Compounds, compositions and methods comprising pyrazole derivatives
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/497
A61K-031/415
C07D-231/20
C07D-403/12
A61P-001/12
출원번호
US-0762899
(2010-04-19)
등록번호
US-8343976
(2013-01-01)
발명자
/ 주소
Penrose, Stephen David
Doyle, Kevin James
출원인 / 주소
Institute for OneWorld Health
대리인 / 주소
Foley & Lardner LLP
인용정보
피인용 횟수 :
1인용 특허 :
56
초록▼
The present invention relates to compounds, compositions and methods for treating a disease in an animal, which disease is responsive to inhibiting of functional cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide by administering to a mammal in need thereof an effective amount of
The present invention relates to compounds, compositions and methods for treating a disease in an animal, which disease is responsive to inhibiting of functional cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide by administering to a mammal in need thereof an effective amount of a compound defined herein (including those compounds set forth in Tables 1-2 or encompassed by formulas Ia, Ib, IIa, and IIb) or compositions comprising these compounds, thereby treating the disease. The present invention particularly, relates to a method of treating diarrhea and polycystic kidney disease.
대표청구항▼
1. A compound of formula Ia or Ib: whereinp is 1, 2, or 3;R1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy and substituted aryloxy;R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alken
1. A compound of formula Ia or Ib: whereinp is 1, 2, or 3;R1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy and substituted aryloxy;R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;R3 and R4 are each independently halo;R5 is selected from the group consisting of hydrogen, hydroxyl, alkoxy, and substituted alkoxy;R6 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; andR8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein said compound exhibits at least one of the following: a) an IC50 of less than 30 μM in the T84 assay;b) a greater than 30% inhibition at 20 μM in the FRT assay; orc) a greater than 35% inhibition at 50 μM in a T84 assay, provided that the compound does not have an IC50 greater than 30 μM. 2. The compound of claim 1, wherein p is 1 or 2. 3. The compound of claim 1, wherein R1 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl. 4. The compound of claim 1, wherein R2 is hydrogen or methyl. 5. The compound of claim 1, wherein R3 and R4 independently are selected from the group consisting of chloro and bromo. 6. The compound of claim 1, wherein R5 and R6 are hydrogen. 7. The compound of claim 1, wherein p is 1 or 2;R1 is substituted phenyl;R2 is hydrogen or methyl;R3 and R4 independently are selected from the group consisting of chloro and bromo;R5, R6, and R8 are hydrogen;or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. 8. A compound selected from the group consisting of: 3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(3-(trifluoromethyl)benzyl)-1H-pyrazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3-(trifluoromethoxy)benzyl)-1H-pyrazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3,3-diphenylpropyl)-1H-pyrazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-phenoxybenzyl)-1H-pyrazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-(3,4-dichlorobenzyl)-1H-pyrazole-5-carboxamide;N-(4-tert-butylbenzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-1H-pyrazole-5-carboxamide;3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-N-(4-(pyridin-2-yloxy)benzyl)-1H-pyrazole-5-carboxamide;N-(4-tert-butylbenzyl)-3-(3,5-dichloro-4-hydroxyphenyl)-N-methyl-1H-pyrazole-5-carboxamide;and3-(3,5-dichloro-4-hydroxyphenyl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-1H-pyrazole-5-carboxamide;or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. 9. A compound of formula: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. 10. A method of treating a disease in an animal, comprising administering to the animal in need thereof an effective amount of the compound of claim 1 or 9, thereby treating the disease, wherein the disease is selected from the group of secretory diarrhea, inflammatory diarrhea, inflammatory bowel disease, infectious diarrhea, or diarrhea associated with chemotherapy. 11. A pharmaceutical composition comprising a compound of claim 1 or claim 9 and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition consisting essentially of a compound of claim 1 or 9 and a pharmaceutically acceptable carrier. 13. A method of treating a disease in an animal, the method consisting essentially of administering to the animal in need thereof an effective amount of the compound of claim 1 or 9, thereby treating the disease, wherein the disease is selected from the group of secretory diarrhea, inflammatory diarrhea, inflammatory bowel disease, infectious diarrhea, or diarrhea associated with chemotherapy.
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