Claims
- 1. A compound represented by the general formula (I): ##STR9## wherein M is (CH.sub.2).sub.m, CH.dbd.CH or C.tbd.C; A is selected from any of piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, NHR.sub.2 or ##STR10## wherein R.sub.9 is selected from any of H, alkyl, CH(NH), CMe(NH) or acyl;
- R.sub.10 is H or C(O)N(R.sup.1)YZ,
- wherein R.sup.1 is selected from H or cycloalkyl;
- R.sub.2 is selected from any of H, alkyl or acyl;
- R.sub.5 is H or C(O)NHQ(CHW).sub.r CO.sub.2 R.sub.8 ; wherein Q is selected from CH.sub.2, CH-aryl, CH-heteroaryl, CH-substituted-heteroaryl or CH-alkyl; W is selected from H or N(R.sub.6)T-R.sub.7 ; wherein R.sub.6 is selected from any of H, alkyl or acyl; T is selected from C(O), C(N-CN) or SO.sub.2 ; R.sub.7 is selected from any of alkyl, aryl, aralkyl, alkoxy, or aminoalkyl; and R.sub.8 is CH.sub.2 C(O)NR.sub.11 R.sub.12, wherein R.sub.11 and R.sub.12 are selected from H, alkyl, or cycloalkyl;
- m is the integer 1, 2, or 3;
- X is selected from any of C(O), C(O)O, C(O)NH, CH.sub.2, or SO.sub.2 ;
- n is the integer 1, 2, or 3;
- r is 0 or 1;
- Y is selected from any of (CH.sub.2).sub.p, CH(R.sup.3) (CH.sub.2).sub.q, (CH.sub.2).sub.q CH(R.sup.3), (CH(CO.sub.2 R.sup.4)CH.sub.2).sub.q, (CH.sub.2).sub.q CHOH or piperidine-3-carboxylic acid; with the proviso that when Y is (CH.sub.2).sub.p and p is 2, X is other than C(O) or when X is C(O) then either R.sup.1 is other than H or R.sub.2 is other than H, and with the proviso that when Y is (CH(CO.sub.2 R.sup.4)CH.sub.2).sub.q X is other than C(O) or CH.sub.2 ;
- p is 2 or 3;
- q is 1, 2, or 3;
- R.sup.3 is alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, aryl, aralkyl or heteroaryl;
- R.sup.4 is H or alkyl or cycloalkyl;
- Z is Ct.sub.2 CHC(O)NR.sub.11 R.sub.12 ; provided that at least one of R.sub.5 and R.sub.10 is hydrogen and R.sub.5 and R.sub.10 are not hydrogen at the same time;
- or the enantiomer or the pharmaceutically acceptable salt thereof.
- 2. The compound of claim 1 wherein the group C(O)N(R.sub.1)YZ is attached at the 3- or 4-position of the central azacycle.
- 3. The compound of claim 1 wherein the group C(O)N(R.sub.1)YZ is attached at the 3-position of the central azacycle.
- 4. The compound of claim 1 wherein R.sub.5 is C(O)NHQ(CHW).sub.r CO.sub.2 R.sub.8.
- 5. A compound of claim 1 of the formula: ##STR11## wherein M is (CH.sub.2).sub.m, CH.dbd.CH or C.tbd.C; A is selected from any of piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, NHR.sub.2 or ##STR12## wherein R.sub.9 is selected from any of H, alkyl, CH(NH), CMe(NH) or acyl;
- R.sub.10 is H or C(O)N(R.sup.1)YZ,
- wherein R.sup.1 is selected from H or cycloalkyl;
- R.sub.2 is H;
- R.sub.5 is H or C(O)NHQ(CHW).sub.r CO.sub.2 R.sub.8 ; wherein Q is selected from CH.sub.2, CH-heteroaryl or CH-substituted-heteroaryl; W is selected from H or N(R.sub.6)T-R.sub.7 ; wherein R.sub.6 is H; T is C(O); R.sub.7 is selected from any of alkyl, aryl, aralkyl, alkoxy, or aminoalkyl; and R.sub.8 is CH.sub.2 C(O)NR.sub.11 R.sub.12 ; wherein R.sub.11 and R.sub.12 are alkyl;
- m is the integer 1 or 2;
- X is selected from any of C(O), C(O)O, C(O)NH, CH.sub.2, or SO.sub.2 ;
- n is the integer 1, 2, or 3;
- r is 0 or 1;
- Y is selected from any of (CH.sub.2).sub.p, CH(R.sup.3) (CH.sub.2).sub.q, (CH.sub.2).sub.q CH(R.sup.3), (CH(CO.sub.2 R.sup.4)CH.sub.2).sub.q, (CH.sub.2).sub.q CHOH or piperidine-3-carboxylic acid; with the proviso that when Y is (CH.sub.2).sub.p and p is 2, X is other than C(O) or when X is C(O) then either R.sup.1 is other than H or R.sup.2 is other than H, and with the proviso that when Y is (CH(CO.sub.2 R.sup.4)CH.sub.2).sub.q X is other than C(O) or CH.sub.2 ;
- p is 2 or 3;
- q is 1;
- R.sup.3 is alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, aryl, aralkyl or heteroaryl;
- R.sup.4 is H;
- Z is CO.sub.2 CH.sub.2 C(O)NR.sub.11 R.sub.12 ; provided that at least one of R.sub.5 and R.sub.10 is hydrogen;
- or the enantiomer or the pharmaceutically acceptable salt thereof.
- 6. The compound of claim 5 wherein the group C(O)N(R.sup.1)YZ is attached at the 3- or 4-position of the central azacycle.
- 7. The compound of claim 5 wherein the group C(O)N(R.sup.1)YZ is attached at the 3-position of the central azacycle.
- 8. The compound of claim 5 wherein R.sub.5 is C(O)NHQ(CHW).sub.r CO.sub.2 R.sub.8.
- 9. The compound of claim 1 wherein:
- R.sub.5 is H or C(O)NHQ(CHW).sub.r CO.sub.2 R.sub.8 ; wherein Q is selected from CH.sub.2, CH-heteroaryl or CH-substituted-heteroaryl; W is selected from H or N(R.sub.6)T-R.sub.7 ; wherein R.sub.6 is H; T is C(O); R.sub.7 is selected from any of alkyl, aryl, aralkyl, alkoxy, or aminoalkyl; and R.sub.8 is CH.sub.2 C(O)NR.sub.11 R.sub.12 ; wherein R.sub.11 and R.sub.12 are alkyl.
- 10. The compound of claim 1 of the formula: ##STR13## wherein R.sub.11 and R.sub.12 are alkyl or taken together are (CH.sub.2).sub.5 ; R.sub.13 is selected from H, 3-pyridyl, 3,4-OCH.sub.2 Ph and 3-bromo-3-pyridyl; and R.sub.14 is selected from H, and NHCO.sub.2 H.sub.2 Ph.
- 11. The compound of claim 1, selected from any of:
- N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(3-pyridyl)] propionic acid 2-(Diethylamino)-2-oxoethyl ester.cndot.2HCl,
- N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(3,4-methylenedioxyphenyl)] propionic acid 2-(Diethylamino)-2-oxoethyl ester.cndot.2HCl,
- N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(5-bromo-3-pyridyl)] propionic acid 2-(Diethylamino)-2-oxoethyl ester.cndot.2HCl,
- N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-benzyloxycarbonylamino-3-amino]propionic acid 2-(Diethylamino)-2-oxoethyl ester.cndot.HCl,
- N-t-Butoxycarbonyl-4-piperidine-3-propenoic acid,
- N-3-(4Piperidinepropenoyl)-R-(-)nipecotyl-[(S)-2-benzyloxycarbonylamino-3-amino]propionic acid 2-(Diethylamino)-2-oxoethyl ester.cndot.HCl, and
- N-3-(4Piperidinepropenoyl)-R-(-)nipecotyl-[(S)-2-benzyloxycarbonylamino-3-amino]propionic acid 2-(Piperidino)-2-oxoethyl ester.cndot.HCl.
- 12. The compound of claim 1 which is:
- N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(3-pyridyl)]propionic acid 2-(Diethylamino)-2-oxoethyl ester.
- 13. A pharmaceutical composition for treating platelet-mediated thrombic disorders comprising the compound of claim 1 in an effective amount for treating such disorders in combination with a pharmaceutically acceptable carrier.
- 14. A method of making the composition of claim 13 comprising mixing an effective amount of the compound with a pharmaceutically acceptable carrier.
- 15. A method of treating platelet-mediated thrombic disorders comprising administering to a patient afflicted with such disorder an effective amount of the compound of claim 1 to treat such disorder.
- 16. The method of claim 15, wherein the amount is 0.1-300 mg/kg/day.
- 17. A method of treating platelet-mediated thrombic disorders comprising administering to a patient afflicted with such disorder an effective amount of the composition of claim 13 to treat such disorder.
- 18. A method of inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient an effective amount of the compound of claim 1.
- 19. The method of claim 18, wherein the amount is 0.1-300 mg/kg/day.
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority from U.S. Ser. No. 60/063366, filed Oct. 29, 1997, the contents of which are hereby incorporated by reference.
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