Antidiabetic 4-hydroxy-2-furoic acids

• US 6,596,760 B1
• Filed: 10/18/2002
• Issued: 07/22/2003
• Est. Priority Date: 10/18/2001
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Li, Xiaohua, Zhang, Bei B., Chen, Shieh-Shung Tom
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): SAEED, KAMAL A
• Application Number:
  US10/274,461
• Publication Number:
  US 20030134890A1
• Time in Patent Office: 277 Days
• Field of Search: 548/455, 514/414, 435/117
• US Class Current: 514/455
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C12P 17/16 containing two or more hetero rings thiamine open chain analogs C12P17/167, i.e. not condensed among themselves or through a common carbocyclic ring system

Abstract

Substituted 4-hydroxy-2-furoic acids are obtained by the fermentation of an asterriquinone, which is a natural product having a 2,5-dioxy-3,6-bis(indolyl)quinone structure. The compounds modulate insulin receptor tyrosine kinase activity and may be useful in the treatment of diabetes and other diseases or conditions characterized by impaired endogenous insulin production or an impaired response to endogenous insulin.

Claims

1. A compound having the formula IIa, IIb or IIc:

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound having Formula IIa, IIb, or IIc, or pharmaceutically acceptable salt thereof as recited in claim 1, and a pharmaceutically acceptable carrier.

3. A method of treating a disease, disorder or condition in a mammal in which production of endogenous insulin, the biological activity of insulin, or insulin sensitivity, or a combination thereof, are impaired, which comprises administering to said mammal a therapeutically effective amount of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, as recited in claim 1.

4. A method of treating diabetes mellitus in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt or prodrug thereof, as defined in claim 1.

5. A method of reducing the blood glucose level in a mammal in need of such reduction which comprises administering to said mammal a therapeutically effective amount of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, as defined in claim 1.

6. A method of treating non-insulin dependent diabetes mellitus in a human or mammal comprising the administration of a therapeutically effective amount of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, as defined in claim 1.

7. A method of treating atherosclerosis in a human or mammal comprising the administration of a therapeutically effective amount of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, as defined in claim 1.

8. A method of treating dyslipidemia in a human or mammal comprising the administration of a therapeutically effective amout of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, as defined in claim 1.

9. A method of treating polycystic ovarian syndrome in a human or mammal in need of such treatment, comprising the administration of a therapeutically effective amount of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, as defined in claim 1.

10. A method of treating a disorder that is characterized by elevated levels of blood sugar and/or insulin resistance in a mammal comprising the administration of a therapuetically effective amount of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, as defined in claim 1.

11. A method of treating conditions or diseases selected from the group consisting of hyperglycemia, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hypertension, atherosclerosis, vascular restenosis, retinopathy, neurodegenerative disease, inflammatory bowel disease, pancreatitis, dyslipidemia, syndrome X, and polycystic ovarian syndrome, comprising the administration of a therapeutically effective amount of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof, as defined in claim 1.

12. A method of treating conditions or diseases selected from the group consisting of hyperglycemia, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hypertension, atherosclerosis, vascular restenosis, retinopathy, neurodegenerative disease, inflammatory bowel disease, pancreatitis, dyslipidemia, syndrome X, and polycystic ovarian syndrome, comprising the administration of a therapeutically effective amount of the pharmaceutical composition of claim 2.

13. A method of treating non-insulin dependent diabetes mellitus in a mammalian patient in need of treatment, comprising the administration of a therapeutically effective amount of the pharmaceutical composition of claim 2.

15. A method of synthesizing a compound having Formula IIa, IIb or IIc, as defined in claim 1, comprising the step of fermenting a compound having formula I, wherein R₂ is —

CH═

CH₂ and R₃ is —

CH₂CH═

C(CH₃)₂;

in a medium containing a culture having the identifying characteristics of ATCC 53771.

16. The method of synthesizing the compounds having the formula IIa, IIb or IIc, as recited in claim 15, wherein the medium comprises a culture of ATCC 53771.

14. A method of treating a disease or condition characterized by inadequate modulation of insulin receptor tyrosine kinase activity, comprising the administration of a therapeutically effective amount of a compound having formula IIa, IIb or IIc, or a pharmaceutically acceptable salt thereof.