Amino acid derivatives

• US 5,378,712 A
• Filed: 03/19/1992
• Issued: 01/03/1995
• 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): Cintins, Marianne M.
• Assistant Examiner(s): Spivack, Phyllis G.
• Application Number:
  US07/854,135
• Time in Patent Office: 1,020 Days
• Field of Search: 546/221, 546/194, 546/208, 546/188, 546/220, 546/242, 546/208, 546/221, 514/327, 514/318, 514/326, 514/315, 514/316, 514/328
• US Class Current: 514/315
• 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 significance given in the description, can be used for the treatment or control 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## or

View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

2. A compound according to claim 1, wherein L is a 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 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, 2 or 3, wherein Q is a group Q¹, n=1, T is hydrogen or methyl and --N(R'"'"')C(R",R'"'"'")CO-- is an α

-aminocarboxylic acid residue selected from the group consisting of Gly, Ala, D-Ala, Val, Leu, Sar, Orn, Lys, Phg, 2-methyl-Pro, Phe, Tyr, 3-iodo-Tyr, 3,5-diiodo-Tyr, Ser(Ac), Ser, Asp, Glu, Pro, 4-benzyloxy-Pro, 4-hydroxy-Pro, 2-piperidylenecarbonyl, NHCH(CH₂ CH₂ NH₂)CO, Trp, Tyr(Me), Tyr(hexyl), O,N(Me)2-Tyr and N(MeOCH₂ CH₂)Gly.

5. A compound according to claims 1, 2 or 3, wherein Q is a group Q², n=1, T is hydrogen and --N(R'"'"')C(R",R'"'"'")CO-- is the Ala residue.

6. A compound according to claim 1, 2 or 3, wherein Q is a group Q⁵, n=1, T is hydrogen, Ar is α

,α

,α

-trifluoro-m-tolyl and --N(R'"'"')C(R",R'"'"'")CO-- is the Ala residue.

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

8. A compound according to claim 1 selected from the group consisting of

[[1-N-(p-Amidinobenzoyl)-L-alanyl]-4-piperidinyl]oxy]acetic acid,

[[1-[N-(p-amidinobenzoyl)-3-(4-hydroxy-3-iodophenyl)-L-alanyl-4-piperidinyl]oxy]acetic acid, and

[[1-[3-acetoxy-N-(p-amidinobenzoyl)-L-alanyl]-4-piperidinyl]oxy]acetic acid.

9. A compound according to claim 1 selected from the group consisting of:

ethyl(S)-1-[2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl]piperidin-4-yloxyacetate,

(S)-1-[2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl]piperidin-4-yloxyacetic acid, and

[1-[N-(4-amidinobenzoyl)-4'"'"'-hexyloxy-L-phenylalanyl]-piperidin-4-yloxy]-acetic acid.

10. A compound according to claim 1, wherein N-substituents R'"'"' or side-chains R" and R"'"'"' are lower alkyl optionally substituted by OH, COOH, NH₂ or aryl.

11. A compound according to claim 1, wherein --N(R'"'"')C(R",R'"'"'")CO-- is an α

-aminocarboxylic residue selected from the group consisting of Gly, Ala, D-Ala, Val, Leu, Sar, Orn, Lys, Phg, 2-methyl-Pro, Phe, Tyr, 3-iodo-Tyr, 3,5-diiodo-Tyr, Ser(Ac), Ser, Asp, Glu, Pro, 4-benzyloxy-Pro, 4-hydroxy-Pro, 2-piperidylenecarbonyl, NHCH(CH₂ CH₂ NH₂)CO, Trp, Tyr(Me), Tyr(hexyl), O,N(Me)2-Tyr and N(MeOCH₂ OCH₂)Gly.

12. [[1-N-(p-Amidinobenzoyl)-L-tyroxyl]-4-piperidinyl]oxy]-acetic acid.

13. A compound of the formula ##STR22## wherein L^o is a group of the formula ##STR23## or

14. A pharmaceutical composition comprising an effective amount of a compound of the formula ##STR25## wherein L is a group of the formula ##STR26## or

View Dependent Claims (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)

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

16. The pharmaceutical composition according to claim 15, wherein L is a group L¹, R is amidino, X is CH, Y is CH and Q is a group Q¹, Q², or Q⁵.

17. The pharmaceutical composition according to claim 14, 15, or 16, wherein Q is a group of Q¹, n=1 and T is hydrogen or methyl and --N(R'"'"')C(R",R'"'"'41 )CO-- is an α

-aminocarboxylic acid residue selected from the group consisting of Gly, Ala, D-Ala, Val, Leu, Sar, Orn, Lys. Phg, 2-methyl-Pro, Phe, Tyr, 3-iodo-Tyr, 3,5-diiodo-Tyr, Ser(Ac), Ser, Asp, Glu, Pro, 4-benzyloxy-Pro, 4-hydroxy-Pro, 2-piperidylenecarbonyl, NHCH(CH₂ CH₂ NH₂)CO, Trp, Tyr(Me), Tyr(hexyl), O,N(Me)2-Tyr and N(MeOCH₂ CH₂)Gly,

18. The pharmaceutical composition according to claims 14, 15 or 16, wherein Q is a group Q², n=1, T is hydrogen and --N(R'"'"')C(R",R'"'"'")CO-- is the Ala residue.

19. The pharmaceutical composition according to claim 14, 15 or 16, wherein Q is a group Q², n=1, T is hydrogen and --N(R'"'"')C(R",R'"'"'")CO-- is the Ala residue.

20. The pharmaceutical composition according to claim 14, wherein the compound of formula I is [[1-N-(p-amidinobenzoyl)-L-tyrosyl]-4-piperidinyl]loxy]-acetic acid.

21. The pharmaceutical composition according to claim 14, wherein --N(R'"'"')C(R",R'"'"'")CO-- is the N(methoxyethyl)Gly residue.

22. The pharmaceutical composition according to claim 14, wherein the compound of formula I is selected from the group consisting of:

[[1-N-(p-Amidinobenzoyl)-L-alanyl]-4-piperidinyl]oxy]acetic acid,

[[1-[N-(p-amidinobenzoyl)-3-(4-hydroxy-3-iodophenyl)-L-alanyl]-4-piperidinyl]oxy]acetic acid, and

[[1-(3-acetoxy-N-(p-amidinobenzoyl)-L-alanyl]-4-piperidinyl]oxy]acetic acid.

23. The pharmaceutical composition according to claim 14 wherein the compound of formula I is selected from the group consisting of:

ethyl(S)-1-[2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl]piperidin-4-yloxyacetate,

(S)-1-[2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl]piperidin-4-yloxyacetic acid, and

[1-[N-(4-amidinobenzoyl)-4'"'"'-hexyloxy-L-phenylalanyl]-piperidin-4-yloxy]-acetic acid.

24. The pharmaceutical composition according to claim 14, wherein N-substituents R'"'"' or side-chains R" and R'"'"'" are lower alkyl optionally substituted by OH, COOH, NH₂ or aryl.

25. The pharmaceutical composition according to claim 14, wherein --N(R'"'"')C(R",R'"'"'")CO-- is an α

-aminocarboxylic acid residue selected from the group consisting of Gly, Ala, D-Ala, Val, Leu, Sar, Orn, Lys, Phg, 2-methyl-Pro, Phe, Tyr, 3-iodo-Tyr, 3,5-diiodo-Tyr, Ser(Ac), Ser, Asp, Glu, Pro, 4-benzyloxy-Pro, 4-hydroxy-Pro, 2-piperidylenecarbonyl, NHCH(CH₂ CH₂ NH₂)CO, Trp, Tyr(Me), Tyr(hexyl), O,N(Me)2-Tyr and N(MeOCH₂ CH₂)Gly.

26. A method for the treatment and/or control of blood platelet thrombi, thrombosis, stroke, cardiac infarct, inflammation, or arteriosclerosis, comprising administering a compound of the formula:

##STR28## wherein L is a group of the formula ##STR29## or

space="preserve" listing-type="equation">R.sup.o --NH(CH.sub.2).sub.t L.sup.2

R is amidino or guanidino, both X and Y are CH,

R^o 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-substitutents 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, esterfied or amidated, and amino groups can be C1-6 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 ##STR30## n is the number 1, T and T'"'"' are hydrogen or a lower-alkyl or phenyl-lower alkyl group which is cleavable under physiological conditions,

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

Ar is phenyl or phenyl substituted with up to three substituents selected from the group consisting of alkyl, hydroxy, lower-alkoxy, halogen and halo-lower alkyl,

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

27. The method of claim 26, wherein L is a group L¹, and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.

28. The method of claim 26, wherein L is a group L¹, R is amidino, X is CH, Y is CH, and Q is a group Q¹, Q², or Q⁵.

29. The method of claim 26, wherein Q is a group Q¹, n=1and T is hydrogen or methyl and --N(R'"'"')C(R",R'"'"'")CO-- is an α

-aminocarboxylic acid residue selected from the group consisting of Gly, Ala, D-Ala, Val, Leu, Sar, Orn, Lys. Phg. 2-methyl-Pro, Phe, Tyr, 3-iodo-Tyr, 3,5-diiodo-Tyr, Ser(Ac), Ser, Asp, Glu, Pro, 4-benzyloxy-Pro, 4-hydroxy Pro, 2-piperidylenecarbonyl, NHCH(CH₂ CH₂ NH₂)CO, Trp, Tyr(Me), Tyr(hexyl), O,N(Me)2-Tyr and N(MeOCH₂ CH₂)Gly,

30. The method of claim 26, wherein Q is a group Q², n=1, T is hydrogen and --N(R'"'"')C(R",R"'"'"')CO-- is the Ala residue.

31. The method of claim 26, wherein Q is a group Q⁵, n=1, T is hydrogen, Ar is α

,α

,α

-trifluoro-m-tolyl and --N(R'"'"')C(R",R'"'"'")CO-- is the Ala residue.

32. The method of claim 26, wherein the compound of formula I is [[1-N-(p-amidinobenzoyl)-L-tyrosyl]-4-piperidinyl]oxy]-acetic acid.

33. The method of claim 26, wherein --N(R'"'"')C(R",R"'"'"')C0-- is the N(methoxy-ethyl)Gly residue.

34. The method of claim 26, wherein the compound of formula I is selected from the group consisting of:

[[1-N-(p-Amidinobenzoyl)-L-alanyl]-4-piperidinyl]oxy]acetic acid,

[[1-[N-(p-amidinobenzoyl)-3-(4-hydroxy-3-iodophenyl)-L-alanyl]-4-piperidinyl]oxy]acetic acid, and

[[1-(3-acetoxy-N-(p-amidinobenzoyl)-L-alanyl]-4-piperidinyl]oxy]acetic acid.

35. The method of claim 26, wherein the compound of formula I is selected from the group consisting of:

ethyl(S)-1-[2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl]piperidin-4-yloxyacetate,

(S)-1-[2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl]piperidin-4-yloxyacetic acid, and

[1-[N-(4-amidinobenzoyl)-4-hexyloxy-L-phenylalanyl]-piperidin-4-yloxy]-acetic acid.

36. The method of claim 26, wherein N-substituents R'"'"' or side-chains R" and R'"'"'" are lower alkyl optionally substituted by OH, COOH, NH₂ or aryl.

37. The method of claim 26, wherein --N(R'"'"')C(R",R'"'"'")CO-- is an α

-aminocarboxylic acid is residue selected from the group consisting of Gly, Ala, D-Ala, Val, Leu, Sar, Orn, Lys, Phg, 2-methyl-Pro, Phe, Tyr, 3-iodo-Tyr, 3,5-diiodo-Tyr, Ser(Ac), Ser, Asp, Glu, Pro, 4-benzyloxy-Pro, 4-hydroxy-Pro, 2-piperidylenecarbonyl, NHCH(CH₂ CH₂ NH₂)CO, Trp, Tyr(Me), Tyr(hexyl), O,N(Me)2-Tyr and N(MeOCH₂ CH₂)Gly.