Amino acid derivatives

• US 5,670,515 A
• Filed: 05/25/1995
• Issued: 09/23/1997
• 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, Weller, Thomas, Hadvary, Paul, Muller, Marcel, Alig, Leo, Hurzeler, Marianne
• Primary Examiner(s): Spivack, Phyllis G.
• Application Number:
  US08/452,616
• Time in Patent Office: 852 Days
• Field of Search: 514/304, 546/125, 546/129
• US Class Current: 514/304
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• 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
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

N-Acyl-α-aminocarboxylic acid derivatives of the formula ##STR1## wherein L, R'"'"' to R'"'"'" and Q have the definitions given in the specification, are for the treatment or prophylaxis of illnesses which are caused by the binding of adhesive proteins to blood platelets, by blood platelet aggregation and cell-cell adhesion. They are manufactured by cleaving off protecting groups in corresponding protected compounds or by converting the cyano group into the amidino group in corresponding nitriles.

Claims

1. A compound of the formula ##STR19## wherein L is a group of the formula ##STR20## R is amidino or guanidino, one of X and Y is CH, and the other is N, 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-substituents R'"'"' or sidechains R" and R'"'"'" of 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## T is hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

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

2. A compound according to claim 1, wherein L is group L¹, and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.

3. A compound according to claim 1, wherein Q is group Q⁷ in which T is hydrogen.

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

9. The compound of claim 1, (S)-8- 2-(4-aminoiminomethyl-benzoylamino)-3-(4-hydroxyphenyl)propionyl!-8-azabicyclo 3.2.1!octan-endo-3-yloxyacetic acid.

5. A compound of the formula ##STR22## wherein L⁰ is ##STR23## in which A is an optionally protected amidino or guanidino group, R⁰¹ is an optionally protected amino or guanidino group, one of X and Y is CH and the other is N,

t is an integer between 2 and 6,

R'"'"', R", R'"'"'", E'"'"', E" and E'"'"'" in the α

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

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

Q and G are each a group of the formula

T is hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

with the proviso that where R⁰¹ is amino or guanidino or where A is amidino or guanidino, at least one of E'"'"', E", E'"'"'" and G contains at least one carboxylic acid ester group and/or ether group and/or protected amino group.

6. A compound of the formula ##STR24## wherein L is a group of the formula ##STR25## 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-substituents R'"'"' or side-chains R" and R'"'"'" of open chain or cyclic, natural or synthetic α

-aminocarboxylic acids, wherein a hydroxy or carboxy group present in R'"'"', R" and R'"'"'" can be etherified or, respectively, esterified or amidated, and amino groups present in R'"'"', R" and R'"'"'" 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 ##STR26## T is hydrogen or a lower-alkyl or phenyl-loweralkyl group which is cleavable under physiological conditions,

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

7. A compound according to claim 6, wherein L is group L¹, and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.

8. A compound according to claim 6, wherein Q is group Q⁷ in which T is hydrogen.

10. A pharmaceutical composition comprising an effective amount of a compound of the formula ##STR27## wherein L is a group of the formula ##STR28## R is amidino or guanidino, one of X and Y is CH, and the other is N, 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-substituents R'"'"' or sidechains R" and R'"'"'" of 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 ##STR29## T is hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

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

11. The pharmaceutical composition according to claim 10, wherein L is group L¹ and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.

12. The pharmaceutical composition according to claim 10, wherein Q is group Q⁷ in which T is hydrogen.

13. The pharmaceutical composition according to claim 10, wherein --N(R'"'"')C(R",R'"'"'")CO-- is the N(methoxyethyl)Gly residue.

14. A pharmaceutical composition comprising an effective amount of a compound of the formula ##STR30## wherein L is a group of the formula ##STR31## 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-substituents R'"'"' or side-chains R" and R'"'"'" of open chain or cyclic, natural or synthetic α

-aminocarboxylic acids, wherein a hydroxy or carboxy group present in R'"'"', R" and R'"'"'" can be etherified or, respectively, esterified or amidated, and amino groups present in R'"'"', R" and R'"'"'" 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;

##STR32## T is hydrogen or a lower-alkyl or phenyl-lower alkyl group which is cleavable under physiological conditions,

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

15. The pharmaceutical composition according to claim 14, wherein L is group L¹, and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.

16. A method for the control or prevention of blood platelet thrombi, thrombosis, stroke, cardiac infarct, inflammation, or arteriosclerosis, comprising administering a compound of the formula ##STR33## wherein L is a group of the formula ##STR34## R is amidino or guanidino, one of X and Y is CH, and the other is N, 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-substituents R'"'"' or sidechains R" and R'"'"'" of 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 ##STR35## T is hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

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

17. The method of claim 16, wherein L is group L¹ and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.

18. The method of claim 16, wherein Q is group Q⁷ in which T is hydrogen.

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

20. A method for inhibiting fibrinogen-, fibronectin- and the Willebrand factor dependent-binding of tumor cells to a fibrinogen receptor of blood platelets comprising administering a compound of the formula ##STR36## wherein L is a group of the formula ##STR37## R is amidino or guanidino, one of X and Y is CH, and the other is N, 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-substituents R'"'"' or sidechains R" and R'"'"'" of 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 ##STR38## T is hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

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

21. A method of wound healing comprising administering a compound of the formula ##STR39## wherein L is a group of the formula ##STR40## R is amidino or guanidino, one of X and Y is CH, and the other is N, 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-substituents R'"'"' or sidechains R" and R'"'"'" of 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 ##STR41## T is hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

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

22. A method for treating osteoporosis comprising administering a compound of the formula ##STR42## wherein L is a group of the formula ##STR43## R is amidino or guanidino, one of X and Y is CH, and the other is N, 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-substituents R'"'"' or sidechains R" and R'"'"'" of 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 ##STR44## T is hydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,

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

23. A method for the control and/or prevention of blood platelet thrombi, thrombosis, stroke, cardiac infarct, inflammation, or arteriosclerosis, comprising administering a compound of the formula ##STR45## wherein L is a group of the formula ##STR46## 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-substituents R'"'"' or side-chains R" and R'"'"'" of open chain or cyclic, natural or synthetic α

-aminocarboxylic acids, wherein a hydroxy or carboxy group present in R'"'"', R" and R'"'"'" can be etherified or, respectively, esterified or amidated, and amino groups present in R'"'"', R" and R'"'"'" 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 ##STR47## T is hydrogen or a lower-alkyl or phenyl-lower alkyl group which is cleavable under physiological conditions,

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