Patent
Quinolinomorphinane derivatives and medicinal use thereof
| العنوان: | Quinolinomorphinane derivatives and medicinal use thereof |
|---|---|
| Patent Number: | 617,207& |
| تاريخ النشر: | January 09, 2001 |
| Appl. No: | 09/194,538 |
| Application Filed: | January 13, 1999 |
| مستخلص: | The present invention provides a quinolinomorphinan derivative or a pharmacologically acceptable acid addition salt thereof, and an agent for curing or preventing cerebral disorders composed of the derivative and salt thereof, which is represented by the following formula (I): ##STR1## (wherein R.sup.1 represents cyclopropylmethyl or the like; R.sup.2 and R.sup.3 independently represent hydroxy, methoxy, or the like; R.sup.4 represents hydrogen, methyl, amino or the like; and (R.sup.5).sub.m represents hydrogen, substituted benzo, or the like. The compounds of the present invention prevent damages of the cerebral nerve cells and are useful as medicine for curing or preventing various cerebral diseases such as cerebral stroke, traumatic cerebral diseases, cerebral edema, and cerebral neurodegenerative diseases. The compounds of the present invention also ameliorate the after-effects of these diseases and prevent the recurrence of these diseases by inhibiting various ischemic, hemorrhagic or traumatic cerebral disorders, and damages of the cerebral nerve cells caused by various nerve degenerations. |
| Inventors: | Nagase, Hiroshi (Kanagawa, JPX); Imamura, Yoshifumi (Kanagawa, JPX); Ohno, Hiroshi (Kanagawa, JPX); Kaneeda, Masanobu (Kanagawa, JPX); Matsuda, Susumu (Kanagawa, JPX); Miyauchi, Yasushi (Kanagawa, JPX) |
| Assignees: | Toray Industries, Inc. (Tokyo, JPX) |
| Claim: | What is claimed is |
| Claim: | 1. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof represented by the following formula (II): ##STR138## |
| Claim: | wherein R.sup.1 is represents hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 2 to 7 carbon atoms, alkanoyl having 1 to 5 carbon atoms, furan-2-ylalkyl (wherein an alkyl moiety has 1 to 5 carbons atoms), or thiophene-2-ylalkyl (wherein an alkyl moiety has 1 to 5 carbon atoms); |
| Claim: | R.sup.2 and R.sup.3 independently represent hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, or arylcarbonyloxy having 7 to 13 carbon atoms; |
| Claim: | m represents an integer of 0 to 4; |
| Claim: | R.sup.5 is each of m substituents on the benzene ring, which independently represent R.sup.18, or two R.sup.5 substituted at adjacent carbons form together a fused ring structure A (wherein residual 0 to 2 substituents R.sup.5 independently represent R.sup.18 or another fused ring structure A); |
| Claim: | the fused ring structure A is a benzo, indeno, naphtho, pyrido, or cycloalkeno having 5 to 7 carbon atoms, which is substituted by 0 to 4 substituents R.sup.9, or unsubstituted dioxoleno; |
| Claim: | R.sup.9 and R.sup.18 (1) independently represent fluoro, chloro, bromo, iodo, nitro, hydroxy, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, isothiocyanato, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxyalkyl having 1 to 3 carbon atoms, SR.sup.6, SOR.sup.6, SO.sub.2 R.sup.6, (CH.sub.2).sub.k CO.sub.2 R.sup.7, SO.sub.2 NR.sup.7 R.sup.8, CONR.sup.7 R.sup.8, (CH.sub.2).sub.k NR.sup.7 R.sup.8, or (CH.sub.2).sub.k N(R.sup.7)COR.sup.8 (wherein k represents an integer of 0 to 5, R.sup.6 represents alkyl having 1 to 5 carbon atoms, and R.sup.7 and R.sup.8 independently represent hydrogen, alkyl having 1 to 5 carbon atoms, or cycloalkylalkyl having 4 to 6 carbon atoms), and/or (2) R.sup.9 and R.sup.18 substituted at adjacent carbons with a ring junction therebetween form together any one of ethano, propano and o-benzeno bridged structures R.sup.9 --R.sup.18 ; |
| Claim: | R.sup.4 represents hydrogen, alkyl having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 5 carbon atoms, aryl having 6 to 12 carbon atoms (which may be substituted by at least one substituent R.sup.17), NR.sup.10 R.sup.11, OR.sup.12 COOR.sup.13 or CONR.sup.14 R.sup.15, or any one of bridged structures R.sup.4 --R.sup.5 of N(R.sup.16)CO, N(R.sup.16)C(.dbd.NH), N(R.sup.16)CH.sub.2, o-benzeno, ethano, propano, and butano, which are formed together by R.sup.4 and R.sup.5 substituted at the peri position; |
| Claim: | R.sup.17 represents fluoro, chloro, bromo, iodo, nitro, amino, hydroxy, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy or cyano; |
| Claim: | R.sup.10, R.sup.11, R.sup.12 and R.sup.16 independently represent hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, or alkanoyl having 1 to 5 carbon atoms; and R.sup.13, R.sup.14 and R.sup.15 independently represent hydrogen, alkyl having 1 to 5 carbon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 13 carbon atoms; (wherein when R.sup.4 is hydrogen, and (1) when m is 1, R.sup.5 is R.sup.18 which represents hydroxy, and (2) when m is an integer of 2 to 4, R.sup.5 is R.sup.18 at least one of which represents hydroxy, or two R.sup.5 form together a fused ring structure A, and the residual 0 to 2 R.sup.5 independently represent R.sup.18 (wherein when the fused ring structure A is benzo, pyrido, or cycloalkeno having 5 to 7 carbon atoms, at least one R.sup.18 represents hydroxy, or at least one R.sup.9 and one R.sup.18 substituted at adjacent carbons with ring junction therebetween form together a bridged structure R.sup.9 --R.sup.18 which is any one of ethano, propano and o-benzeno), or must form another fused ring structure A); and |
| Claim: | formula (II) includes (+) form, (-) form and (.+-.) form. |
| Claim: | 2. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 1, wherein R.sup.4 is hydrogen, alkyl having 1 to 5 carbon atoms, or NR.sup.10 R.sup.11, or R.sup.4 and R.sup.5 substituted at the peri position form together a bridged structure R.sup.4 --R.sup.5 of N(R.sup.16)CO or N(R.sup.16)C(.dbd.NH). |
| Claim: | 3. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 1, wherein R.sup.4 is hydroxyalkyl having 1 to 5 carbon atoms, aryl having 6 to 12 carbon atoms (which may be substituted by at least one substituent R.sup.17), OR.sup.12, COOR.sup.13, or CONR.sup.14 R.sup.15. |
| Claim: | 4. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 2, wherein R.sup.5 is each of m substituents on the benzene ring, which are independently R.sup.18. |
| Claim: | 5. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 2, wherein two R.sup.5 groups substituted at adjacent carbons form together a fused ring structure A (the remaining 0 to 2 R.sup.5 groups independently represent R.sup.18 or form another fused ring structure A). |
| Claim: | 6. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 3, wherein R.sup.5 is each of m substituents on the benzene ring, which are independently R.sup.18. |
| Claim: | 7. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 4, wherein R.sup.4 is hydrogen. |
| Claim: | 8. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 4, wherein R.sup.4 is alkyl having 1 to 5 carbon atoms. |
| Claim: | 9. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 4, wherein R.sup.4 is NR.sup.10 R.sup.11. |
| Claim: | 10. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 4, wherein R.sup.4 and R.sup.5 substituted at the peri position form together a bridged structure R.sup.4 --R.sup.5 of N(R.sup.16)CO or N(R.sup.16)C(.dbd.NH). |
| Claim: | 11. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 5, wherein R.sup.4 is hydrogen. |
| Claim: | 12. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 5, wherein R.sup.4 is NR.sup.10 R.sup.11. |
| Claim: | 13. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 9, wherein R.sup.10 and R.sup.11 are hydrogen. |
| Claim: | 14. A quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof according to claim 10, wherein R.sup.16 is hydrogen. |
| Claim: | 15. A medical composition containing an effective amount of quinolinomorphinan compound or pharmacologically acceptable acid addition salt thereof represented by the following formula (II): ##STR139## |
| Claim: | R.sup.10, R.sup.11, R.sup.12 and R.sup.16 independently represent hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, or alkanoyl having 1 to 5 carbon atoms; and R.sup.13, R.sup.14 and R.sup.15 independently represent hydrogen, alkyl having 1 to 5 carbon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 13 carbon atoms; (wherein when R.sup.4 is hydrogen, and (1) when m is 1, R.sup.5 is R.sup.18 which represents hydroxy, and (2) when m is an integer of 2 to 4, R.sup.5 is R.sup.18 at least one of which represents hydroxy, or two R.sup.5 form together a fused ring structure A, and the residual 0 to 2 R.sup.5 independently represent R.sup.18 (wherein when the fused ring structure A is benzo, pyrido, or cycloalkeno having 5 to 7 carbon atoms, at least one R.sup.18 represents hydroxy, or at least one R.sup.9 and one R.sup.18 substituted at adjacent carbons with a ring junction therebetween form together a bridged structure R.sup.9 --R.sup.18 which is any one of ethano, propano and o-benzeno), or must form another fused ring structure A); and |
| Claim: | formula (II) includes (+), form (-) form and (.+-.) form. |
| Claim: | 16. A method of curing or preventing worsening of cerebral disorder comprising administering an effective amount of a quinolinomorphinan compound or a pharmacologically acceptable acid addition salt thereof, which is represented by the following formula (I): ##STR140## |
| Claim: | wherein R.sup.1 represents hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 2 to 7 carbon atoms, alkanoyl having 1 to 5 carbon atoms, furan-2-ylalkyl (wherein an alkyl moiety has 1 to 5 carbon atoms), or thiophene-2-ylalkyl (wherein an alkyl moiety has 1 to 5 carbon atoms); |
| Claim: | R.sup.10, R.sup.11, R.sup.12 and R.sup.16 independently represent hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, or alkanoyl having 1 to 5 carbon atoms; and R.sup.13, R.sup.14 and R.sup.15 independently represent hydrogen, alkyl having 1 to 5 carbon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 13 carbon atoms; and |
| Claim: | formula (I) includes (+) form, (-) form and (.+-.) form. |
| Claim: | 17. A method of curing or preventing worsening of cerebral disorder according to claim 16, wherein R.sup.4 is hydrogen, alkyl having 1 to 5 carbon atoms, or NR.sup.10 R.sup.11, or R.sup.4 and R.sup.5 substituted at the peri position form together a bridged structure R.sup.4 --R.sup.5 of N(R.sup.16)CO or N(R.sup.16)C(.dbd.NH). |
| Claim: | 18. A method of curing or preventing worsening of cerebral disorder according to claim 16, wherein R.sup.4 is hydroxyalkyl having 1 to 5 carbon atoms, aryl having 6 to 12 carbon atoms (which may be substituted by at least one substituent R.sup.17), OR.sup.12, COOR.sup.13, or CONR.sup.14 R.sup.15. |
| Claim: | 19. A method of curing or preventing worsening of cerebral disorder according to claim 17, wherein R.sup.5 is each of m substituents on the benzene ring, which are independently R.sup.18. |
| Claim: | 20. A method of curing or preventing worsening of cerebral disorder according to claim 17, wherein two R.sup.5 groups substituted at adjacent carbons form together a fused ring structure A (the remaining 0 to 2 R.sup.5 groups independently represent R.sup.18 or form another fused ring structure A). |
| Claim: | 21. A method of curing or preventing worsening of cerebral disorder according to claim 18, wherein R.sup.5 is each of m substituents on the benzene ring, which are independently R.sup.18. |
| Claim: | 22. A method of curing or preventing worsening of cerebral disorder according to claim 19, wherein R.sup.4 is hydrogen. |
| Claim: | 23. A method of curing or preventing worsening of cerebral disorder according to claim 19, wherein R.sup.4 is alkyl having 1 to 5 carbon atoms. |
| Claim: | 24. A method of curing or preventing worsening of cerebral disorder according to claim 19, wherein R.sup.4 is NR.sup.10 R.sup.11. |
| Claim: | 25. A method of curing or preventing worsening of cerebral disorder according to claim 19, wherein R.sup.4 and R.sup.5 substituted at the peri position form together a bridged structure R.sup.4 --R.sup.5 of N (R.sup.16) CO or N(R.sup.16)C(.dbd.NH). |
| Claim: | 26. A method of curing or preventing worsening of cerebral disorder according to claim 20, wherein R.sup.4 is hydrogen. |
| Claim: | 27. A method of curing or preventing worsening of cerebral disorder according to claim 20, wherein R.sup.4 is NR.sup.10 R.sup.11. |
| Claim: | 28. A method of curing or preventing worsening of cerebral disorder according to claim 24, wherein R.sup.10 and R.sup.11 are hydrogen. |
| Claim: | 29. A method of curing or preventing worsening of cerebral disorder according to claim 25, wherein R.sup.16 is hydrogen. |
| Current U.S. Class: | 514/279; 546/37 |
| Current International Class: | C07D51500; A61K 3144 |
| Primary Examiner: | Davis, Zinna Northington |
| Attorney, Agent or Firm: | Birch, Stewart, Kolasch & Birch, LLP |
| رقم الانضمام: | edspgr.0617207. |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |