Claims for Patent: RE46375

Summary for Patent: RE46375

Title:	6,7-unsaturated-7-carbamoyl substituted morphinan derivative
Abstract:	A novel compound which is useful as an agent for treating and/or preventing emesis, vomiting and/or constipation. A compound represented by the formula (I): ##STR00001## wherein R.sup.1 and R.sup.2 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted aryl etc., R.sup.3 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy etc., R.sup.4 is hydrogen or lower alkyl, R.sup.5 is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl, or a pharmaceutically .[.acceptably.]. .Iadd.acceptable .Iaddend.salt, or a solvate thereof is provided.
Inventor(s):	Inagaki; Masanao (Toyonaka, JP), Hara; Shin-ichiro (Toyonaka, JP), Haga; Nobuhiro (Osaka, JP), Tamura; Yoshinori (Toyonaka, JP), Goto; Yoshihisa (Amagasaki, JP), Hasegawa; Tsuyoshi (Toyonaka, JP)
Assignee:	Shionogi & Co., Ltd. (Osaka, JP)
Application Number:	15/064,538
Patent Claims:	1. A compound represented by the formula (I): ##STR00424## wherein R.sup.1 and R.sup.2 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkylsulfonyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, an optionally substituted heterocyclic group, optionally substituted arylsulfonyl, or R.sup.1 and R.sup.2 are taken together with the nitrogen atom to which they are attached to form optionally substituted heterocycle; R.sup.3 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, mercapto, optionally substituted lower alkylthio, optionally substituted amino, optionally substituted carbamoyl, optionally substituted acyl, optionally substituted acyloxy, optionally substituted aryl, or an optionally substituted heterocyclic group; or the group represented by the formula: ##STR00425## wherein ring A and ring B are each independently optionally substituted nitrogen-containing heterocycle optionally containing additional nitrogen atom, oxygen atom, and/or sulfur atom in the ring; a broken line indicates the presence or the absence of a bond; when a broken line indicates the presence of a bond, p is 0; when a broken line indicates the absence of a bond, p is 1; R.sup.a is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted lower alkynyl; and R.sup.b is hydrogen or oxo; R.sup.4 is hydrogen or lower alkyl; .Iadd.and.Iaddend. R.sup.5 is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl, or a pharmaceutically acceptable salt, or a solvate thereof. 2. The compound according to claim 1, wherein R.sup.3 is hydroxy, or a pharmaceutically acceptable salt, or a solvate thereof. 3. The compound according to claim 1, wherein R.sup.3 is optionally substituted amino, or a pharmaceutically acceptable salt, or a solvate thereof. 4. The compound in claim 1, wherein R.sup.1 is hydrogen or lower alkyl, R.sup.2 is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted cycloalkyl, or an optionally substituted heterocyclic group, and R.sup.5 is cyclopropylmethyl, or a pharmaceutically acceptable salt or a solvate thereof. 5. A pharmaceutical composition containing a compound in any one of claims 1 to 4, or a pharmaceutically acceptable salt, or a solvate thereof. 6. A composition having an opioid receptor antagonistic activity containing a compound in any one of claims 1 to 4, or a pharmaceutically acceptable salt, or a solvate thereof. 7. A composition for treating and/or preventing emesis, vomiting and/or constipation containing a compound in any one of claims 1 to 4, or a pharmaceutically acceptable salt, or a solvate thereof. 8. A composition for alleviating, treating, and/or preventing a side effect induced by a compound having opioid receptor agonistic activity containing a compound in any one of claims 1 to 4, or a pharmaceutically acceptable salt, or a solvate thereof. 9. A composition for alleviating, treating and/or preventing a side effect according to claim 8, wherein the side effect is emesis, vomiting and/or constipation. 10. A composition .Iadd.for alleviating, treating and/or preventing a side effect .Iaddend.according to claim 9, wherein the compound having the opioid receptor agonistic activity is morphine, oxycodone, or a pharmaceutically acceptable salt, or a solvate thereof. 11. A method for alleviating, treating and/or preventing emesis, vomiting and/or constipation, comprising administering the compound in any one of claims 1 to 4, or a pharmaceutically acceptable salt, or a solvate thereof. 12. An analgesic composition containing a compound having an opioid receptor agonistic activity, and an effective amount of compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, or a solvate thereof, for alleviating and/or preventing a side effect induced by administration of the compound having an opioid receptor agonistic activity. 13. A method for alleviating, treating and/or preventing emesis, vomiting and/or constipation, comprising administering a compound, or a pharmaceutically acceptable salt, or a solvate thereof, wherein the compound is represented by the formula (I): ##STR00426## wherein R.sup.1 is hydrogen; R.sup.2 is selected from lower alkyl optionally substituted with lower alkoxy, lower alkoxycarbonyl, or a heterocyclic group optionally substituted with lower alkyl or phenyl; phenyl optionally substituted with lower alkyl, lower alkoxy, halogen, or cyano lower alkyl; cycloalkyl optionally substituted with lower alkoxycarbonyl or lower alkoxy lower alkyl; or a heterocyclic group optionally substituted with lower alkoxy or oxo; R.sup.3 is hydroxyl; R.sup.4 is hydrogen; and R.sup.5 is cyclopropylmethyl; or a pharmaceutically acceptable salt, or a solvate thereof. 14. A method for alleviating, treating and/or preventing emesis, vomiting and/or constipation, comprising administering a compound, or a pharmaceutically acceptable salt, or a solvate thereof, wherein the compound is represented by the formula (I): ##STR00427## wherein R.sup.1 is hydrogen; R.sup.2 is lower alkyl optionally substituted with lower alkoxy or with a heterocyclic group that is optionally substituted with aryl; phenyl optionally substituted with lower alkyl or with lower alkoxy; cycloalkyl substituted with lower alkylcarbonyl; or a heterocyclic group substituted with lower alkoxy or with aryl; R.sup.3 is hydroxyl; R.sup.4 is hydrogen; and R.sup.5 is cyclopropylmethyl; or a pharmaceutically acceptable salt, or solvate thereof. 15. A method for alleviating, treating and/or preventing emesis, vomiting and/or constipation, comprising administering ##STR00428## ##STR00429## ##STR00430## ##STR00431## or a pharmaceutically acceptable salt, or a solvate thereof. 16. The method according to claim 15, wherein the administered compound, or a pharmaceutically acceptable salt, or solvate thereof, is ##STR00432## ##STR00433## or a pharmaceutically acceptable salt, or a solvate thereof. .Iadd.17. The compound according to claim 1 which is a pharmaceutically acceptable solvate of .Iaddend. ##STR00434## .Iadd.18. The compound according to claim 17 wherein the pharmaceutically acceptable solvate is a hydrate..Iaddend. .Iadd.19. The pharmaceutical composition according to claim 5 containing a pharmaceutically acceptable solvate of .Iaddend. ##STR00435## .Iadd.20. The pharmaceutical composition according to claim 19 in the form of a tablet..Iaddend. .Iadd.21. The analgesic composition according to claim 12 wherein the compound for alleviating and/or preventing a side effect induced by administering of the compound having an opioid receptor agonistic activity is a pharmaceutically acceptable solvate of .Iaddend. ##STR00436## .Iadd.22. The analgesic composition according to claim 21 wherein the compound having an opioid receptor agonistic activity is morphine, oxycodone, or a pharmaceutically acceptable salt thereof..Iaddend. .Iadd.23. A method for alleviating, treating and/or preventing emesis, vomiting and/or constipation comprising administering a compound of the formula .Iaddend. ##STR00437## or pharmaceutically acceptable salt thereof. .Iadd.24. A method for alleviating, treating and/or preventing emesis, vomiting and/or constipation comprising administering a compound of the formula .Iaddend. ##STR00438## .Iadd.25. A method according to claim 23 wherein the compound administered is the p-toluene sulfonic acid salt of .Iaddend. ##STR00439## .Iadd.26. A method for alleviating, treating and/or preventing emesis, vomiting and/or constipation comprising administering a pharmaceutically acceptable solvate of a compound of the formula .Iaddend. ##STR00440## .Iadd.27. The method according to claim 23 wherein the compound is administered orally in the form of a tablet..Iaddend. .Iadd.28. The method according to claim 25 wherein the compound is administered orally in the form of a tablet..Iaddend. .Iadd.29. A method for treating opioid-induced constipation comprising administering a compound of the formula ##STR00441## or a pharmaceutically acceptable salt or solvate thereof..Iaddend. .Iadd.30. A method for treating opioid-induced constipation comprising administering a compound of the formula .Iaddend. ##STR00442## .Iadd.31. The method according to claim 29 wherein the compound administered is the p-toluene sulfonic acid salt of .Iaddend. ##STR00443## .Iadd.32. The method according to claim 31 wherein the compound is administered orally in the form of a tablet..Iaddend. .Iadd.33. The method according to claim 29 wherein the compound is administered in a dose of 0.01 mg to 200 mg/day..Iaddend. .Iadd.34. The method according to claim 31 wherein the compound is administered in a dose of 0.01 mg to 200 mg/day..Iaddend. .Iadd.35. The composition of claim 19 further comprising a compound having opioid receptor agonistic activity..Iaddend. .Iadd.36. The composition of claim 35 wherein the compound having opioid receptor agonistic activity is morphine, oxycodone, or a pharmaceutically acceptable salt thereof..Iaddend. .Iadd.37. The method of claim 25 wherein the compound is administered in a dose of 0.01 mg to 200 mg/day..Iaddend.