Claims
- 1. A compound of the formula:
- 2. A compound of the formula:
- 3. A compound of the formula:
- 4. A compound of the formula:
- 5. A compound of the formula:
- 6. The compound of any one of claims 1-5, wherein each R1 is hydrogen.
- 7. The compound of claim 5, wherein the aryl is naphthyl.
- 8. The compound of claim 5, wherein R1 is phenyl substituted with a sulfo group in the 2 position, or a pharmaceutically acceptable salt thereof.
- 9. The compound of any one of claims 1-4, wherein each R1 and R2 is hydrogen and aryl or substituted aryl, respectively.
- 10. The compound of claim 9, wherein the aryl or substituted aryl is naphthyl or substituted naphthyl.
- 11. The compound of claim 9, wherein the aryl or substituted aryl is phenyl or substituted phenyl.
- 12. The compound of claim 1, wherein Z is OH or NR1R2.
- 13. The compound of claim 12, wherein Z is OH, R1 is hydrogen and R2 is a substituted aryl.
- 14. The compound of claim 13, wherein R2 is a substituted naphthyl.
- 15. The compound of claim 14, wherein R2 is a naphthyl substituted with S(O)2OH, or a pharmaceutically acceptable salt thereof.
- 16. The compound of claim 12, wherein Z is NR1R2, R1 is hydrogen and R2is a substituted aryl.
- 17. The compound of claim 16, wherein R2 is a substituted phenyl.
- 18. The compound of claim 17, wherein the phenyl is substituted with one or two S(O)2OH; or —C(O)OR wherein R is hydrogen or a lower alkyl.
- 19. The compound of claim 18, wherein the compound is selected from the group consisting of 4-({3,5-bis[N-(4-sulfophenyl)carbamoyl]phenyl}carbonylamino)-benzenesulfonic acid, 2-({3,5-bis[N-(2-sulfophenyl)carbamoyl]phenyl}-carbonylamino)benzenesulfonic acid, 3-({3,5-bis[N-(3-sulfophenyl)carbamoyl]-phenyl}carbonylamino) benzenesulfonic acid, methyl 3-[(3 , 5-bis{N-[3-(methoxycarbonyl)phenyl]carbamoyl}phenyl)carbonylamino]benzoate, methyl 4-({[3,5-bis(N-{[4-(methoxycarbonyl)phenyl]methyl}carbamoyl)phenyl]carbonyl-amino}methyl) benzoate, methyl 4-[(3,5-bis{N-[4-(methoxycarbonyl)phenyl]-carbamoyl}phenyl)carbonylamino]benzoate, 3-({3,5-bis[N-(2,3-dicarboxyphenyl)-carbamoyl]phenyl}carbonylamino)benzene-1,2-dicarboxylic acid, and methyl 2-[(3,5-bis{N-[2-(methoxycarbonyl)phenyl]carbamoyl}phenyl)carbonylamino]-benzoate.
- 20. The compound of claim 16, wherein R2 is a substituted naphthyl.
- 21. The compound of claim 20, wherein the naphthyl is substituted with one or two S(O)2OH; or —C(O)OR wherein R is hydrogen or a lower alkyl.
- 22. The compound of claim 21, wherein the naphthyl is substituted with S(O)2OH, or a pharmaceutically acceptable salt thereof.
- 23. The compound of claim 21 selected from the group consisting of 5-({3,5-bis[N-(6-sulfonaphthyl)carbamoyl]phenyl}carbonylamino)naphthalene-2-sulfonic acid, 8-({3,5-bis[N-(7-sulfonaphthyl)carbamoyl]phenyl}carbonylamino)-naphthalene-2-sulfonic acid, 5-({3,5-bis[N-(5-sulfonaphthyl)carbamoyl]phenyl}-carbonylamino)naphthalenesulfonic acid, 4-({3,5-bis[N-(4-sulfonaphthyl)-carbamoyl]phenyl}carbonylamino)naphthalenesulfonic acid, 2-({3,5-bis[N-(1 -sulfo(2-naphthyl))carbamoyl]phenyl}carbonylamino)naphthalene-sulfonic acid, 6-({3,5-bis[N-(6-sulfo(2-naphthyl))carbamoyl]phenyl}carbonyl-amino)naphthalene-2-sulfonic acid, 6-({3,5-bis[N-(5-sulfo(2-naphthyl))-carbamoyl]phenyl}carbonylamino)naphthalenesulfonic acid, 7-({3,5-bis[N-(7-sulfo(2-naphthyl))carbamoyl]phenyl}carbonylamino)naphthalene-2-sulfonic acid, and 8-({3,5-bis[N-(8-sulfonaphthyl)carbamoyl]phenyl} carbonylamino)naphthalenesulfonic acid.
- 24. A compound of the formula
- 25. The compound of claim 24, wherein Q is —C(O)OR, —C(O)NRR′, —S(O)2R, —S(O)2NRR′, —S(O)2OR, or tetrazolyl, where R and R′ are, independently, hydrogen, lower alkyl, or substituted lower alkyl, and n and n′ are independently 0, 1, 2, 3, 4, or 5.
- 26. The compound of claim 25, wherein n is 1.
- 27. The compound of claim 25, wherein Q is C(O)OR, C(O)NRR′, —S(O)2NRR′, —S(O)2OR, or tetrazolyl.
- 28. The compound of claim 27, wherein Q is —S(O)2NRR′ or —S(O)2OR.
- 29. The compound of claim 28, wherein Q is —S(O)2OH, or a pharmaceutically acceptable salt thereof.
- 30. The compound of claim 29, wherein n′ is 0, 1, 2, 3, 4, or 5, and Q′ is a non-interfering substituent selected from the group consisting of lower alkyl, substituted lower alkyl, acetyl, cyano, halo, nitro, —SR, —OR, —NRR′, aryl, substituted aryl, —C(O)R, —C(O)OR, —C(O)NRR′, heteroaryl, or substituted heteroaryl, where each R and R′ is, independently, hydrogen, lower alkyl, or substituted lower alkyl.
- 31. The compound of claim 27, wherein Q is —C(O)OH or tetrazolyl, or a pharmaceutically acceptable salt thereof.
- 32. The compound of claim 1 selected from the group consisting of 4-({3,5-bis[N-(4-carboxyphenyl)carbamoyl]phenyl}carbonylamino)benzoic acid, 3,5-bis[N-(6-sulfonaphthyl)carbamoyl] benzoic acid, 2-({3,5-bis[N-(2-carboxy-phenyl)carbamoyl]phenyl}carbonylamino)benzoic acid, and 4-{[(3,5-bis{N-[(4-carboxyphenyl)methyl]carbamoyl}phenyl)carbonylamino]-methyl}benzoic acid, or the pharmaceutically acceptable salts thereof, as a single stereoisomer or mixture of stereoisomers thereof.
- 33. A compound of the formula:
- 34. A pharmaceutical composition comprising a compound of the formula:
- 35. The pharmaceutical composition of claim 34 for treating a mammalian disease state selected from the group consisting of hyperglycemia, type I diabetes, and type II diabetes.
- 36. A method of treatment of a mammal suffering from hyperglycemia, type 1 diabetes, or type 2 diabetes, comprising administering a therapeutically effective amount of a compound of the formula:
- 37. The method of claim 36 further comprising administering an additional form of therapy for hyperglycemia, type 1 diabetes, or type 2 diabetes to a mammal in need of the treatment.
- 38. The method of claim 37, wherein said additional form of therapy comprises a therapeutically effective amount of insulin.
- 39. The method of claim 38, wherein the therapeutically effective amount of insulin is a lesser amount than a therapeutically effective amount of insulin required when insulin is administered alone.
- 40. The method of claim 36, wherein said mammal is a human.
- 41. A method of preparing a test compound which stimulates insulin receptor kinase activity, comprising
(a) submitting a compound of the formula: 34wherein: R1 and R2 are, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, aryl(lower)alkyl, substituted aryl(lower)alkyl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, or lower alkenyl, or R1 and R2 together with the conjoining nitrogen are C3-C9 heteroaryl, or C3-C5 heterocyclyl; and Z is OH, Cl, Br, F, OR1 or NR1R2wherein R1 and R2 are as defined above; or a pharmaceutically acceptable salt thereof, as a single stereoisomer or mixture of stereoisomers thereof, to an assay of insulin receptor kinase stimulation and noting the results of the assay; (b) submitting a test compound to the assay and noting the results of the assay; (c) comparing the results of the assays, whereby a test compound which stimulates similar or greater insulin receptor kinase activity than the compound tested in (a) above is identified as a compound which stimulates insulin receptor kinase activity; and (d) preparing the identified compound by a method known per se.
- 42. A method of performing an assay, said assay comprising contacting an insulin receptor with a compound, the method comprising performing the assay with a compound of the formula:
- 43. A method of performing an assay, said assay comprising contacting an insulin receptor with a compound, the method comprising performing the assay with a compound of claim 33.
- 44. A method of stimulating the kinase activity of the insulin receptor in vivo or in vitro, comprising contacting the insulin receptor, or the kinase portion thereof, with a compound of the formula:
- 45. A method of activating the insulin receptor, comprising contacting the insulin receptor, or the kinase portion thereof, with a compound of the formula:
- 46. A method of activating the insulin receptor, comprising contacting the insulin receptor on the surface of a mammalian cell, or the kinase portion thereof, with a compound of the formula:
- 47. A method of stimulating glucose uptake in cells displaying insulin receptors, comprising contacting the cells with a compound of the formula:
- 48. A method of stimulating glucose uptake in mammalian cells displaying insulin receptors, comprising contacting the cells with a compound of the formula:
- 49. A process for the preparation of a compound of Formula I
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the priority under 35 USC119(e) of US Provisional Application No. 60/230,738, filed Sep. 7, 2000.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60230738 |
Sep 2000 |
US |