Naphthyridine derivatives as potassium channel modulators
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A01N-043/54
A61K-031/505
C07D-401/00
C07D-403/00
C07D-405/00
C07D-409/00
C07D-411/00
C07D-413/00
C07D-417/00
C07D-419/00
출원번호
US-0181126
(2008-07-28)
등록번호
US-8563566
(2013-10-22)
발명자
/ 주소
Vernier, Jean-Michel
De la Rosa, Martha
출원인 / 주소
Valeant Pharmaceuticals International
대리인 / 주소
Jones Day
인용정보
피인용 횟수 :
0인용 특허 :
55
초록▼
This invention provided compounds of formula I where W and Z are, independently, CH or N, and where other substituents are defined herein. Such compounds are potassium channel modulators. The invention also provides a composition comprising a pharmaceutically acceptable carrier or excipient and at l
This invention provided compounds of formula I where W and Z are, independently, CH or N, and where other substituents are defined herein. Such compounds are potassium channel modulators. The invention also provides a composition comprising a pharmaceutically acceptable carrier or excipient and at least one of the following: a pharmaceutically effective amount of a compound of formula I; a pharmaceutically acceptable salt of a compound of formula I; a pharmaceutically acceptable ester of a compound of formula I. The invention also provides a method of preventing or treating a disease or disorder which is affected by activities of potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a salt or ester or solvate thereof.
대표청구항▼
1. A compound of formula IB where W and Z are, independently, CH or N;where R1 and R2, are, independently, H, halogen, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, CH2C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, O
1. A compound of formula IB where W and Z are, independently, CH or N;where R1 and R2, are, independently, H, halogen, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, CH2C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, and trifluoromethyl, where m is zero, 1, or 2;or R1 and R2, together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring, which ring may be saturated, unsaturated, or aromatic, which optionally contains one or two heteroatoms selected independently from O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl;R′ is H, halogen, CF3, or C1-C3 alkyl;R3 and R4 are, independently, H, NH2, (C1-C3 alkyl)NH, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C3 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, and trifluoromethyl;R5 is C1-C6 alkyl, (CHR6), C3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is phenyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, or imidazolyl, wherein said C1-C6 alkyl group is optionally substituted with hydroxy, methoxy, methylthio, or halogen, and where said cycloalkyl and cycloalkenyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl and trifluoromethyl; R6 is hydrogen, methyl, halogen, or methoxy; or a pharmaceutically acceptable salt thereof. 2. A compound of formula IA where W and Z are CH, R′ is halogen, C1-C3 alkyl, or H,R1 and R2, are, independently, H, halogen, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, CH2C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, and trifluoromethyl, where m is zero, 1, or 2;or R1 and R2, together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring, which ring may be saturated, unsaturated, or aromatic, which optionally contains one or two heteroatoms selected independently from O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl;R3 and R4 are, independently, H, NH2, (C1-C3 alkyl)NH, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C3 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, and trifluoromethyl;R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is phenyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, or imidazolyl, wherein said C1-C6 alkyl group is optionally substituted with hydroxy, methoxy, methylthio, or halogen, and where said cycloalkyl and cycloalkenyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl; R6 is hydrogen, methyl, halogen, or methoxy; or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1, where W and Z are CH and R′ is halogen, C1-C3 alkyl, or H. 4. A compound of formula IA where W and Z are both N, R′ is halogen, C1-C3 alkyl, or H,R1 and R2, are, independently, H, halogen, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, CH2C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, and trifluoromethyl, where m is zero, 1, or 2;or R1 and R2, together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring, which ring may be saturated, unsaturated, or aromatic, which optionally contains one or two heteroatoms selected independently from O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl;R3 and R4 are, independently, H, NH2, (C1-C3 alkyl)NH, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C3 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, and trifluoromethyl;R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is phenyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, or imidazolyl, wherein said C1-C6 alkyl group is optionally substituted with hydroxy, methoxy, methylthio, or halogen, and where said cycloalkyl and cycloalkenyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl; R6 is hydrogen, methyl, halogen, or methoxy; or a pharmaceutically acceptable salt thereof. 5. The compound of claim 1, where W and Z are both N, and R′ is halogen, C1-C3 alkyl, or H. 6. The compound of claim 1, where W is N, Z is CH, and R′ is halogen, C1-C3 alkyl, or H. 7. The compound of claim 2, where R3 and R4 are, independently, methyl, amino, aminomethyl, methoxy, trifluoromethyl, or chloro. 8. The compound of claim 3, where R3 and R4 are, independently, methyl, amino, aminomethyl, methoxy, trifluoromethyl, or chloro. 9. The compound of claim 7, where R3 and R4 are, independently chloro, trifluoromethyl, methoxy, or methyl, R5 is C5-C6 alkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl, said C5-C6 alkyl group optionally substituted with methoxy or halogen, and said cycloalkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl. 10. The compound of claim 8, where R3 and R4 are, independently chloro, trifluoromethyl, methoxy, or methyl, and R5 is C5-C6 alkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl, said C5-C6 alkyl group optionally substituted with methoxy or halogen, and said cycloalkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl. 11. The compound of claim 9, where R3 and R4 are, independently chloro, trifluoromethyl, or methyl, and R5 is C5-C6 alkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl, said C5-C6 alkyl group optionally substituted with methoxy or halogen, and said cycloalkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl. 12. The compound of claim 10, where R1 is H, halogen, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, or C(═O)C1-C6 alkyl. 13. The compound of claim 11, where R1 is H, halogen, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, or C(═O)C1-C6alkyl. 14. The compound of claim 12, where R5 is C5-C6 alkyl or CH2(CHR6)wC3-C6 cycloalkyl, where w=1 and R6 is H, methyl, or methoxy. 15. The compound of claim 13, where R5 is C5-C6 alkyl or CH2(CHR6)wC3-C6 cycloalkyl, where w=1 and R6 is H, methyl, or methoxy. 16. The compound of claim 14, where R3 and R4 are both methyl, and R5 is neopentyl or 2-cyclohexyl ethyl. 17. The compound of claim 15, where R3 and R4 are both methyl, and R5 is neopentyl or 2-cyclohexyl ethyl. 18. The compound of claim 16, where R1 is F or CF3, and R2 is H or F. 19. The compound of claim 17, where R1 is F or CF3, and R2 is H or F. 20. The compound of claim 2 selected from the group consisting of: 21. A composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of the compound of claim 1; and ii) a pharmaceutically acceptable salt of the compound of claim 1. 22. The composition of claim 21, in which the pharmaceutically acceptable carrier is microcrystalline cellulose. 23. A tablet for oral dosing comprising a pharmaceutically acceptable carrier and from approximately 100 to approximately 700 mg of the compound of claim 1 or a salt thereof. 24. The tablet of claim 23, further comprising a lubricant. 25. The tablet of claim 23, further comprising a disintegrant. 26. The tablet of claim 23, wherein the tablet is chewable. 27. A pharmaceutical syrup for pediatric use, comprising from approximately 100 to approximately 700 mg per dose of the compound of claim 1 or a salt thereof. 28. The compound of claim 4, wherein the compound is: 29. A compound selected from the group consisting of: 30. A composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of the compound of claim 2; and ii) a pharmaceutically acceptable salt of the compound of claim 2. 31. The composition of claim 30, in which the pharmaceutically acceptable carrier is microcrystalline cellulose. 32. A composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of the compound of claim 4; and ii) a pharmaceutically acceptable salt of the compound of claim 4. 33. The composition of claim 32, in which the pharmaceutically acceptable carrier is microcrystalline cellulose. 34. A tablet for oral dosing comprising a pharmaceutically acceptable carrier and from approximately 100 to approximately 700 mg of the compound of claim 2 or a salt thereof. 35. The tablet of claim 34, further comprising a lubricant. 36. The tablet of claim 34, further comprising a disintegrant. 37. The tablet of claim 34, wherein the tablet is chewable. 38. A pharmaceutical syrup for pediatric use, comprising from approximately 100 to approximately 700 mg per dose of the compound of claim 2 or a salt thereof. 39. A tablet for oral dosing comprising a pharmaceutically acceptable carrier and from approximately 100 to approximately 700 mg of the compound of claim 4 or a salt thereof. 40. The tablet of claim 39, further comprising a lubricant. 41. The tablet of claim 39, further comprising a disintegrant. 42. The tablet of claim 39, wherein the tablet is chewable. 43. A pharmaceutical syrup for pediatric use, comprising from approximately 100 to approximately 700 mg per dose of the compound of claim 4 or a salt thereof.
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