal to inhibit platelet aggregation comprising administering a therapeutically effective amount of at least one compound of claim 1 to a mammal in need of such treatment.

10. A method of treating a mammal to inhibit platelet aggregation as recited in claim 9 comprising administering a therapeutically effective amount of the compound of claim 4, 5, or 6 to a mammal in need of such treatment.

6. A substituted β

amino acid derivative which is

t-Butyl β

- 2- 4-(aminoiminomethyl)phenyl!amino!carbonyl!cyclopropyl!carbonyl!amino!phenylpropanoate.