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, R.sup.0 is hydrogen or amidino,
- t is an integer between 2 and 6,
- R', R" and R'", in the .alpha.-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 .alpha.-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.sub.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 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,
- 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 hydrated or solvates and physiologically usable salts thereof.
- 2. A compound according to claim 1, wherein L is a group L.sup.1, 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 L.sup.1, R is amidino, X is CH, Y is N, and Q is a group Q.sup.1, Q.sup.2, or Q.sup.5.
- 4. A compound according to claim 1, 2 or 3, wherein Q is a group Q.sup.1, n=1 and T is hydrogen or methyl, and --N(R')C(R",R'") CO-- is a 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(CH.sub.2 CH.sub.2 NH.sub.2)CO, Trp, Tyr (Me), Tyr(hexyl) and O,N(Me).sub.2 -Tyr.
- 5. A compound according to claim 1, 2 or 3, wherein Q is a group Q.sup.2, 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 Q.sup.5, n=1, T is hydrogen, Ar is .alpha.,.alpha.,.alpha.-trifluoro-m-tolyl and --N(R')C (R",R'")CO-- is the Ala residue.
- 7. A compound according to claim 1, wherein Q is a group Q.sup.3, n=0 and T is hydrogen.
- 8. A compound according to claim 1, wherein --N(R')C(R",R'")CO-- is the N(methoxyethyl)Gly residue.
- 9. A compound according to claim 1, selected from the group consisting of:
- [[1-[N-[(5-amidino-2-pyridyl)carbonyl]-L-alanyl]-4-piperidinyl]oxy]acetic acid, and
- [[1-[N-[(5-amidino-2-pyridyl)carbonyl]-L-tyrosyl]-4-piperidinyl]oxy]acetic acid.
- 10. A compound according to claim 1, (S)-1-[2-(5-Amidinopyridin-2-ylcarbonylamino)-3-(4-methoxyphenyl)propionyl]piperidin-4-yloxyacetic acid.
- 11. A compound of the formula ##STR22## wherein L.sup.0 is a group of the formula ##STR23## in which A is an optionally protected amidino or guanidino group,
- R.sup.01 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 .alpha.-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 .alpha.-aminocarboxylic 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.sub.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 ##STR24## n is the number 1, T and T' are hydrogen or lower-alkyl or phenyl-lower-alkyl group which is cleavable under physiological conditions,
- V and V' are hydrogen or lower-alkyl,
- 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, with the proviso that where R.sup.01 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.
- 12. A pharmaceutical composition comprising an effective amount of a compound of the formula ##STR25## wherein L is a group of the formula ##STR26## R is amidino or guanidino, one of C and Y is CH, and the other is N, R.sup.0 is hydrogen or amidino,
- t is an integer between 2 and 6,
- R', R" and R'", in the .alpha.-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 .alpha.-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.sub.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 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,
- 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 and a pharmaceutically inert carrier.
- 13. The pharmaceutical composition according to claim 12, wherein L is a group L.sup.1 and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.
- 14. The pharmaceutical composition according to claim 13, wherein L is a group L.sup.1, R is amidino, X is CH, Y is N, and Q is a group Q.sup.1,Q.sup.2, or Q.sup.5.
- 15. The pharmaceutical composition according to claim 12, 13 or 14, whereto Q is a group Q.sup.1, n=1 and T is hydrogen or methyl, and --N(R')C(R",R'") CO-- is a 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(CH.sub.2 CH.sub.2 NH.sub.2)CO, Trp, Tyr (Me), Tyr(hexyl) and O,N(Me).sub.2 -Tyr.
- 16. The pharmaceutical composition according to claim 12, 13 or 14, wherein Q is a group Q.sup.2, n=1, T is hydrogen and --N(R')C(R",R'")CO-- is the Ala residue.
- 17. The pharmaceutical composition according to claim 12, 13 or 14, wherein Q is a group Q.sup.5, n=1, T is hydrogen, Ar is .alpha.,.alpha.,.alpha.-trifluoro-m-tolyl and --N(R')C(R",R'") CO-- is the Ala residue.
- 18. The pharmaceutical composition according to claim 12, wherein the compound of formula I is selected from the group consisting of
- [[1-[N-[(5-amidino-2-pyridyl)carbonyl]-L-alanyl]-4-piperidinyl]oxy]acetic acid,
- [[1-[N-[(5-amidino-2-pyridyl)carbonyl]-L-tyrosyl]-4-piperidinyl]oxy]acetic acid.
- 19. The pharmaceutical composition according to claim 12, wherein Q is a group Q.sup.3, n=0 and T is hydrogen.
- 20. The pharmaceutical composition according to claim 12, wherein --N(R')C(R",R'")CO-- is the N(methoxyethyl)Gly residue.
- 21. The pharmaceutical composition according to claim 12 wherein the compound of formula I is
- (S)-1-[2-(5-Amidinopyridin-2-ylcarbonylamino)-3-(4-methoxyphenyl)propionyl]piperidin-4-yloxyacetic acid.
- 22. 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 ##STR28## wherein L is a group of the formula ##STR29## R is amidino or guanidino, one of X and Y is CH, and the other is N, R.sup.0 is hydrogen or amidino,
- t is an integer between 2 and 6,
- R', R" and R'", in the .alpha.-aminocarboxylic acid residue of the formula --N(R')C(R",R'")CO--, are hydrogen or N-substituent R' or sidechains R" and R'" of open chain or cyclic, natural or synthetic .alpha.-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.sub.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 ##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 to V' are hydrogen or lower-alkyl,
- 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.
- 23. The method of claim 22, wherein L is a group L.sup.1 and T in the group Q is hydrogen or a lower-alkyl group cleavable under physiological conditions.
- 24. The method of claim 22, wherein L is a group L.sup.1, R is amidino, X is CH, Y is CH or N, and Q is a group Q.sup.1, Q.sup.2, or Q.sup.5.
- 25. The method of claim 22, wherein Q is a group Q.sup.1, n=1 and T is hydrogen or methyl, and --N(R')C(R",R'")CO-- is a 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(CH.sub.2 CH.sub.2 NH.sub.2)CO, Trp, Tyr (Me), Tyr(hexyl) and O,N(Me).sub.2 -Tyr.
- 26. The method of claim 22, wherein Q is a group Q.sup.2, n=1, T is hydrogen and --N(R')C(R",R'")CO-- is the Ala residue.
- 27. The method of claim 22, wherein Q is a group Q.sup.5, n=1, T is hydrogen, Ar is .alpha.,.alpha.,.alpha.-trifluoro-m-tolyl and --N(R')C(R",R'")CO-- is the Ala residue.
- 28. The method of claim 22, wherein the compound of formula I is selected from the group consisting of
- [[1-[N-[(5-amidino-2-pyridyl)carbonyl]-L-alanyl]-4-piperidinyl]oxy]acetic acid and
- [[1-[N-[(5-amidino-2-pyridyl)carbonyl]-L-tyrosyl]-4-piperidinyl]oxy]acetic acid.
- 29. The method of claim, 22, wherein Q is a group Q.sub.3, n=0 and T is hydrogen.
- 30. The method of claim 22, wherein --N(R')C(R",R"')CO-- is the N(methoxy-ethyl)Gly residue.
- 31. The method of claim 22, wherein the compound of formula I is:
- (S)-1-[2-(5-Amidinopyridin-2-ylcarbonylamino)-3-(4-methoxyphenyl)propionyl]piperidin-4-yloxyacetic acid.
- 32. A method for inhibiting fibrinogen-, fibronectin- and the Willebrand Factor-dependent binding of tumor cells to a fibrinogen receptor of blood platelets comprising administering to a host in need of said inhibition a compound of the formula ##STR31## wherein L is a group of the formula ##STR32## R is amidino or guanidino, one of X and Y is CH, and the other is N, R.sup.0 is hydrogen or amidino,
- t is an integer between 2 and 6,
- R', R" and R'", in the .alpha.-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 .alpha.-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.sub.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 ##STR33## 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,
- 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.
- 33. A method of wound healing comprising administering a compound of the formula ##STR34## wherein L is group of formula ##STR35## R is amidino or guanidino, one of X and Y is CH, and the other is N, R.sup.0 is hydrogen or amidino,
- t is an integer between 2 and 6,
- R', R" and R'", in the .alpha.-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 .alpha.-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.sub.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 ##STR36## 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,
- 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.
- 34. A method for treating osteoporosis comprising administering a compound of the formula ##STR37## wherein L is a group of the formula ##STR38## R is amidino or guanidino, one of X and Y is CH, and the other is N, R.sup.0 is hydrogen or amidino,
- t is an integer between 2 and 6,
- R', R" and R'", in the .alpha.-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 .alpha.-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.sub.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 ##STR39## 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,
- 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, and
- as well as hydrates or solvates and physiologically usable salts thereof.
Priority Claims (2)
Number |
Date |
Country |
Kind |
910/91 |
Mar 1991 |
CHX |
|
176/92 |
Jan 1992 |
CHX |
|
Parent Case Info
This is a division of application Ser. No. 08/854,135 filed Mar. 19, 1992 now U.S. Pat. No. 5,378,712.
US Referenced Citations (7)
Foreign Referenced Citations (7)
Number |
Date |
Country |
9172086 |
Aug 1992 |
AUX |
2037153 |
Sep 1991 |
CAX |
0 082 088 |
Dec 1982 |
EPX |
332008 |
Feb 1989 |
EPX |
0372486 |
Dec 1989 |
EPX |
0381033 |
Jan 1990 |
EPX |
0445796 |
Mar 1991 |
EPX |
Non-Patent Literature Citations (3)
Entry |
Analytical Biochemistry 151, 1985, 169-171. |
Science 231, 1986, 1559-62. |
Chem.Abstr. vol. 92, 1980, 92:208785S. |
Divisions (1)
|
Number |
Date |
Country |
Parent |
854135 |
Mar 1992 |
|