Amino acid derivatives

• US 5,545,658 A
• Filed: 05/25/1995
• Issued: 08/13/1996
• Est. Priority Date: 03/26/1991
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Steiner, Beat, H urzeler, Marianne, Weller, Thomas, Hadvary, Paul, Alig, Leo, M uller, Marcel
• Primary Examiner(s): Spivack, Phyllis G.
• Application Number:
  US08/452,615
• Time in Patent Office: 446 Days
• Field of Search: 514/423, 548/530, 548/537
• US Class Current: 514/423
• 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 2601/12 with a six-membered ring
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/48 having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/06 Oxygen atoms

Abstract

N-Acyl-α-aminocarboxylic acid derivatives of the formula ##STR1## wherein L, R'"'"' to R'"'"'" and Q have the significance given in the description, can be used for the treatment or prophylaxis of illnesses which are caused by the binding of adhesive proteins to blood platelets and by blood platelet aggregation and cell-cell adhesion.

Claims

1. A compound of the formula ##STR19## wherein L is a group of the formula ##STR20## R is amidino or guanidino, both X and Y are CH, R⁰ is hydrogen or amidino,

t is an integer between 2 and 6,

R'"'"', R" and R'"'"'", in the α

-aminocarboxylic acid residue of the formula --N(R'"'"')C(R",R'"'"'")CO--, are hydrogen or N-substituent R'"'"' or sidechains R" and R'"'"'" are open chain or cyclic, natural or synthetic α

-aminocarboxylic acids, wherein a hydroxy or carboxy group present in the N-substituent R'"'"' and sidechains R" and R'"'"'" can be etherified, or, respectively, esterified or amidated, and amino groups can be C_1-6 alkanoylated or aroylated, and wherein R'"'"' and R" together with the N atom and C atom to which they are attached can form a 4- to 6-membered ring;

Q is a group of the formula ##STR21## n is the number 0, v is an integer between 0 and 3,

T and T'"'"' are hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

V to V'"'"'" are hydrogen or lower-alkyl,

U and U'"'"' are hydrogen, C_1-6 -alkanoyl or aroyl, and

Ar is aryl

as well as hydrates or solvates and physiologically usable salts thereof.

2. A compound according to claim 1, wherein L is a group L¹, R'"'"', R" and R'"'"'", in the α

-aminocarboxylic acid residue of the formula --N(R'"'"')C(R",R'"'"'")CO--, are hydrogen or N-substituent R'"'"' or sidechains R" and R'"'"'" are open chain or cyclic, natural or synthetic α

-aminocarboxylic acids, wherein a hydroxy or carboxy group present in the N-substituent R'"'"' and sidechains R" and R'"'"'" can be etherified, or, respectively, esterified or amidated, and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.

3. A compound according to claim 2, wherein L is a group L¹, R is amidino, X is CH, Y is CH, and Q is a group Q¹, Q², or Q⁵.

4. A compound according to claim 1, wherein Q is a group Q³, n=0 and T is hydrogen.

5. A compound according to claim 1, wherein --N(R'"'"')C(R",R'"'"'")CO-- is the N(methoxyethyl)Gly residue.

6. The compound of claim 1, (S)-cis-1-[2-(4-amidinobenzoylamino)propionyl]-4-carboxymethoxy-pyrrolidin-3-yloxy acetic acid.

7. A pharmaceutical composition comprising an effective amount of a compound of the formula ##STR22## wherein L is a group of the formula ##STR23## R is amidino or guanidino, both X and Y are CH, R⁰ is hydrogen or amidino,

t is an integer between 2 and 6,

R'"'"', R" and R'"'"'", in the α

-aminocarboxylic acid residue of the formula --N(R'"'"')C(R",R'"'"'")CO--, are hydrogen or N-substituent R'"'"' or sidechains R" and R'"'"'" are open chain or cyclic, natural or synthetic α

-aminocarboxylic acids, wherein a hydroxy or carboxy group present in the N-substituent R'"'"' and sidechains R" and R'"'"'" can be etherified, or, respectively, esterified or amidated, and amino groups can be C_1-6 alkanoylated or aroylated, and wherein R'"'"' and R" together with the N atom and C atom to which they are attached can form a 4- to 6-membered ring;

Q is a group of the formula ##STR24## n is the number 0, v is an integer between 0 and 3,

T and T'"'"' are hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

V to V'"'"'" are hydrogen or lower-alkyl,

U and U'"'"' are hydrogen, C_1-6 -alkanoyl or aroyl, and

Ar is aryl

as well as hydrates or solvates and physiologically usable salts thereof and a pharmaceutically inert carrier.

8. The pharmaceutical composition according to claim 7, wherein L is a group L¹, R'"'"', R" and R'"'"'", in the α

-aminocarboxylic acid residue of the formula --N(R'"'"')C(R",R'"'"'")CO--, are hydrogen or N-substituent R'"'"' or sidechains R" and R'"'"'" are open chain or cyclic, natural or synthetic α

-aminocarboxylic acids, wherein a hydroxy or carboxy group present in the N-substituent R'"'"' and sidechains R" and R'"'"'" can be etherified, or, respectively, esterified or amidated, and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.

9. The pharmaceutical composition according to claim 8, wherein L is a group L¹, R is amidino, X is CH, Y is CH, and Q is a group Q¹, Q², or Q⁵.

10. The pharmaceutical composition according to claim 7, wherein Q is a group Q³, n=0 and T is hydrogen.

11. The pharmaceutical composition according to claim 7, wherein --N(R'"'"')C(R",R'"'"'")CO-- is the N(methoxyethyl)Gly residue.

12. A method for the treatment or prophylaxis of blood platelet thrombi, thrombosis, stroke, cardiac infarct, inflammation, or arteriosclerosis, comprising administering a compound of the formula ##STR25## wherein L is a group of the formula ##STR26## R is amidino or guanidino, both X and Y are CH, R⁰ is hydrogen or amidino,

t is an integer between 2 and 6,

R'"'"', R" and R'"'"'", in the α

-aminocarboxylic acid residue of the formula --N(R'"'"')C(R",R'"'"'")CO--, are hydrogen or N-substituent R'"'"' or sidechains R" and R'"'"'" are open chain or cyclic, natural or synthetic α

-aminocarboxylic acids, wherein a hydroxy or carboxy group present in the N-substituent R'"'"' and sidechains R" and R'"'"'" can be etherified, or, respectively, esterified or amidated, and amino groups can be C_1-6 alkanoylated or aroylated, and wherein R'"'"' and R" together with the N atom and C atom to which they are attached can form a 4- to 6-membered ring;

Q is a group of the formula ##STR27## n is the number 0, v is an integer between 0 and 3,

T and T'"'"' are hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

V to V'"'"'" are hydrogen or lower-alkyl,

U and U'"'"' are hydrogen, C_1-6 -alkanoyl or aroyl, and

Ar is aryl

as well as hydrates or solvates and physiologically usable salts thereof.

13. The method of claim 12, wherein L is a group L¹, R'"'"', R" and R'"'"'", in the α

-aminocarboxylic acid residue of the formula --N(R'"'"')C(R",R'"'"'")CO--, are hydrogen or N-substituent R'"'"' or sidechains R" and R'"'"'" are open chain or cyclic, natural or synthetic α

-aminocarboxylic acids, wherein a hydroxy or carboxy group present in the N-substituent R'"'"' and sidechains R" and R'"'"'" can be etherified, or, respectively, esterified or amidated, and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.

14. The method of claim 12, wherein L is a group L¹, R is amidino, X is CH, Y is CH, and Q is a group Q¹, Q², or Q⁵.

15. The method of claim 12, wherein Q is a group Q³, n=0 and T is hydrogen.

16. The method of claim 12, wherein --N(R'"'"')C(R",R'"'"'")CO-- is the N(methoxy-ethyl)Gly residue.