Claims for Patent: 6,469,030

Summary for Patent: 6,469,030

Title:	Methods for the treatment and prevention of ileus
Abstract:	Methods for the treatment and/or prevention of ileus are disclosed. The methods comprise administering to a patient an effective amount of a peripheral mu opioid antagonist compound. Preferred compounds for use in the methods include piperidine-N-alkylcarboxylates.
Inventor(s):	John J. Farrar, Peter J. Schied, William K. Schmidt, Randall L. Carpenter
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US09/725,708
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,469,030
Patent Claims:	1. A method of treating or preventing ileus comprising administering to a patient an effective amount of a compound of the following formula (I): wherein: R1 is hydrogen or alkyl; R2 is hydrogen, alkyl or alkenyl; R3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl; R4 is hydrogen, alkyl or alkenyl; A is OR5 or NR6R7; wherein: R5 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R6 is hydrogen or alkyl; R7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl, aryl-substituted alkyl, or alkylene substitued B or, together with the nitrogen atom to which they are attached, R6 and R7 form a heterocyclic ring selected from pyrrole and piperidine; B is C(═O)W or NR8R9; wherein; R8 is hydrogen or alkyl; R9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R8 and R9 form a heterocyclic ring selected from pyrrole and piperidine; W is OR10, NR11R12, or OE; wherein R10 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R11 is hydrogen or alkyl; R12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene substituted C(═O)Y or, together with the nitrogen atom to which they are attached, R11 and R12 form a heterocyclic ring selected from pyrrole and piperidine; E is alkylene substituted (C═O)D, or —R13OC(═O)R14; wherein R13 is alkyl substituted alkylene; R14 is alkyl; D is OR15 or NR16R17 wherein: R15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl; R17 is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R16 and R17 form a heterocyclic ring selected from pyrrole and piperidine; Y is OR18 or NR19R20; wherein: R18 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R19 is hydrogen or alkyl; R20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R19 and R20 form a heterocyclic ring selected from pyrrole and piperidine; R21 is hydrogen or alkyl; and n is 0 to 4; or a stereoisomer, prodrug, or pharmaceutically acceptable salt, hydrate or N-oxide thereof. 2. A method according to claim 1 wherein the compound of formula (I) is a trans 3,4-isomer. 3. A method according to claim 1 wherein R1 is hydrogen; R2 is alkyl; n is 1 or 2; R3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl; and R4 is alkyl. 4. A method according to claim 3 wherein A is OR5 in which R5 is hydrogen or alkyl. 5. A method according to claim 3 wherein A is NR6R7 in which R6 is hydrogen and R7 is alkylene substituted B wherein B is C(O)W. 6. A method according to claim 5 wherein R7 is (CH2)q—B in which q is about 1 to about 3; and W is OR10 in which R10 is hydrogen, alkyl, phenyl-substituted alkyl, cycloalkyl or cycloalkyl-substituted alkyl. 7. A method according to claim 5 wherein W is NR11R12 in which R11 is hydrogen or alkyl, and R12 is hydrogen, alkyl or alkylene substituted C(═O)Y. 8. A method according to claim 7 wherein R12 is (CH2)mC(O)Y in which m is 1 to 3 and Y is OR18 or NR19R20 wherein R18, R19 and R20 are independently hydrogen or alkyl. 9. A method according to claim 5 wherein W is OE in which E is CH2C(═O)D wherein D is OR15 or NR16R17 in which R15 is hydrogen or alkyl, R16 is methyl or benzyl and R17 is hydrogen. 10. A method according to claim 5 wherein W is OE in which E is R13OC(═O)R14, wherein R13 is —CH(CH3)— or —CH(CH2CH3)— and R14 is alkyl. 11. A method according to claim 1 wherein the configuration at positions 3 and 4 of the piperidine ring is each R. 12. A method according to claim 1 wherein said compound is selected from the group consisting of Q—CH2CH(CH2(C6H5))C(O)OH, Q—CH2CH2CH(C6H5)C(O)NHCH2C(O)OCH2CH2, Q—CH2CH2CH(C6H5)C(O)NHCH2C(O)OH, Q—CH2CH2CH(C6H5)C(O)NHCH2C(O)NHCH3, Q—CH2CH2CH(C6H5)C(O)NHCH2C(O)NHCH2CH3, G—NH(CH2)2C(O)NH2, G—NH(CH2)2C(O)NHCH3, G—NHCH2C(O)NH2, G—NHCH2C(O)NHCH3, G—NHCH3C(O)NHCH2CH3, G—NH(CH2)3C(O)OCH2CH3, G—NH(CH2)3C(O)NHCH3, G—NH(CH2)2C(O)OH, G—NH(CH2)3C(O)OH, Q—CH2CH(CH2(C6H11))C(O)NHCH2C(O)OH, Q—CH2CH(CH2(C6H11)C(O)NH(CH2)2C(O)OH, Q—CH2CH(CH2(C6H11)C(O)NH(CH2)2C(O)NH2, Z—NHCH2C(O)OCH2CH3, Z—NHCH2C(O)OH, Z—NHCH2C(O)NH2, Z—NHCH2C(O)N(CH3)2, Z—NHCH2C(O)NHCH(CH3)2, Z—NHCH2C(O)OCH2CH(CH3)2, Z—NH(CH2)2C(O)OCH2(C6H5), Z—NH(CH2C(O)OH, Z—NH(CH2)2C(O)NHCH2CH3, Z—NH(CH2)3C(O)NHCH3, Z—NHCH2C(O)NHCH2C(O)OH, Z—NHCH2C(O)OCH2C(O)OCH3, Z—NHCH2C(O)O(CH2)4CH3, Z—NHCH2C(O)OCH2C(O)NHCH3, Z—NHCH2C(O)O—(4-methoxycyclohexyl), Z—NHCH2C(O)OCH2C(O)NHCH2(C6H5) or Z—NHCH2C(O)OCH(CH3)OC(O)CH3; wherein: Q represents 13. A method according to claim 12 wherein said compound is Q-CH2CH(CH2(C6H5))C(O)OH. 14. A method according to claim 13 wherein said compound is (3R, 4R, S)- Q-CH2CH(CH2(C6H5))C(O)OH. 15. A method according to claim 12 wherein said compound is selected from the group consisting of (3R,4R,S)-Z—NHCH2C(O)OCH2CH(CH3)2, (+)-Z—NHCH2C(O)OH, (−)-Z—NHCH2C(O)OH, (3R,4R,R)-Z—NHCH2C(O)—OCH2CH(CH3)2, (3S,4S,S)-Z—NHCH2C(O)OCH2CH(CH3)2, (3S,4S,R)-Z—NHCH2C(O)OCH2CH(CH3)2, (3R,4R)-Z—NHCH2C(O)NHCH2(C6 H5) or (3R,4R)-G—NH(CH2)3C(O)OH. 16. A method according to claim 15 wherein said compound is selected from the group consisting of (+)-Z—NHCH2C(O)OH and (−)-Z—NHCH2C(O)OH. 17. A method according to claim 16 wherein said compound is (+)-Z—NHCH2C(O)OH. 18. A method according to claim 1 wherein said compound is a substantially pure stereoisomer. 19. A method according to claim 1 wherein the ileus is selected from the group consisting of postsurgical ileus and postpartum ileus. 20. A method according to claim 19 wherein the ileus is postsurgical ileus. 21. A method according to claim 20 wherein said postsurgical ileus is postsurgical paralytic ileus. 22. A method according to claim 1 wherein the compound of formula (I) is a peripheral mu opioid antagonist compound. 23. A method according to claim 1 further comprising administering an opiate or an opioid to said patient. 24. A method according to claim 23 wherein said opiate or opioid comprises an opioid analgesic. 25. A method according to claim 24 wherein said opioid analgesic comprises a mu opioid agonist. 26. A method according to claim 1 further comprising administering to said patient a compound which slows gut motility.