Claims for Patent: 5,250,542

Summary for Patent: 5,250,542

Title:	Peripherally selective piperidine carboxylate opioid antagonists
Abstract:	3,4,4-trisubstitutedpiperidinyl-N-alkylcarboxylates and intermediates for their preparation are provided. These piperidine-N-alkylcarboxylates are useful as peripheral opioid antagonists.
Inventor(s):	Cantrell; Buddy E. (Fountaintown, IN), Zimmerman; Dennis M. (Mooresville, IN)
Assignee:	Eli Lilly and Company (Indianapolis, IN)
Application Number:	07/916,783
Patent Claims:	1. A trans-3,4 isomer of a compound of the formula (I) ##STR14## wherein R.sup.1 is hydrogen or C.sub.1 -C.sub.5 alkyl; R.sup.2 is hydrogen, C.sub.1 -C.sub.5 alkyl or C.sub.2 -C.sub.6 alkenyl; R.sup.3 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, phenyl, cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, cycloalkyl-substituted C.sub.1 -C.sub.3, alkyl C.sub.5 -C.sub.8 cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl or phenyl-substituted C.sub.1 -C.sub.3 alkyl; wherein: R.sup.4 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl, C.sub.5 -C.sub.8 cycloalkenyl-substituted C.sub.1 -C.sub.3 alkyl or phenyl-substituted C.sub.1 -C.sub.3 alkyl; R.sup.5 is hydrogen or C.sub.1 -C.sub.3 alkyl; R.sup.6 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, cycloalkyl, phenyl, cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl, C.sub.5 -C.sub.8 cycloalkenyl, C.sub.5 -C.sub.8 cycloalkenyl-substituted C.sub.1 -C.sub.3 alkyl, phenyl-substituted C.sub.1 -C.sub.3 alkyl, or (CH.sub.2).sub.q --B; or R.sup.5 and R.sup.6 together with N form a saturated non aromatic 4- to 6-membered heterocyclic ring; ##STR15## R.sup.7 is hydrogen or C.sub.1 -C.sub.3 alkyl; R.sup.8 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl, cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, C.sub.5 -C.sub.8 cycloalkenyl-substituted C.sub.1 -C.sub.3 alkyl, phenyl or phenyl-substituted C.sub.1 -C.sub.3 alkyl; or R.sup.7 and R.sup.8 together with N form a saturated non aromatic 4- to 6-membered heterocyclic ring; W is OR.sup.9, NR.sup.10 R.sup.11, or OE; R.sup.9 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl, C.sub.5 -C.sub.8 cycloalkenyl-substituted C.sub.1 -C.sub.3 alkyl or phenyl-substituted C.sub.1 -C.sub.3 alkyl; R.sup.10 is hydrogen or C.sub.1 -C.sub.3 alkyl; R.sup.11 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, phenyl, cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl, phenyl-substituted C.sub.1 -C.sub.3 alkyl, ##STR16## R.sup.10 and R.sup.11 together with N form a saturated non aromatic 4- 6-membered heterocyclic ring; ##STR17## R.sup.12 is C.sub.1 -C.sub.3 alkyl substituted methylene, R.sup.13 is C.sub.1 -C.sub.10 alkyl; D is OR.sup.14 or NR.sup.15 R.sup.16 ; wherein: R.sup.14 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl, or C.sub.5 -C.sub.8 cycloalkenyl-substituted C.sub.1 -C.sub.3 alkyl or phenyl-substituted C.sub.1 -C.sub.3 alkyl; R.sup.15 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, phenyl, phenyl-substituted C.sub.1 -C.sub.3 alkyl, cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl or C.sub.5 -C.sub.8 cycloalkenyl-substituted C.sub.1 -C.sub.3 alkyl; and R.sup.16 is hydrogen or C.sub.1 -C.sub.3 alkyl; or R.sup.15 and R.sup.16 together with N form a saturated non aromatic 4- to 6-membered heterocyclic ring; Y is OR.sup.17 or NR.sup.18 R.sup.19 ; R.sup.17 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl, C.sub.5 -C.sub.8 cycloalkenyl-substituted C.sub.1 -C.sub.3 alkyl, or phenyl-substituted C.sub.1 -C.sub.3 alkyl; R.sup.18 is hydrogen or C.sub.1 -C.sub.3 alkyl; and R.sup.19 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, phenyl, cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl, C.sub.5 -C.sub.8 cycloalkenyl-substituted C.sub.1 -C.sub.3 alkyl, or phenyl-substituted C.sub.1 -C.sub.3 alkyl; or R.sup.18 and R.sup.19 together with N form a saturated non aromatic 4- to 6-membered heterocyclic ring; n is 0-; q is 1-4; m is 1-4; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein R.sup.1 is hydrogen; R.sup.2 is C.sub.1 -C.sub.3 alkyl; n=1 or 2; and R.sup.3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl. 3. The compound of claim 2 wherein A is OR.sup.4 and R.sup.4 is hydrogen or C.sub.1 -C.sub.3 alkyl. 4. The compound of claim 2 wherein A is NR.sup.5 R.sup.6 in which R.sup.5 is hydrogen and R.sup.6 is (CH.sub.2).sub.q --B wherein q is 1 to 3 and B is --C(O)W. 5. The compound of claim 4 wherein W is OR.sup.9 and R.sup.9 is hydrogen, C.sub.1 -C.sub.5 alkyl, phenyl-substituted C.sub.1 -C.sub.2 alkyl, C.sub.5 -C.sub.6 cycloalkyl, or C.sub.5 -C.sub.6 cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl. 6. The compound of claim 4 wherein W is NR.sup.10 R.sup.11 in which R.sup.10 is hydrogen or C.sub.1 -C.sub.3 alkyl, and R.sup.11 is hydrogen, C.sub.1 -C.sub.3 alkyl or (CH.sub.2).sub.m C(O)Y. 7. The compound of claim 6 wherein m is 1 to 3 and Y is OR.sup.17 or NR.sup.18 R.sup.19 wherein R.sup.17, R.sup.18 and R.sup.19 are independently hydrogen or C.sub.1 -C.sub.3 alkyl. 8. The compound of claim 4 wherein W is OCH.sub.2 C(O)OD in which D is OR.sup.14 or NR.sup.15 R.sup.16 wherein R.sup.14 is hydrogen or C.sub.1 -C.sub.3 alkyl, R.sup.15 is hydrogen and R.sup.16 is methyl or benzyl. 9. The compound of claim 4 wherein W is OR.sup.12 O C(O)R.sup.13, wherein R.sup.12 is --CH(CH.sub.3)-- or --CH(CH.sub.2 CH.sub.3)-- and R.sup.13 is C.sub.1 -C.sub.3 alkyl. 10. The compound of claim 1 wherein the configuration at positions 3 and 4 of the piperidine ring is each R. 11. The compound of claim 1 selected from the group consisting of QCH.sub.2 CH[CH.sub.2 (C.sub.6 H.sub.5)]C(O)OH, QCH.sub.2 CH.sub.2 CH(C.sub.6 H.sub.5)C(O)NHCH.sub.2 C(O)-OCH.sub.2 CH.sub.2, QCH.sub.2 CH.sub.2 CH(C.sub.6 H.sub.5)C(O)NHCH.sub.2 C(O)OH, Q-CH.sub.2 CH.sub.2 CH-(C.sub.6 H.sub.5)C(O)NHCH.sub.2 C(O)NHCH.sub.3, Q-CH.sub.2 CH.sub.2 CH(C.sub.6 H.sub.5)C(O)NHCH.sub.2 C(O)-NHCH.sub.2 CH.sub.3, G-NH(CH.sub.2).sub.2 C(O)NH.sub.2, G-NH(CH.sub.2).sub.2 C(O)NHCH.sub.3, G-NHCH.sub.2 C(O)NH.sub.2, G-NHCH.sub.2 C(O)NHCH.sub.3, G-NHCH.sub.3 C(O)NHCH.sub.2 CH.sub.3, G-NH(CH.sub.2).sub.3 C(O)OCH.sub.2 CH.sub.3, G-NH(CH.sub.2).sub.3 C(O)NHCH.sub.3, G-NH(CH.sub.2).sub.2 C(O)-OH, G-NH(CH.sub.2).sub.3 C(O)OH, QCH.sub.2 CH[CH.sub.2 (C.sub.6 H.sub.11)]C(O)NHCH.sub.2 C(O)OH, QCH.sub.2 CH[CH.sub.2 (C.sub.6 H.sub.11)]C(O)NH(CH.sub.2) .sub.2 C(O)OH, QCH.sub.2 CH[CH.sub.2 (C.sub.6 H.sub.11)]-C(O)NH(CH.sub.2).sub.2 C(O)NH.sub.2, Z-NHCH.sub.2 C(O)OCH.sub.2 CH.sub.3, Z-NHCH.sub.2 C(O)OH, Z-NHCH.sub.2 C(O)NH.sub.2, Z-NHCH.sub.2 C(O)N(CH.sub.3).sub.2, Z-NHCH.sub.2 C(O)NHCH(CH.sub.3).sub.2, Z-NHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, Z-NH(CH.sub.2).sub.2 C(O)OCH.sub.2 (C.sub.6 H.sub.5), Z-NH-(CH.sub.2 C(O)OH, Z-NH(CH.sub.2).sub.2 C(O)NHCH.sub.2 CH.sub.3, Z-NH(CH.sub.2).sub.3 C(O)NHCH.sub.3, Z-NHCH.sub.2 C(O)NHCH.sub.2 C(O)OH, Z-NHCH.sub.2 C(O)OCH.sub.2 C(O)OCH.sub.3, Z-NHCH.sub.2 -C(O)O(CH.sub.2).sub.4 CH.sub.3, Z-NHCH.sub.2 C(O)OCH.sub.2 C(O)NHCH.sub.3, Z-NHCH.sub.2 C(O)O-(4-methoxycyclohexyl), Z-NHCH.sub.2 C(O)OCH.sub.2 C(O)NHCH.sub.2 (C.sub.6 H.sub.5), and Z-NHCH.sub.2 C(O)OCH(CH.sub.3)OC(O)CH.sub.3, wherein: ##STR18## and pharmaceutically acceptable salts thereof. 12. A compound of claim 11 selected from the group consisting of (3R,4R,S)-Z-NHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (+)Z-NHCH.sub.2 C(O)OH, (--)Z-NHCH.sub.2 C(O)OH, (3R,4R,R)-ZNHCH.sub.2 C(O)-OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,S)-ZNHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,R)-ZNHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3R,4R)-ZNHCH.sub.2 C(O)NHCH.sub.2 (C.sub.6 H.sub.5) and (3R,4R)-G-NH(CH.sub.2).sub.3 C(O)OH, and pharmaceutically acceptable salts thereof. 13. A substantially pure stereoisomer of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 14. A pharmaceutical formulation comprising a compound of claim 1 or the salt thereof in combination with a pharmaceutically acceptable excipient. 15. A pharmaceutical formulation comprising a compound of claim 11 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient. 16. A method for treating irritable bowel syndrome in a patient said method comprising administering to said patient an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 17. A method for binding a peripheral opioid receptor in a patient which comprises administering to said patient an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 18. The method of claim 17 wherein said peripheral effect being treated is constipation, nausea or vomiting. 19. A method for blocking mu receptors in mammals comprising administering to a mammal requiring blocking of a mu receptor a receptor blocking dose of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 20. A method for treating idiopathic constipation in a patient said method comprising administering to said patient an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 21. A method of claim 16 wherein the compound is one wherein R.sup.1 is hydrogen; R.sup.2 is C.sub.1 -C.sub.3 alkyl; n=1 or 2; and R.sup.3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl. 22. A method of claim 21 wherein the compound is one wherein A is NR.sup.5 R.sup.6 and R.sup.5 is hydrogen, R.sup.6 is (CH.sub.2).sub.q --B, q is 1 to 3 and B is --C(O)W. 23. A method of claim 22 wherein the compound is one wherein W is OR.sup.9 and R.sup.9 is hydrogen, C.sub.1 -C.sub.5 alkyl, phenyl-substituted C.sub.1 -C.sub.2 alkyl, C.sub.5 -C.sub.6 cycloalkyl, or C.sub.5 -C.sub.6 cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl. 24. A method for treating irritable bowel syndrome in a patient comprising administering to the patient an effective amount of a compound of claim 11. 25. A method of claim 24 wherein the compound is selected from the group consisting of (3R,4R,S)-Z-NHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (+)Z-NHCH.sub.2 C(O)OH, (--)Z-NHCH.sub.2 C(O)OH, (3R,4R,R)-ZNHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,S)-ZNCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,R)-ZNHCH.sub.2 C(O)OCH.sub.2 CH-(CH.sub.3).sub.2, (3R,4R)-ZNHCH.sub.2 C(O)NHCH.sub.2 (C.sub.6 H.sub.5) and (3R,4R)-G-NH(CH.sub.2).sub.3 C(O)OH. 26. A method of claim 18 wherein the compound is one wherein R.sup.1 is hydrogen; R.sup.2 is C.sub.1 -C.sub.3 alkyl; n=1 or 2; and R.sup.3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl. 27. A method of claim 26 wherein the compound is one wherein A is NR.sup.5 R.sup.6 and R.sup.5 is hydrogen, R.sup.6 is (C.sub.2).sub.q --B, q is 1 to 3 and B is --C(O)W. 28. A method of claim 27 wherein the compound is one wherein W is OR.sup.9 and R.sup.9 is hydrogen, C.sub.1 -C.sub.5 alkyl, phenyl-substituted C.sub.1 -C.sub.2 alkyl, C.sub.5 -C.sub.6 cycloalkyl, or C.sub.5 -C.sub.6 cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl. 29. A method for binding a peripheral opioid receptor in a patient which comprises administering to said patient an effective amount of a compound of claim 11. 30. A method of claim 29 wherein the compound is one selected from the group consisting of (3R,4R,S)-Z-NHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (+)Z-NHCH.sub.2 C(O)OH, (--)Z-NHCH.sub.2 C(O)OH, (3R,4R,R)-ZNHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,S)-ZNCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,R)-ZNHCH.sub.2 C(O)OCH.sub.2 CH-(CH.sub.3).sub.2, (3R,4R)-ZNHCH.sub.2 C(O)NHCH.sub.2 (C.sub.6 H.sub.5) and (3R,4R)-G-NH(CH.sub.2).sub.3 C(O)OH. 31. A method of claim 19 wherein the compound is one wherein R.sup.1 is hydrogen; R.sup.2 is C.sub.1 -C.sub.3 alkyl; n=1 or 2; and R.sup.3 is benzyl, phenyl, cyclohexyl or cyclohexylmethyl. 32. A method of claim 31 wherein the compound is one wherein A is NR.sup.5 R.sup.6 and R.sup.5 is hydrogen, R.sup.6 is (CH.sub.2).sub.q --B, q is 1 to 3 and B is --C(O)W. 33. A method of claim 32 wherein the compound is one wherein W is OR.sup.9 and R.sup.9 is hydrogen, C.sub.1 -C.sub.5 alkyl, phenyl-substituted C.sub.1 -C.sub.2 alkyl, C.sub.5 -C.sub.6 cycloalkyl, or C.sub.5 -C.sub.6 cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl. 34. A method for blocking a mu receptor in a mammal comprising administering to a mammal requiring blocking of a mu receptor a receptor blocking dose of a compound of claim 11. 35. A method of claim 34 wherein the compound is one selected from the group consisting of (3R,4R,S)-Z-NHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (+)Z-NHCH.sub.2 C(O)OH, (--)Z-NHCH.sub.2 C(O)OH, (3R,4R,R)-ZNHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,S)-ZNCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,R)-ZNHCH.sub.2 C(O)OCH.sub.2 -CH(CH.sub.3).sub.2, (3R,4R)-ZNHCH.sub.2 C(O)NHCH.sub.2 (C.sub.6 H.sub.5) and (3R,4R)-G-NH(CH.sub.2).sub.3 C(O)OH. 36. A method of claim 20 wherein the compound is one wherein R.sup.1 is hydrogen; R.sup.2 is C.sub.1 -C.sub.3 alkyl; n=1 or 2; and R.sup.3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl. 37. A method of claim 36 wherein the compound is one wherein A is NR.sup.5 R.sup.6 and R.sup.5 is hydrogen, R.sup.6 is (CH.sub.2).sub.q --B, q is 1 to 3 and B is --C(O)W. 38. A method of claim 37 wherein the compound is one wherein W is OR.sup.9 and R.sup.9 is hydrogen, C.sub.1 -C.sub.5 alkyl, phenyl-substituted C.sub.1 -C.sub.2 alkyl, C.sub.5 -C.sub.6 cycloalkyl, or C.sub.5 -C.sub.6 cycloalkyl-substituted C.sub.1 -C.sub.3 alkyl. 39. A method for treating idiopathic constipation in a patient comprising administering to the patient an effective amount of a compound of claim 11. 40. A method of claim 39 wherein the compound is one selected from the group consisting of (3R,4R,S)-Z-NHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (+)Z-NHCH.sub.2 C(O)OH, (--)Z-NHCH.sub.2 C(O)OH, (3R,4R,R)-ZNHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,S)-ZNHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,R)-ZNHCH.sub.2 C(O)OCH.sub.2 CH-(CH.sub.3).sub.2, (3R,4R)-ZNHCH.sub.2 C(O)NHCH.sub.2 (C.sub.6 H.sub.5) and (3R,4R)-G-NH(CH.sub.2).sub.3 C(O)OH.