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):	Buddy E. Cantrell, Dennis M. Zimmerman
Assignee:	Eli Lilly and Co
Application Number:	US07/916,783
Patent Claims:	1. A trans-3,4 isomer of a compound of the formula (I) ##STR14## wherein R1 is hydrogen or C1 -C5 alkyl;R2 is hydrogen, C1 -C5 alkyl or C2 -C6 alkenyl; R3 is hydrogen, C1 -C10 alkyl, C3 -C10 alkenyl, phenyl, cycloalkyl, C5 -C8 cycloalkenyl, cycloalkyl-substituted C1 -C3, alkyl C5 -C8 cycloalkyl-substituted C1 -C3 alkyl or phenyl-substituted C1 -C3 alkyl; A is OR.sup.4 or NR.sup.5 R.sup.6 ; wherein: R4 is hydrogen, C1 -C10 alkyl, C2 -C10 alkenyl, cycloalkyl, C5 -C8 cycloalkenyl, cycloalkyl-substituted C1 -C3 alkyl, C5 -C8 cycloalkenyl-substituted C1 -C3 alkyl or phenyl-substituted C1 -C3 alkyl; R5 is hydrogen or C1 -C3 alkyl; R6 is hydrogen, C1 -C10 alkyl, C3 -C10 alkenyl, cycloalkyl, phenyl, cycloalkyl-substituted C1 -C3 alkyl, C5 -C8 cycloalkenyl, C5 -C8 cycloalkenyl-substituted C1 -C3 alkyl, phenyl-substituted C1 -C3 alkyl, or (CH2)q --B; or R5 and R6 together with N form a saturated non aromatic 4- to 6-membered heterocyclic ring; ##STR15## R7 is hydrogen or C1 -C3 alkyl; R8 is hydrogen, C1 -C10 alkyl, C3 -C10 alkenyl, cycloalkyl-substituted C1 -C3 alkyl, cycloalkyl, C5 -C8 cycloalkenyl, C5 -C8 cycloalkenyl-substituted C1 -C3 alkyl, phenyl or phenyl-substituted C1 -C3 alkyl; or R7 and R8 together with N form a saturated non aromatic 4- to 6-membered heterocyclic ring; W is OR9, NR10 R11, or OE; R9 is hydrogen, C1 -C10 alkyl, C2 -C10 alkenyl, cycloalkyl, C5 -C8 cycloalkenyl, cycloalkyl-substituted C1 -C3 alkyl, C5 -C8 cycloalkenyl-substituted C1 -C3 alkyl or phenyl-substituted C1 -C3 alkyl; R10 is hydrogen or C1 -C3 alkyl; R11 is hydrogen, C1 -C10 alkyl, C3 -C10 alkenyl, phenyl, cycloalkyl, C5 -C8 cycloalkenyl, cycloalkyl-substituted C1 -C3 alkyl, phenyl-substituted C1 -C3 alkyl, ##STR16## R10 and R11 together with N form a saturated non aromatic 4- 6-membered heterocyclic ring; ##STR17## R12 is C1 -C3 alkyl substituted methylene, R13 is C1 -C10 alkyl; D is OR14 or NR15 R16 ;wherein: R14 is hydrogen, C1 -C10 alkyl, C2 -C10 alkenyl, cycloalkyl, C5 -C8 cycloalkenyl, cycloalkyl-substituted C1 -C3 alkyl, or C5 -C8 cycloalkenyl-substituted C1 -C3 alkyl or phenyl-substituted C1 -C3 alkyl; R15 is hydrogen, C1 -C10 alkyl, C3 -C10 alkenyl, phenyl, phenyl-substituted C1 -C3 alkyl, cycloalkyl, C5 -C8 cycloalkenyl, cycloalkyl-substituted C1 -C3 alkyl or C5 -C8 cycloalkenyl-substituted C1 -C3 alkyl; and R16 is hydrogen or C1 -C3 alkyl; or R15 and R16 together with N form a saturated non aromatic 4- to 6-membered heterocyclic ring; Y is OR17 or NR18 R19 ; R17 is hydrogen, C1 -C10 alkyl, C2 -C10 alkenyl, cycloalkyl, C5 -C8 cycloalkenyl, cycloalkyl-substituted C1 -C3 alkyl, C5 -C8 cycloalkenyl-substituted C1 -C3 alkyl, or phenyl-substituted C1 -C3 alkyl; R18 is hydrogen or C1 -C3 alkyl; and R19 is hydrogen, C1 -C10 alkyl, C3 -C10 alkenyl, phenyl, cycloalkyl, C5 -C8 cycloalkenyl, cycloalkyl-substituted C1 -C3 alkyl, C5 -C8 cycloalkenyl-substituted C1 -C3 alkyl, or phenyl-substituted C1 -C3 alkyl; or R18 and R19 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 R1 is hydrogen; R2 is C1 -C3 alkyl; n=1 or 2; and R3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl. 3. The compound of claim 2 wherein A is OR4 and R4 is hydrogen or C1 -C3 alkyl. 4. The compound of claim 2 wherein A is NR5 R6 in which R5 is hydrogen and R6 is (CH2)q --B wherein q is 1 to 3 and B is --C(O)W. 5. The compound of claim 4 wherein W is OR9 and R9 is hydrogen, C1 -C5 alkyl, phenyl-substituted C1 -C2 alkyl, C5 -C6 cycloalkyl, or C5 -C6 cycloalkyl-substituted C1 -C3 alkyl. 6. The compound of claim 4 wherein W is NR10 R11 in which R10 is hydrogen or C1 -C3 alkyl, and R11 is hydrogen, C1 -C3 alkyl or (CH2)m C(O)Y. 7. The compound of claim 6 wherein m is 1 to 3 and Y is OR17 or NR18 R19 wherein R17, R18 and R19 are independently hydrogen or C1 -C3 alkyl. 8. The compound of claim 4 wherein W is OCH2 C(O)OD in which D is OR14 or NR15 R16 wherein R14 is hydrogen or C1 -C3 alkyl, R15 is hydrogen and R16 is methyl or benzyl. 9. The compound of claim 4 wherein W is OR12 O C(O)R13, wherein R12 is --CH(CH3)-- or --CH(CH2 CH3)-- and R13 is C1 -C3 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 ofQCH2 CH[CH2 (C6 H5)]C(O)OH, QCH2 CH2 CH(C6 H5)C(O)NHCH2 C(O)-OCH2 CH2, QCH2 CH2 CH(C6 H5)C(O)NHCH2 C(O)OH, Q-CH2 CH2 CH-(C6 H5)C(O)NHCH2 C(O)NHCH3, Q-CH2 CH2 CH(C6 H5)C(O)NHCH2 C(O)-NHCH2 CH3, G-NH(CH2)2 C(O)NH2, G-NH(CH2)2 C(O)NHCH3, G-NHCH2 C(O)NH2, G-NHCH2 C(O)NHCH3, G-NHCH3 C(O)NHCH2 CH3, G-NH(CH2)3 C(O)OCH2 CH3, G-NH(CH2)3 C(O)NHCH3, G-NH(CH2)2 C(O)-OH, G-NH(CH2)3 C(O)OH, QCH2 CH[CH2 (C6 H11)]C(O)NHCH2 C(O)OH, QCH2 CH[CH2 (C6 H11)]C(O)NH(CH2) 2 C(O)OH, QCH2 CH[CH2 (C6 H11)]-C(O)NH(CH2)2 C(O)NH2, Z-NHCH2 C(O)OCH2 CH3, Z-NHCH2 C(O)OH, Z-NHCH2 C(O)NH2, Z-NHCH2 C(O)N(CH3)2, Z-NHCH2 C(O)NHCH(CH3)2, Z-NHCH2 C(O)OCH2 CH(CH3)2, Z-NH(CH2)2 C(O)OCH2 (C6 H5), Z-NH-(CH2 C(O)OH, Z-NH(CH2)2 C(O)NHCH2 CH3, Z-NH(CH2)3 C(O)NHCH3, Z-NHCH2 C(O)NHCH2 C(O)OH, Z-NHCH2 C(O)OCH2 C(O)OCH3, Z-NHCH2 -C(O)O(CH2)4 CH3, Z-NHCH2 C(O)OCH2 C(O)NHCH3, Z-NHCH2 C(O)O-(4-methoxycyclohexyl), Z-NHCH2 C(O)OCH2 C(O)NHCH2 (C6 H5), and Z-NHCH2 C(O)OCH(CH3)OC(O)CH3, wherein: ##STR18## and pharmaceutically acceptable salts thereof. 12. A compound of claim 11 selected from the group consisting of (3R,4R,S)-Z-NHCH2 C(O)OCH2 CH(CH3)2, (+)Z-NHCH2 C(O)OH, (--)Z-NHCH2 C(O)OH, (3R,4R,R)-ZNHCH2 C(O)-OCH2 CH(CH3)2, (3S,4S,S)-ZNHCH2 C(O)OCH2 CH(CH3)2, (3S,4S,R)-ZNHCH2 C(O)OCH2 CH(CH3)2, (3R,4R)-ZNHCH2 C(O)NHCH2 (C6 H5) and (3R,4R)-G-NH(CH2)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 R1 is hydrogen; R2 is C1 -C3 alkyl; n=1 or 2; and R3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl. 22. A method of claim 21 wherein the compound is one wherein A is NR5 R6 and R5 is hydrogen, R6 is (CH2)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 OR9 and R9 is hydrogen, C1 -C5 alkyl, phenyl-substituted C1 -C2 alkyl, C5 -C6 cycloalkyl, or C5 -C6 cycloalkyl-substituted C1 -C3 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-NHCH2 C(O)OCH2 CH(CH3)2, (+)Z-NHCH2 C(O)OH, (--)Z-NHCH2 C(O)OH, (3R,4R,R)-ZNHCH2 C(O)OCH2 CH(CH3)2, (3S,4S,S)-ZNCH2 C(O)OCH2 CH(CH3)2, (3S,4S,R)-ZNHCH2 C(O)OCH2 CH-(CH3)2, (3R,4R)-ZNHCH2 C(O)NHCH2 (C6 H5) and (3R,4R)-G-NH(CH2)3 C(O)OH. 26. A method of claim 18 wherein the compound is one wherein R1 is hydrogen; R2 is C1 -C3 alkyl; n=1 or 2; and R3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl. 27. A method of claim 26 wherein the compound is one wherein A is NR5 R6 and R5 is hydrogen, R6 is (C2)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 OR9 and R9 is hydrogen, C1 -C5 alkyl, phenyl-substituted C1 -C2 alkyl, C5 -C6 cycloalkyl, or C5 -C6 cycloalkyl-substituted C1 -C3 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-NHCH2 C(O)OCH2 CH(CH3)2, (+)Z-NHCH2 C(O)OH, (--)Z-NHCH2 C(O)OH, (3R,4R,R)-ZNHCH2 C(O)OCH2 CH(CH3)2, (3S,4S,S)-ZNCH2 C(O)OCH2 CH(CH3)2, (3S,4S,R)-ZNHCH2 C(O)OCH2 CH-(CH3)2, (3R,4R)-ZNHCH2 C(O)NHCH2 (C6 H5) and (3R,4R)-G-NH(CH2)3 C(O)OH. 31. A method of claim 19 wherein the compound is one wherein R1 is hydrogen; R2 is C1 -C3 alkyl; n=1 or 2; and R3 is benzyl, phenyl, cyclohexyl or cyclohexylmethyl. 32. A method of claim 31 wherein the compound is one wherein A is NR5 R6 and R5 is hydrogen, R6 is (CH2)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 OR9 and R9 is hydrogen, C1 -C5 alkyl, phenyl-substituted C1 -C2 alkyl, C5 -C6 cycloalkyl, or C5 -C6 cycloalkyl-substituted C1 -C3 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-NHCH2 C(O)OCH2 CH(CH3)2, (+)Z-NHCH2 C(O)OH, (--)Z-NHCH2 C(O)OH, (3R,4R,R)-ZNHCH2 C(O)OCH2 CH(CH3)2, (3S,4S,S)-ZNCH2 C(O)OCH2 CH(CH3)2, (3S,4S,R)-ZNHCH2 C(O)OCH2 -CH(CH3)2, (3R,4R)-ZNHCH2 C(O)NHCH2 (C6 H5) and (3R,4R)-G-NH(CH2)3 C(O)OH. 36. A method of claim 20 wherein the compound is one wherein R1 is hydrogen; R2 is C1 -C3 alkyl; n=1 or 2; and R3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl. 37. A method of claim 36 wherein the compound is one wherein A is NR5 R6 and R5 is hydrogen, R6 is (CH2)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 OR9 and R9 is hydrogen, C1 -C5 alkyl, phenyl-substituted C1 -C2 alkyl, C5 -C6 cycloalkyl, or C5 -C6 cycloalkyl-substituted C1 -C3 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-NHCH2 C(O)OCH2 CH(CH3)2, (+)Z-NHCH2 C(O)OH, (--)Z-NHCH2 C(O)OH, (3R,4R,R)-ZNHCH2 C(O)OCH2 CH(CH3)2, (3S,4S,S)-ZNHCH2 C(O)OCH2 CH(CH3)2, (3S,4S,R)-ZNHCH2 C(O)OCH2 CH-(CH3)2, (3R,4R)-ZNHCH2 C(O)NHCH2 (C6 H5) and (3R,4R)-G-NH(CH2)3 C(O)OH.