Aryl sulfonamide compounds and uses related thereto
View Patent ↗The present invention provides Aryl Sulfonamide Compounds having the formula: and prodrugs or pharmaceutically acceptable salts or prodrugs thereof. The Aryl Sulfonamide Compounds are useful for treating diabetes, obesity, and other diseases and disorders.
1. A compound having the formula:
or pharmaceutically acceptable salts, stereoisomers, or thereof, wherein:
R 1 , R 2 and R 3 are independently selected from —H, -halo, —OH, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl and -aryl; and at least one of R 1 , R 2 and R 3 is other than —H;
R 4 is —H, -halo, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, —C 2 -C 8 hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), -aryl-(C 1 -C 6 alkyl), —C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —C(OR′)R′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —N(R′) 2 , or —NR′C(O)R′;
R 5 is —H, -halo, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), -aryl-(C 1 -C 6 alkyl),—C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —C(OR′)R′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —N(R′) 2 , or —NR′C(O)R′, or R 5 and R 6 , together with the carbon atom to which they are attached, join to form an optionally substituted cycloalkane ring;
R 6 is —H, -halo, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), -aryl-(C 1 -C 6 alkyl),—C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —C(OR′)R′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —N(R′) 2 , or —NR′C(O)R′;
R 7 is selected from the group consisting of —H, -halo, —CN, —NO 2 , amino and —C 1 -C 8 alkyl;
Q is selected from the group consisting of -halo, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), -aryl-(C 1 -C 6 alkyl), —C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —C(OR′)R′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —N(R′) 2 , or —NR′C(O)R′;
L 1 is a direct bond, —C 1 -C 7 alkylene- or —C 1 -C 7 heteroalkylene-;
L 2 is a direct bond, —C 1 -C 7 alkylene- or —C 1 -C 7 heteroalkylene-;
wherein each occurrence of is R is independently —H, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -alkoxyalkyl, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), or -aryl-(C 1 -C 6 alkyl), or two R′ groups, when attached to the same nitrogen atom, can be combined with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl group; and
wherein when R 1 , R 2 and R 3 are each —F or —CH 3 , R 4 is other than —H; and
said compound is other than
wherein R a is selected from 4-methoxyphenyl, 4-chlorophenyl and 4-bromophenyl and R b is 4-fluorophenyl or 4-bromophenyl.
2. The compound of claim 1 , wherein Q is -aryl or -heteroaryl.
3. The compound of claim 2 , wherein Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, triazolyl, pyrimidyl, pyridazinyl, benzothiophenyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, indazolyl, carbazolyl, carbolinyl, quinolyl, isoquinolyl, quinoxalinyl and quinazolinyl.
4. The compound of claim 2 , wherein R 1 is methyl or —OH.
5. The compound of claim 4 , wherein R 1 , R 2 and R 3 are each methyl.
6. The compound of claim 4 , wherein R 1 is —OH and R 2 and R 3 are independently methyl or trifluoromethyl.
7. The compound of claim 2 , wherein L 1 is —C 1 -C 7 alkylene and L 2 is a direct bond.
8. The compound of claim 7 , wherein L 1 is —CH 2 — and L 2 is a direct bond.
9. The compound of claim 2 , wherein L 1 is —C 1 -C 7 alkylene and L 2 is —C 1 -C 7 alkylene.
10. The compound of claim 9 , wherein L 1 and L 2 are each —CH 2 —.
11. The compound of claim 2 , wherein R 5 and R 6 and the carbon atom to which they are attached combine to form a cycloalkane.
12. The compound of claim 11 , wherein R 5 and R 6 and the carbon atom to which they are attached combine to form a cyclopropane ring.
13. The compound of claim 11 , wherein R 5 and R 6 and the carbon atom to which they are attached combine to form a cyclobutane ring.
14. The compound of claim 11 , wherein R 5 and R 6 and the carbon atom to which they are attached combine to form a cyclopentane ring.
15. The compound of claim 1 , wherein Q is —C 1 -C 8 alkyl, -cycloalkyl, -heterocycle, -heteroaryl, -aryl, —OR′, —C(O)OR′ or —CON(R′) 2 .
16. The compound of claim 15 , wherein Q is —C(O)OR′ or —CON(R′) 2 .
17. The compound of claim 16 , wherein Q is —COOH or —CONH 2 .
18. The compound of claim 16 , wherein R 1 is methyl or —OH.
19. The compound of claim 18 , wherein R 1 , R 2 and R 3 are each methyl.
20. The compound of claim 18 , wherein R 1 is —OH and R 2 and R 3 are independently methyl or trifluoromethyl.
21. The compound of claim 16 , wherein L 1 is —C 1 -C 7 alkylene and L 2 is a direct bond.
22. The compound of claim 21 , wherein L 1 is —CH 2 — and L 2 is a direct bond.
23. The compound of claim 16 , wherein L 1 is —C 1 -C 7 alkylene and L 2 is —C 1 -C 7 alkylene.
24. The compound of claim 23 , wherein L 1 and L 2 are each —CH 2 —.
25. The compound of claim 16 , wherein R 5 and R 6 and the carbon atom to which they are attached combine to form a (C 3 -C 6 )cycloalkane ring.
26. The compound of claim 25 , wherein R 5 and R 6 and the carbon atom to which they are attached combine to form a cyclopropane ring.
27. The compound of claim 25 , wherein R 5 and R 6 and the carbon atom to which they are attached combine to form a cyclobutane ring.
28. The compound of claim 25 , wherein R 5 and R 6 and the carbon atom to which they are attached combine to form a cyclopentane ring.
29. The compound of claim 3 , having the structure:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
30. The compound of claim 17 , having the structure:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
31. The compound of claim 1 , having the structure:
32. A pharmaceutical composition comprising the compound of any one of claims 1 , 29 , 30 and 31 and a pharmaceutically acceptable vehicle or carrier.
33. A pharmaceutical combination comprising the compound of any one of claims 1 , 29 , 30 and 31 and an additional therapeutic agent.
34. The pharmaceutical combination of claim 33 , wherein the additional therapeutic agent is useful for treating a condition or disorder selected from the group consisting of type II diabetes, syndrome X, obesity, polycystic ovarian disease, an eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, muscle wasting, cognitive disorders, dementia, depression, psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and an immune disorder.
35. A pharmaceutical composition comprising the pharmaceutical combination of claim 33 and a pharmaceutically acceptable carrier or vehicle.
36. A pharmaceutical composition comprising a pharmaceutical combination of claim 34 and a pharmaceutically acceptable carrier or vehicle.
37. A method of treating a condition or disorder selected from the group consisting of type II diabetes, syndrome X, obesity, an eating disorder, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, and glaucoma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):
or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, wherein:
R 1 , R 2 and R 3 are independently selected from —H, -halo, —OH, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl and -aryl, and at least one of R 1 , R 2 and R 3 is other than —H;
R 4 is —H, -halo, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, —C 2 -C 8 hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), -aryl-(C 1 -C 6 alkyl), —C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —C(OR′)R′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —N(R′) 2 , or —NR′C(O)R′;
R 5 is —H, -halo, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), -aryl-(C 1 -C 6 alkyl),—C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —C(OR′)R′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —N(R′) 2 , or —NR′C(O)R′, or R 5 and R 6 , together with the carbon atom to which they are attached, join to form an optionally substituted cycloalkane ring;
R 6 is —H, -halo, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), -aryl-(C 1 -C 6 alkyl),—C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —C(OR′)R′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —N(R′) 2 , or —NR′C(O)R′;
R 7 is selected from the group consisting of —H, -halo, —CN, —NO 2 , amino and —C 1 -C 8 alkyl;
Q is selected from the group consisting of —H, -halo, —CN, —NO 2 , —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), -aryl-(C 1 -C 6 alkyl),—C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —C(OR′)R′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —N(R′) 2 , or —NR′C(O)R′;
L 1 is a direct bond, —C 1 -C 7 alkylene- or —C 1 -C 7 heteroalkylene-;
L 2 is a direct bond, —C 1 -C 7 alkylene- or —C 1 -C 7 heteroalkylene-;
wherein each occurrence of is R′ is independently —H, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, -alkoxy, -alkoxyalkyl, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-(C 1 -C 6 alkyl), -heterocycle-(C 1 -C 6 alkyl), -heteroaryl-(C 1 -C 6 alkyl), or -aryl-(C 1 -C 6 alkyl), or two R′ groups, when attached to the same nitrogen atom, can be combined with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl group; and
wherein when R 1 , R 2 and R 3 are each —F or —CH 3 , R 4 is other than —H.
38. A method of treating a condition or disorder selected from the group consisting of type II diabetes, syndrome X, obesity, an eating disorder, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, and glaucoma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
39. The method of claim 38 , wherein the condition or disorder is type II diabetes or obesity.
40. The method of claim 38 , wherein the compound is administered orally, parenterally or topically.
41. The method of claim 38 , wherein the compound is administered in combination with a second therapeutic agent.
42. The method of claim 38 , wherein the patient is a human.
43. The method of claim 41 , wherein the second therapeutic agent is useful for treating a condition or disorder selected from the group consisting of type II diabetes, syndrome X, obesity, polycystic ovarian disease, an eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, muscle wasting, cognitive disorders, dementia, depression, psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and an immune disorder.
44. The compound of claim 1 , that is enantiomerically pure.
45. The compound of claim 1 , that is diasteromerically pure.
46. The compound of claim 1 , that is in isolated and purified form.