Compounds, compositions and methods comprising pyrazole derivatives
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.
1. A compound of formula Ia or Ib:
wherein
p is 1, 2, or 3;
R 1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy and substituted aryloxy;
R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
R 3 and R 4 are each independently halo;
R 5 is selected from the group consisting of hydrogen, hydroxyl, alkoxy, and substituted alkoxy;
R 6 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; and
R 8 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 IC 50 of less than 30 μM in the T84 assay;
b) a greater than 30% inhibition at 20 μM in the FRT assay; or
c) a greater than 35% inhibition at 50 μM in a T84 assay, provided that the compound does not have an IC 50 greater than 30 μM.
2. The compound of claim 1 , wherein p is 1 or 2.
3. The compound of claim 1 , wherein R 1 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl.
4. The compound of claim 1 , wherein R 2 is hydrogen or methyl.
5. The compound of claim 1 , wherein R 3 and R 4 independently are selected from the group consisting of chloro and bromo.
6. The compound of claim 1 , wherein R 5 and R 6 are hydrogen.
7. The compound of claim 1 , wherein
p is 1 or 2;
R 1 is substituted phenyl;
R 2 is hydrogen or methyl;
R 3 and R 4 independently are selected from the group consisting of chloro and bromo;
R 5 , R 6 , and R 8 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;
and
3-(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.