Pentafluorobenzenesulfonamides and analogs
View Patent ↗The invention provides methods and compositions relating to novel pentafluorophenylsulfonamide derivatives and analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly atherosclerosis and hypercholesterolemia, or as lead compounds for the development of such agents. The compositions include compounds of the general formula I:
1. A compound having the formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y is —S(O)— or —SO 2 —; and
Z is NR 1 R 2 ; wherein R 2 is an optionally substituted heteroaryl group having only one or two heteroatoms in the heteroaryl ring system thereof, and R 1 is selected from
hydrogen,
substituted or unsubstituted (C2–C10)alkyl,
substituted or unsubstituted (C1–C10)alkoxy,
substituted or unsubstituted (C3–C6)alkenyl,
substituted or unsubstituted (C2–C6)heteroalkyl,
substituted or unsubstituted (C3–C6)heteroalkenyl,
substituted or unsubstituted (C3–C6)alkynyl,
substituted or unsubstituted (C3–C8)cycloalkyl,
substituted or unsubstituted (C5–C7)cycloalkenyl,
substituted or unsubstituted (C5–C7)cycloalkadienyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy,
substituted or unsubstituted aryl-(C3–C8)cycloalkyl,
substituted or unsubstituted aryl-(C5–C7)cycloalkenyl,
substituted or unsubstituted aryloxy-(C3–C8)cycloalkyl,
substituted or unsubstituted aryl-(C1–C4)alkyl,
substituted or unsubstituted aryl-(C1–C4)alkoxy,
substituted or unsubstituted aryl-(C3–C6)alkenyl,
substituted or unsubstituted aryloxy-(C1–C4)alkyl, and
substituted or unsubstituted aryloxy-(C2–C4)heteroalkyl,
provided that
in the case that Y is —S(O 2 )—, and R 1 is hydrogen or methyl, then R 2 is a substituted heteroaryl group:
in the case that Y is —S(O 2 )—, and R 2 is a ring system chosen from 5-quinolyl, or 4-pyridyl, then either R 1 is not hydrogen or R 2 is substituted by at least one substituent that is not hydrogen;
in the case that Y is —S(O 2 )— and R 2 is 2-methylbenzothiazol-5-yl, 6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl, 5-carbomethoxypyrazin-2-yl, 4-carboethoxy-1-phenylpyrazol-5-yl, 3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-trifluoromethyl-1-,3-,4-thiadiazol-5-yl, 4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl, 7-chloro-5-methyl-1,8-naphthyridin-2-yl, 5,7-dimethyl-1,8-naphthyridin 2-yl, or 3-cyanopyrazol-4-yl, then R 1 is a group other than hydrogen;
wherein said compound has pharmacological activity; and
with the proviso that heteroaryl is other than 4-pyrimidyl.
2. The compound of claim 1 , wherein R 1 is hydrogen or lower alkyl, and Y is —S(O 2 ).
3. A compound of claim 1 , wherein R 1 is an optionally substituted (C2–C10)alkyl or optionally substituted (C2–C6)heteroalkyl.
4. A compound of claim 1 , wherein heteroaryl is selected from the group consisting of 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
5. The compound of claim 4 , wherein R 1 is hydrogen or lower alkyl, and Y is —S(O 2 ).
6. The compound of claim 1 , wherein R 1 is other than unsubstituted (C2–C10)alkyl.
7. A compound of claim 1 , wherein the compound is selected from the group consisting of 5-Pentafluorophenylsulfonamidoindazole; 5-Pentafluorophenylsulfonamidoindole, 4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyridine; 4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyridine; 2-Pentafluorophenylsulfonamidothiophene; 3-Pentafluorophenylsulfonamidothiophene; 3-Pentafluorophenylsulfonamidopyridine; 4-Pentafluorophenylsulfonamidopyridine; 2-Chloro-5-Pentafluorophenylsulfonamidopyridine; 6-Pentafluorophenylsulfonamidoquinoline; 5-Pentafluorophenylsulfonamidobenzo[a]thiophene; 5-Pentafluorophenylsulfonamidobenzo[a]furan; 2-Methoxy-5-Pentafluorophenylsulfonamidopyridine; and 2-Anilino-3-pentafluorophenylsulfonamidopyridine.
8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y is —S(O) or —S(O) 2 —; and
Z is NR 1 R 2 ; wherein R 2 is optionally substituted heteroaryl and R 1 is selected from hydrogen
substituted or unsubstituted (C1–C10)alkyl,
substituted or unsubstituted (C1–C10)alkoxy,
substituted or unsubstituted (C3–C6)alkenyl,
substituted or unsubstituted (C2–C6)heteroalkyl,
substituted or unsubstituted (C3–C6)heteroalkenyl,
substituted or unsubstituted (C3–C6)alkynyl,
substituted or unsubstituted (C3–C8)cycloalkyl,
substituted or unsubstituted (C5–C7)cycloalkenyl,
substituted or unsubstituted (C5–C7)cycloalkadienyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy,
substituted or unsubstituted aryl-(C3–C8)cycloalkyl,
substituted or unsubstituted aryl-(C5–C7)cycloalkenyl,
substituted or unsubstituted aryloxy-(C3–C8)cycloalkyl,
substituted or unsubstituted aryl-(C1–C4)alkyl,
substituted or unsubstituted aryl-(C1–C4)alkoxy,
substituted or unsubstituted aryl-(C3–C6)alkenyl,
substituted or unsubstituted aryloxy-(C1–C4)alkyl,
substituted or unsubstituted aryloxy-(C2–C4)heteroalkyl,
substituted or unsubstituted heteroaryl,
substituted or unsubstituted heteroaryloxy,
substituted or unsubstituted heteroaryl-(C1–C4)alkyl,
substituted or unsubstituted heteroaryl-(C1–C4)alkoxy,
substituted or unsubstituted heteroaryl-(C1–C4)heteroalkyl,
substituted or unsubstituted heteroaryl-(C3–C6)alkenyl,
substituted or unsubstituted heteroaryloxy-(C1–C4)alkyl, and
substituted or unsubstituted heteroaryloxy-(C2–C4)heteroalkyl,
provided that:
in the case that Y is —S(O 2 )—, and R 1 is hydrogen or methyl, then R 2 is substituted heteroaryl group:
in the case that Y is —S(O 2 )—, and R 2 is a ring system chosen from 5-quinolyl, or 4-pyridyl, then either R 1 is not hydrogen or R 2 is substituted by at least one substituent that is not hydrogen;
in the case that Y is —S(O 2 )— and R 2 is 2-methylbenzothiazol-5-yl, 6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl, 5-carbomethoxypyrazin-2-yl, 4-carboethoxy-1-phenylpyrazol-5-yl, 3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-trifluoromethyl-1-,3-,4-thiadiazol-5-yl, 4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl, 7-chloro-5-methyl-1,8-naphthyridin-2-yl, 5,7-dimethyl-1,8-naphthyridin 2-yl, or 3-cyanopyrazol-4-yl, then R 1 is a group other than hydrogen.
9. The composition of claim 8 wherein
Y is —S(O) 2 —.
10. The composition of claim 9 , wherein R 1 is hydrogen or lower alkyl, and R 2 is optionally substituted pyridyl.
11. The composition of claim 8 , wherein the compound is 5-Pentafluorophenylsulfonamidoindazole, or 5-Pentafluorophenylsulfonamidoindole.
12. The composition of claim 9 , wherein R 1 is an optionally substituted (C2–C10)alkyl or optionally substituted (C2–C6)heteroalkyl.
13. A pharmaceutical composition of claim 8 , wherein R 1 is hydrogen or lower alkyl, and Y is —S(O 2 ).
14. A pharmaceutical composition of claim 8 , wherein said compound is capable of increasing LDL receptor gene expression in a cell.
15. The composition of claim 8 , wherein the compound is selected from the group consisting of 4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyridine; 4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyridine; 2-Pentafluorophenylsulfonamidothiophene; 3-Pentafluorophenylsulfonamidothiophene; 3-Pentafluorophenylsulfonamidopyridine; 4-Pentafluorophenylsulfonamidopyridine; 2-Chloro-5-Pentafluorophenylsulfonamidopyridine; 6-Pentafluorophenylsulfonamidoquinoline; 5-Pentafluorophenylsulfonamidobenzo[a]thiophene; 5-Pentafluorophenylsulfonamidobenzo[a]furan; 5-Pentafluorophenylsulfonamidoindazole; 2-Methoxy-5-Pentafluorophenylsulfonamidopyridine; and 2-Anilino-3-pentafluorophenylsulfonamidopyridine.
16. A method of treating a disease state characterized by abnormally high low density lipoprotein particles or cholesterol levels in the blood selected from the group consisting of atherosclerosis, pancreatitis, hypercholesterolemia and hyperlipoproteinemia, which method comprises administering to a mammalian subject in need thereof a therapeutically effective amount of a composition containing a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y is —S(O)— or —S(O) 2 —;
Z is —NR 1 R 2 ; where R 2 is optionally substituted heteroaryl and R 1 is selected from hydrogen,
substituted or unsubstituted (C1–C10)alkyl,
substituted or unsubstituted (C1–C10)alkoxy,
substituted or unsubstituted (C3–C6)alkenyl,
substituted or unsubstituted (C2–C6)heteroalkyl,
substituted or unsubstituted (C3–C6)heteroalkenyl,
substituted or unsubstituted (C3–C6)alkynyl,
substituted or unsubstituted (C3–C8)cycloalkyl,
substituted or unsubstituted (C5–C7)cycloalkenyl,
substituted or unsubstituted (C5–C7)cycloalkadienyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy,
substituted or unsubstituted aryl-(C3–C8)cycloalkyl,
substituted or unsubstituted aryl-(C5–C7)cycloalkenyl,
substituted or unsubstituted aryloxy-(C3–C8)cycloalkyl,
substituted or unsubstituted aryl-(C1–C4)alkyl,
substituted or unsubstituted aryl-(C1–C4)alkoxy,
substituted or unsubstituted aryl-(C1–C4)heteroalkyl,
substituted or unsubstituted aryl-(C3–C6)alkenyl,
substituted or unsubstituted aryloxy-(C1–C4)alkyl,
substituted or unsubstituted aryloxy-(C2–C4)heteroalkyl,
substituted or unsubstituted heteroaryl,
substituted or unsubstituted heteroaryloxy,
substituted or unsubstituted heteroaryl-(C1–C4)alkyl,
substituted or unsubstituted heteroaryl-(C1–C4)alkoxy,
substituted or unsubstituted heteroaryl-(C1–C4)heteroalkyl,
substituted or unsubstituted heteroaryl-(C3–C6)alkenyl,
substituted or unsubstituted heteroaryloxy-(C1–C4)alkyl, and
substituted or unsubstituted heteroaryloxy-(C2–C4)heteroalkyl,
provided that:
in the case that Y is —S(O 2 )—, and R 1 is hydrogen or methyl, then R 2 is a substituted heteroaryl group:
in the case that Y is —S(O 2 )—, and R 2 is a ring system chosen from 5-quinolyl, or 4-pyridyl, then either R 1 is not hydrogen or R 2 is substituted by at least one substituent that is not hydrogen;
in the case that Y is —S(O 2 )— and R 2 is 2-methylbenzothiazol-5-yl, 6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl, 5-carbomethoxypyrazin-2-yl, 4-carboethoxy-1-phenylpyrazol-5-yl, 3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-trifluoromethyl-1-,3-,4-thiadiazol-5-yl, 4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl, 7-chloro-5-methyl-1,8-naphthyridin-2-yl, 5,7-dimethyl-1,8-naphthyridin 2-yl, or 3-cyanopyrazol-4-yl, then R 1 is a group other than hydrogen.
17. The method of claim 16 wherein
Y is —S(O 2 )—.
18. The method of claim 16 , wherein the composition is administered orally.
19. The method of claim 16 , wherein the subject is human.
20. The method of claim 16 , wherein the composition is administered in combination with a therapeutically effective amount of a hypolipemic agent or a hypocholesterolemic agent that is not represented by formula I.
21. A method of claim 16 , wherein R 1 is hydrogen or lower alkyl, and Y is —S(O 2 ).
22. A method of claim 17 , wherein R 1 is an optionally substituted (C2–C10)alkyl or optionally substituted (C2–C6)heteroalkyl.
23. A method of claim 16 wherein said compound is capable of increasing LDL receptor gene expression in a cell.
24. A method of claim 16 , wherein R 2 is a monocyclic heteroaryl group.
25. A method of claim 16 , wherein said R 2 heteroaryl group has only one heteroatom in the heteroaryl ring system.
26. A method of reducing the level of low density lipoprotein particles or cholesterol in the blood of a mammalian subject suffering from a disease selected from the group consisting of atherosclerosis, pancreatitis, hypercholesterolemia and hyperlipoproteinemia, which method comprises administering to said subject a therapeutically effective amount of a composition containing a compound of claim 1 , whereby said level of low density lipoprotein particles or cholesterol is reduced.
27. A method of claim 26 , wherein the subject is human.
28. A method of claim 16 , wherein the compound is selected from the group consisting of 5-Pentafluorophenylsulfonamidoindazole; 5-Pentafluorophenylsulfonamidoindole, 4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyridine; 4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyridine; 2-Pentafluorophenylsulfonamidothiophene; 3-Pentafluorophenylsulfonamidothiophene; 3-Pentafluorophenylsulfonamidopyridine; 4-Pentafluorophenylsulfonamidopyridine; 2-Chloro-5-Pentafluorophenylsulfonamidopyridine; 6-Pentafluorophenylsulfonamidoquinoline; 5-Pentafluorophenylsulfonamidobenzo[a]thiophene; 5-Pentafluorophenylsulfonamidobenzo[a]furan; 2-Methoxy-5-Pentafluorophenylsulfonamidopyridine; and 2-Anilino-3-pentafluorophenylsulfonamidopyridine.