Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-217/02
C07D-217/22
A61K-031/472
출원번호
US-0894877
(2007-08-22)
등록번호
US-8293911
(2012-10-23)
발명자
/ 주소
Vernier, Jean-Michel
De La Rosa, Martha Alicia
Chen, Huanming
Wu, Jim Zhen
Larson, Gary Lee
Cheney, Ian Wayne
출원인 / 주소
Valeant Pharmaceuticals International
대리인 / 주소
Jones Day
인용정보
피인용 횟수 :
1인용 특허 :
50
초록▼
This invention provides a compound of formula IA where X═O or S; Y is O or S; q=1 or 0; and other substituents are defined herein. Such compounds can affect the opening of, or otherwise modulate, voltage-gated potassium channels. They are potentially useful for the treatment and prevention of disea
This invention provides a compound of formula IA where X═O or S; Y is O or S; q=1 or 0; and other substituents are defined herein. Such compounds can affect the opening of, or otherwise modulate, voltage-gated potassium channels. They are potentially useful for the treatment and prevention of diseases and disorders which are affected by activation or modulation of potassium ion channels. One such condition is seizure disorders.
대표청구항▼
1. A compound of formula IA whereinR1 and R2, vary independently, and are selected from the group consisting of H, CN, halogen, CH2CN, OH, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl; NH—C1-C6 alkyl; N(C1-C6 alkyl)-C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH2, C(═O
1. A compound of formula IA whereinR1 and R2, vary independently, and are selected from the group consisting of H, CN, halogen, CH2CN, OH, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl; NH—C1-C6 alkyl; N(C1-C6 alkyl)-C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH2, C(═O)NH—C1-C6alkyl, SO2NH2, NHSO2—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, Ar, (CH2)mthienyl, (CH2)mimidazolyl, (CH2)mpyrazyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, and (CH2)mpyrimidyl, whereinm=zero, 1, or 2;Ar is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S;orR1 and R2, together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring; wherein said fused ring may be saturated, unsaturated, or aromatic, and said fused ring optionally contains one or two heteroatoms selected independently from the group consisting of O, N, and S;R′ is selected from the group consisting of H, halogen, phenyl, 2-(N,N-dimethylamino)ethyl, CF3, OC1-C3 alkyl and C1-C3 alkyl;R3 and R4 vary independently, and are selected from the group consisting of H, CN, halogen, CF3, OCF3, OC1-C3 alkyl, and C1-C3 alkyl;X is O or S;Y is O or S;q=1 or zero; andR5 is selected from the group consisting of 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, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR6)wCH2Ar, whereinw=zero, 1, 2, or 3;Ar is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from the group consisting of N, O, and S; andR6 is selected from the group consisting of H or C1-C3 alkyl; where all cycloalkyl and cycloalkenyl optionally contain one or two ring heteroatoms selected independently from N, O, and S;wherein all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R′, R3, R4, R5, R6, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C1-C3 alkyl, halogen, OH, OEt, OMe, CN, CH2F, OCF3, and CF3; and wherein, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with a carbonyl group. 2. The compound of claim 1, wherein: R1 and R2, vary independently, and are selected from the group consisting of H, halogen, CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SCH3, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, phenyl, pyridyl, pyrrolyl, thienyl, (CH2)mphenyl, (CH2)mpyrrolyl, and (CH2)mpyridyl; wherein said cycloalkyl groups optionally contain one or two heteroatoms selected independently from the group consisting of O, N, and S;wherein said alkyl, cycloalkyl, phenyl, pyrrolyl, and pyridyl groups are optionally substituted with one or two groups selected, independently, from halogen, methyl, ethyl, or trifluoromethyl; andwherein m is zero, 1, or 2;R′ is selected from the group consisting of H, halogen, phenyl, 2-(N,N-dimethylamino)ethyl, CF3, OC1-C3 alkyl and C1-C3 alkyl;R3 and R4 vary independently, and are selected from the group consisting of H, halogen, CF3, OCF3, OC1-C3 alkyl, and C1-C3 alkyl;X is O or S;Y is O or S;q=1 or 0;R5 is selected from the group consisting of 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, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR7)wCH2Ar; wherein w=0-3;Ar is selected from the group consisting of phenyl, pyrimidyl, or pyridyl, and a 5-member heteroaromatic ring; wherein said heteroaromatic ring contains 1 or 2 ring heteroatoms selected independently from the group consisting of N, O, and S; andR6 is selected from the group consisting of H and methyl;wherein all cycloalkyl and cycloalkenyl groups in R5 optionally contain one or two ring heteroatoms selected independently from the group consisting of N, O, and S; andwherein all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C1-C3 alkyl, halogen, OEt, OMe, and trifluoromethyl. 3. The compound of claim 1, wherein: R1 and R2, vary independently, and are selected from the group consisting of H, halogen, CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SCH3, (CH2)m cyclopropyl, (CH2)mcyclobutyl, (CH2)m cyclopentyl, (CH2)m cyclohexyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, and (CH2)mpyrimidyl; wherein said cyclopentyl and said cyclohexyl groups optionally contain one or two ring heteroatoms selected independently from the group consisting of O, N, and S;wherein said alkyl, cycloalkyl, phenyl, pyrrolyl, and pyridyl groups are optionally substituted with one or two groups selected, independently, from the group consisting of halogen, CH3, ethyl, and CF3; andm is zero, 1, or 2;R′ is selected from the group consisting of H, halogen, CF3, and C1-C3 alkyl;R3 and R4 vary independently, and are selected from the group consisting of H, halogen, CF3, OCF3, OC1-C3 alkyl, and C1-C3 alkyl;X is O or S;Y is O;q=1 or 0;R5 is selected from the group consisting of 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, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR6)wCH2Ar; wherein w=0-3,Ar is selected from the group consisting of phenyl, pyridyl, and a 5-member heteroaromatic ring, wherein said heteroaromatic ring contains 1 or 2 ring heteroatoms selected independently from the group consisting of N, O, and S;R6 is H or methyl;wherein all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from the group consisting of N, O, and S; andwherein all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C1-C3 alkyl, halogen, OMe, OEt, and CF3. 4. The compound of claim 2, wherein: R1 and R2, vary independently, and are selected from the group consisting of H, halogen, CF3, OC1-C3 alkyl, C1-C6 alkyl, C(═O)OC1-C3 alkyl, OC(═O)C1-C3 alkyl, and C(═O)C1-C3 alkyl;R′ is selected from the group consisting of H, F, CH3, and ethyl;R3 and R4 vary independently, and are selected from the group consisting of H, F, Cl, CF3, OCF3, OC1-C3 alkyl, and C1-C3 alkyl; andR5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, or (CHR6)wAr, CH2(CHR6)wAr, or (CHR6)wCH2Ar. 5. The compound of claim 1, wherein: R2 is H or F;R′ is H;R3 is selected from the group consisting of H, CH3, OCH3, CF3, OCF3, and Cl;R4 is selected from the group consisting of CH3, OCH3, CF3, OCF3, and Cl; andR5 is C3-C6 alkyl or (CH2)wC3-C6 cycloalkyl. 6. The compound of claim 1 or claim 2, wherein: R1 is halogen or CF3;R2 is H or F;R′ is H;R3 and R4 vary independently, and are selected from the group consisting of H, CH3, OCH3, CF3, OCF3, or Cl; andR5 is selected from the group consisting of 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, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR6)wCH2Ar. 7. The compound of claim 1 which is a compound of formula IA-1 wherein: R1 is selected from the group consisting of H, halogen, CN, CH2CN, CF3, C1-C6 alkyl, OCH3, (C═O)OCH3, O(C═O)CH3, OCF3, (CH2)mC3-C6 cycloalkyl, phenyl, and pyridyl;R2 is selected from the group consisting of H, F, OCH3, CH3, and CF3;R3 and R4 vary independently, and are selected from the group consisting of H, F, Cl, CF3, OCF3, OC1-C3 alkyl, or C1-C3 alkyl; andR5 is selected from the group consisting of 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, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR6)wCH2Ar, wherein w=0-3;Ar is phenyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl; andR6 is C1-C3 alkyl;wherein all alkyl, cycloalkyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C1-C3 alkyl, halogen, OCH3, OCH2CH3, CN, and CF3. 8. The compound of claim 7, wherein: R1 is selected from the group consisting of H, F, Cl, Br, CF3, C1-C6 alkyl, OCH3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, and OCH2CH3;R′ is selected from the group consisting of H, CH3, CH2CH3, or halogen;R3 and R4 vary independently, and are selected from the group consisting of H, F, Cl, CF3, OCF3, OCH3, and CH3; andR5 is selected from the group consisting of C1-C6 alkyl, CH2C3-C6 cycloalkyl, CH2CH2C3-C6 cycloalkyl, CH═CH—C3-C6 cycloalkyl, CH═CH—C5-C6 cycloalkenyl, CH2C5-C6 cycloalkenyl, CH2CH2C5-C6 cycloalkenyl, C2-C6 alkenyl, and (CH2)wAr; wherein w=1 or 2;Ar is selected from the group consisting of phenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furyl, thienyl, pyrrolyl, and pyridyl;wherein all alkyl, cycloalkyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of CH3, halogen, OCH3, OCH2CH3, CN, and CF3. 9. The compound of claim 8, wherein: R1 is selected from the group consisting of F, CF3, Cl, CH3, CH2CH3, SCH3, OCH3, CH2OCH3, CH2OCH2CH3, OCF3, phenyl, thienyl, and H;R2 is selected from the group consisting of H, F, Cl, and OCH3;R′ is selected from the group consisting of H, F, CH2CH3, and CH3;R3 and R4 vary independently, and are selected from the group consisting of H, Cl, CH3, CF3, OCH3, and OCF3; andR5 is selected from the group consisting of C4-C6 alkyl, (CH2)wAr, and (CH2)wC5-C6 cycloalkyl; wherein w is 1, 2, or 3. 10. The compound of claim 9, wherein: R1 is selected from the group consisting of F, CF3, Cl, CH3, OCH3, CH2OCH3, and H;R2 is selected from the group consisting of H, F, CH3, and Cl;R′ is H;R3 is selected from the group consisting of H, Cl, CH3, CF3, OCH3, and OCF3;R4 is selected from the group consisting of Cl, OCH3, and CH3; andR5 is C4-C6 alkyl or 2-cyclopentyl ethyl. 11. The compound of claim 10, wherein R3 and R4 are both CH3 or both OCH3; and R5 is C5-C6 alkyl. 12. The compound of claim 3, wherein: R′ and R2 are H;R3 and R4 are both methyl; andR5 is C5-C6 alkyl or (CH2)wC5-C6 cycloalkyl; wherein w is 1, 2, or 3. 13. A compound according to claim 1, wherein said compound is one of the following: N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide;N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide;N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3-cyclopentylpropanamide;N-(2-chloro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethylphenyl)-3,3-dimethylbutanamide;N-[2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl phenyl]-3,3-dimethylbutanamide;N-[2-chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl phenyl]-3-cyclopentylpropionamide;N-[2,6-dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;N-[2-chloro-6-trifluoromethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;N-[2-chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl phenyl]-3,3-dimethylbutanamide;N-[4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide;N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl phenyl]-3,3-dimethylbutanamide;N-[2-chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl-phenyl]-3,3-dimethylbutanamide;N-[4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide;N-[2-chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide;N-[2-chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide;N-[2-chloro-6-methyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;N-[2-chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]-3,3-dimethylbutanamide;N-[2-chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-phenyl]-3,3-dimethylbutanamide;N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethylphenyl]-3,3-dimethylbutanamide;N-[2-chloro-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;N-[4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethyl-phenyl]-3,3-dimethylbutanamide;3,3-dimethyl-N-[2-trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]butanamide;N-[4-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide;N-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methoxy-6-methyl-phenyl]-3,3-dimethylbutanamide;N-[2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethoxy-phenyl]-3,3-dimethylbutanamide;N-[4-(3,4-dihydro-M-isoquinolin-2-yl)-2,6-dimethoxy-phenyl]-3,3-dimethylbutanamide;N-[2,6-dimethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl butanamide;N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl-thiobutanamide;[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-carbamic acid ethyl ester; andN-[2,6-Dimethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl butanamide.
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