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Claims for Patent: 6,469,030

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Claims 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): Farrar; John J. (Chester Springs, PA), Schied; Peter J. (Southampton, PA), Schmidt; William K. (Newark, DE), Carpenter; Randall L. (Waban, MA)
Assignee: Adolor Corporation (Exton, PA)
Application Number:09/725,708
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): ##STR16##

wherein: R.sup.1 is hydrogen or alkyl; R.sup.2 is hydrogen, alkyl or alkenyl; R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl; R.sup.4 is hydrogen, alkyl or alkenyl; A is OR.sup.5 or NR.sup.6 R.sup.7 ; wherein: R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.6 is hydrogen or alkyl; R.sup.7 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, R.sup.6 and R.sup.7 form a heterocyclic ring selected from pyrrole and piperidine; B is ##STR17##

C(.dbd.O)W or NR.sup.8 R.sup.9 ; wherein; R.sup.8 is hydrogen or alkyl; R.sup.9 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, R.sup.8 and R.sup.9 form a heterocyclic ring selected from pyrrole and piperidine; W is OR.sup.10, NR.sup.11 R.sup.12, or OE; wherein R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.11 is hydrogen or alkyl; R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene substituted C(.dbd.O)Y or, together with the nitrogen atom to which they are attached, R.sup.11 and R.sup.12 form a heterocyclic ring selected from pyrrole and piperidine; E is ##STR18##

alkylene substituted (C.dbd.O)D, or --R.sup.13 OC(.dbd.O)R.sup.14 ;

wherein R.sup.13 is alkyl substituted alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16 R.sup.17

wherein: R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl; R.sup.17 is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R.sup.16 and R.sup.17 form a heterocyclic ring selected from pyrrole and piperidine; Y is OR.sup.18 or NR.sup.19 R.sup.20 ;

wherein: R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.19 is hydrogen or alkyl; R.sup.20 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, R.sup.19 and R.sup.20 form a heterocyclic ring selected from pyrrole and piperidine; R.sup.21 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 R.sup.1 is hydrogen; R.sup.2 is alkyl; n is 1 or 2; R.sup.3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl; and R.sup.4 is alkyl.

4. A method according to claim 3 wherein A is OR.sup.5 in which R.sup.5 is hydrogen or alkyl.

5. A method according to claim 3 wherein A is NR.sup.6 R.sup.7 in which R.sup.6 is hydrogen and R.sup.7 is alkylene substituted B wherein B is C(O)W.

6. A method according to claim 5 wherein R.sup.7 is (CH.sub.2).sub.q --B in which q is about 1 to about 3; and W is OR.sup.10 in which R.sup.10 is hydrogen, alkyl, phenyl-substituted alkyl, cycloalkyl or cycloalkyl-substituted alkyl.

7. A method according to claim 5 wherein W is NR.sup.11 R.sup.12 in which R.sup.11 is hydrogen or alkyl, and R.sup.12 is hydrogen, alkyl or alkylene substituted C(.dbd.O)Y.

8. A method according to claim 7 wherein R.sup.12 is (CH.sub.2).sub.m C(O)Y in which m is 1 to 3 and Y is OR.sup.18 or NR.sup.19 R.sup.20 wherein R.sup.18, R.sup.19 and R.sup.20 are independently hydrogen or alkyl.

9. A method according to claim 5 wherein W is OE in which E is CH.sub.2 C(.dbd.O)D wherein D is OR.sup.15 or NR.sup.16 R.sup.17 in which R.sup.15 is hydrogen or alkyl, R.sup.16 is methyl or benzyl and R.sup.17 is hydrogen.

10. A method according to claim 5 wherein W is OE in which E is R.sup.13 OC(.dbd.O)R.sup.14, wherein R.sup.13 is --CH(CH.sub.3)-- or --CH(CH.sub.2 CH.sub.3)-- and R.sup.14 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--CH.sub.2 CH(CH.sub.2 (C.sub.6 H.sub.5))C(O)OH, Q--CH.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, Q--CH.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, Q--CH.sub.2 CH(CH.sub.2 (C.sub.6 H.sub.11))C(O)NHCH.sub.2 C(O)OH, Q--CH.sub.2 CH(CH.sub.2 (C.sub.6 H.sub.11)C(O)NH(CH.sub.2).sub.2 C(O)OH, Q--CH.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) or Z--NHCH.sub.2 C(O)OCH(CH.sub.3)OC(O)CH.sub.3 ; wherein: Q represents ##STR19##

13. A method according to claim 12 wherein said compound is Q-CH.sub.2 CH(CH.sub.2 (C.sub.6 H.sub.5))C(O)OH.

14. A method according to claim 13 wherein said compound is (3R, 4R, S)- Q-CH.sub.2 CH(CH.sub.2 (C.sub.6 H.sub.5))C(O)OH.

15. A method according to claim 12 wherein said 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)-Z--NHCH.sub.2 C(O)--OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,S)-Z--NHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3S,4S,R)-Z--NHCH.sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2, (3R,4R)-Z--NHCH.sub.2 C(O)NHCH.sub.2 (C.sub.6 H.sub.5) or (3R,4R)-G--NH(CH.sub.2).sub.3 C(O)OH.

16. A method according to claim 15 wherein said compound is selected from the group consisting of (+)-Z--NHCH.sub.2 C(O)OH and (-)-Z--NHCH.sub.2 C(O)OH.

17. A method according to claim 16 wherein said compound is (+)-Z--NHCH.sub.2 C(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.
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