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1. WO1997041102 - DERIVES CARBOXAMIDE DE PYRROLIDINE, PIPERIDINE ET HEXAHYDROAZEPINE UTILISES DANS LE TRAITEMENT DE TROUBLES THROMBOTIQUES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

WE CLAIM:

1. A compound represented by the general formula (I):



(0

wherein M is (CH2)m or piperidin-1-yl;

wherein A is selected from any of piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl,

NHR2, or "9 wherein Rg is selected from any of H, alkyl,
CH(NH), CMe(NH) or acyl;

wherein Rio is H or C(0)N(R1 )YZ

wherein Ri is selected from H or cycloalkyl;

wherein R2 is selected from any of H, alkyl or acyl;

wherein R5 is H or C(0)NHQ(CHW)rCθ2Rβ; wherein Q is selected from CH2, CH-aryl, CH-heteroaryl, CH-substituted-heteroaryl or CH-alkyl; W is selected from H or N(R6)T-R7, wherein Re is selected from any of H, alkyl or acyl, T is selected fron C(O), C(N-CN) or SO2, and R7 is selected from any of alkyl, aryl, aralkyl, alkoxy, or aminoalkyl; and Rs is selected from H, alkyl or aralkyl.

wherein m is the integer 1 , 2, or 3;

wherein X is selected from any of C(O), C(0)0, C(0)NH, CH2, or S02;

wherein n is the integer 1 , 2, or 3;

wherein r is 0 or 1 ;

wherein R1 is selected from H or cycloalkyl;

wherein Y is selected from any of (CH2)p, CH(R3)(CH2)q,
(CH2)qCH(R3), (CH(COR4)CH2)q, (CH2)qCHOH or piperidine-3-carboxyiic acid; with the proviso that when Y is (CH2)p and p is 2, X is other than C(O) or when X is C(O) then either R1 is other than H or R2 is other than H, and with the proviso that when Y is (CH(Cθ2R4)CH2)q X is other than C(O) or

CH2;

wherein p is 2 or 3;

wherein q is 1 , 2, or 3;

wherein R3 is alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, aralkyl or heteroaryl;

wherein R4 is H or alkyl or cycloalkyl;

wherein Z is CO2H, Cθ2alkyl, SO3H, PO3H2 , or 5-tetrazole; provided that at least one of R5 and Ri 0 is hydrogen;
or the enantiomer or the pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R5 is H, R-| rj is H or C(0)N(R1 )YZ , M is (CH2)m and A is selected from any of piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl or
NHR2.

3. The compound of claim 1 , wherein R5 is H and R2 is hydrogen.

4. The compound of claim 1 , wherein R5 is H and m is 1or 2.

5. The compound of claim 1 , wherein R5 is H and X is C(O).

6. The compound of claim 1 , wherein R5 is H and R1 is hydrogen.

7. The compound of claim 1 , wherein R5 is H and Y is 4-oxo-nipecotic acid.

8. The compound of claim 1 , wherein R5 is H and q is 1.

9. The compound of claim 1 , wherein R5 is H and R3 is aryl.

10. The compound of claim 1 , wherein R5 is H and R4 is hydrogen.

11. The compound of claim 1 , wherein R5 is H and Z is CO2H.

12. The compound of claim 1 , wherein the group C(0)N(R1 )YZ is attached at the 3- or 4-position of the central azacycle.

13. The compound of claim 1 , wherein the group C(0)N(R1 )YZ is attached at the 3-position of the central azacycle.

14. The compound of claim 1 , selected from any of:

N-3-(4-Piperidinepropionyl)-nipecotyl-(3-amino-3-phenyl) propionic acid

N-(4-Piperidinemethylaminocarbonyl)-nipecotyl-(3-amino-2-methyl) propionic acid

N-(4-Piperidinemethyloxycarbonyl)-nipecotyl-D-aspartic acid α-methyl ester

N-3-(4-Piperidinepropionyl)-pyrrolidine-3-carboxy-[3-amino-3-(4-tolyl)] propionic acid

N-3-(4-Piperidinepropionyl)-isonipecotyl-(3-amino-3-methyl) propionic acid

N-3-(4-Piperidinepropionyl)-isonipecotyI-[3-amino-3-(4-carboxyphenyl)] propionic acid

N-3-(4-N-Methyl-piperidinepropionyl)-nipecotyl-3-aminopropionic acid

N-3-(4-Piperidinepropionyl)-nipecotyl-4-oxonipecotic acid N-3-(4-Piperidinepropionyl)-nipecotyl-[3-amino-3-(2-trimethylsilylethynyl)] propionic acid

N-(6-Aminocaproyl)-nipecotyl-3-amino-3-(3-pyridyl)propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-(3-amino-2-hydroxy) propionic acid

N-3-(4-Piperidineethanesulfonyl)-nipecotyl-3-aminopropionic acid

N-3-(4-Piperidinepropionyl)-nipecotyl-5H-(2-aminoethyl)tetrazole

N-3-(4-N-Methyl-piperazinepropionyl)-nipecotyl-[3-amino-3-(3,4-methylenedioxyphenyl)]propionic acid

N-3-(4-N-Methyl-piperazinepropionyl)-nipecotyl-[3-amino-3-(3,-quinolinyl)]propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(3,4-methylenedioxyphenyl)]propionic acid

N-3-(4-Piperidinepropionyl)-hexahydroazepine-3-carboxy-[3-amino-3-(3-quinolinyl)]propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(3-quinolinyl)]propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(2-f-butylethynyl)] propionic acid

N-3-(4-Piperidinepropyl)-nipecotyl-[(S)-3-amino-3-(3,4-methylenedioxyphenyl)]propionic acid, and

N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(3-pyridyl)] propionic acid.

15. The compound of claim 1, wherein Rι0 is H, R5 is H or

C(0)NHQ(CHW)rCOOR8, M is piperidin-1 -yl and A is

16. The compound of claim 1 , wherein R10 is H and X is C(O).

17. The compound of claim 1 , wherein R10 is H and Q is (CH2).

18. The compound of claim 1 , wherein R10 is H and W is N(R6)-T-R7.

19. The compound of claim 1 , wherein R10 is H and T is C(O).

20. The compound of claim 1 , wherein R10 is H and R9 is H.

21. The compound of claim 1 , wherein R10 is H and R6 is H.

22. The compound of claim 1 , wherein R10 is H and R7 is NH(CH2)zPh.

23. The compound of claim 1 , wherein R10 is H and R7 is H.

24. The compound of claim 1 , wherein n is 2.

25. The compound of claim 1 , selected from any of:

N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(3-methoxyanilino)carbonylamino-3-amino]propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-benzyloxycarbonylamino-3-amino]propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(3-chlorobenzyloxy)carbonylamino-3-amino]propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-benzylsulfonylamino-3-amino]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(3,5-dimethoxyanilino)carbonylamino-3-amino]propionic acid

N-[(4,4'-Bipiperidin-1-yl-)carbonyl]-R-(-)-nipecotyl-[(S)-3-amino-3-(3-pyridyl)] propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(2-naphthylamino)carbonylamino-3-amino]propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-aminomethyl-5-(S)-(3-N-benzyl)imidazoline-2,4-dione • HCI

N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(2-phenethylamino)carbonylamino-3-amino]propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-3-amino-3-(6-methyl-3-pyridyl)] propionic acid

N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-3-amino-3-(5-bromo-3-pyridyl)] propionic acid, and

N-3-(4-Formamidinopiperidinepropionyl)-R-(-)nipecotyl-[(S)-3-amino-3-(3-pyridyl)] propionic acid.

26. A composition for treating platelet-mediated thrombotic disorders comprising the compound of Claim 1 in an effective amount for treating such disorders in combination with a pharmaceutically acceptable carrier.

27. A method of treating platelet-mediated thrombotic disorders comprising administering to a patient afflicted with such disorder an effective amount of the compound of Claim 1 to treat such disorder.

28. The method of Claim 17, wherein the amount is 0.1 -300 mg/kg/day.

29. A process for preparing a compound of the formula AG4



AG4

comprising treating a compound of the formula AG3



AG3

with penicillin amidase.

30. The process of claim 19, wherein the compound of the formula AG3 was placed in a water solution and the pH was adjusted to about 7.5 prior to treatment with penicillin amidase.

31. A compound of the formula AG4:



AG4