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Treatment of insulin resistance syndrome and type 2 diabetes with PDE9 inhibitors

a technology of insulin resistance syndrome and pde9 inhibitor, which is applied in the direction of drug composition, extracellular fluid disorder, metabolic disorder, etc., can solve the problems of impaired insulin signaling for glucose uptake in insulin resistant individuals, huge population at risk of complications, and extremely common obesity

Inactive Publication Date: 2005-03-31
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

According to a further aspect the present invention additionally provides for the use of a PDE9 inhibitor or a pharmaceutical composition thereof for the treatment of the insulin resistance syndrome in a subject having type 2 diabetes mellitus or impaired glucose tolerance or having a family history of diabetes and at least one of the following conditions: dyslipidemia, hypertension, hyperuricemia, a pro-coagulant state, atherosclerosis or truncal obesity.
According to a further aspect the present invention additionally provides a method of elevating intracellular cGMP in a mammal in need thereof comprising administering to said mammal a PDE9 inhibitor, a prodrug thereof, a pharmaceutically acceptable salt of said PDE9 inhibitor or of said prodrug, or a pharmaceutical composition comprising a PDE9 inhibitor. It is particularly preferred that type 2 diabetes, insulin resistance syndrome or hypertension is treated thereby.

Problems solved by technology

Obesity is an extremely common problem in the industrialized world and is associated with the clinical conditions mentioned above.
Considering this potential patient group alone forms an immense population potentially at risk for the development of complications of IRS.
There is impaired signaling of insulin for glucose uptake in insulin resistant individuals.
Diabetes mellitus is characterized by metabolic defects in production and utilization of carbohydrates, resulting in elevated blood glucose or hyperglycemia due to the failure to maintain appropriate blood sugar levels.
Reduction in hyperglycemia by treatment with a PDE9 inhibitor will lower the level of protein glycation and result in a diminution in these diabetic complications.

Method used

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  • Treatment of insulin resistance syndrome and type 2 diabetes with PDE9 inhibitors
  • Treatment of insulin resistance syndrome and type 2 diabetes with PDE9 inhibitors
  • Treatment of insulin resistance syndrome and type 2 diabetes with PDE9 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 160

3-Cyclopentyl-5-(2-trifluoromethoxy-benxyl)-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one

5-Cyclopentyl-4-[2-(2-trifluoromethoxy-phenyl)-acetylamino]-1H-pyrazole-3-carboxylic acid amide (120 mg, 0.303 mmol) and potassium tert-butoxide (102 mg, 0.909 mmol) were suspended in isopropylalcohol (5 ml) and the reaction was heated to reflux, under nitrogen, for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was removed, acidified to pH 2 with 2N HCl, and extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with saturated sodium carbonate solution (3×10 ml), dried over MgSO4, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol (95:5, by volume) to give 3-cyclopentyl-5-(2-trifluoromethoxy-benxyl)-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (21 mg) as...

example 161

3-Isobutyl-5-(2-trifluoromethoxy-benxyl)-116-dihydro-pyrazolo[4,3-d]pyrimidin-7-one

5-Isobutyl-4-[2-(2-trifluoromethoxy-phenyl)-acetylamino]-1H-pyrazole-3-carboxylic acid amide (140 mg, 0.365 mmol) and potassium tert-butoxide (123 mg, 1.09 mmol) were suspended in isopropylalcohol (6 ml) and the reaction was heated to reflux, under nitrogen, for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was removed, acidified to pH 2 with 2N HCl, and extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with saturated sodium carbonate solution (3×10 ml), dried over MgSO4, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to give 3-isobutyl-5-(2-trifluoromethoxy-benxyl)-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (27 mg) as an off-whi...

example 162

3-Pyridin-3-yl-5-(2-trifluoromethoxy-benxyl)-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one

5-Pyridin-3-yl-4-[2-(2-trifluoromethoxy-phenyl)-acetylamino]-1H-pyrazole-3-carboxylic acid amide (345 mg, 0.85 mmol) and potassium tert-butoxide (286 mg, 2.55 mmol) were suspended in isopropylalcohol (5 ml) and the reaction was heated to 55° C. under nitrogen for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was removed, acidified to pH 2 with 2N HCl, and extracted with ethyl acetate (2×15 ml) and dichloromethane (2×15 ml). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 95:5, by volume). The product was triturated with methanol (3 ml), dichloromethane (3 ml) and diethylether (3 ml) t...

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Abstract

This invention is directed to a method of treating insulin resistance syndrome (IRS), hypertension and / or type 2 diabetes in a mammal comprising administering to said mammal a cGMP PDE9 inhibitor or a pharmaceutical composition thereof. This invention is also directed to such methods wherein said cGMP PDE9 inhibitor is used in combination with other agents to treat IRS, hypertension and / or type 2 diabetes.

Description

FIELD OF THE INVENTION This invention relates to the use of cGMP PDE9 inhibitors for the treatment of type 2 diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, type 1 diabetes and / or insulin resistance syndrome (IRS). This invention also relates to combinations comprising cGMP PDE9 inhibitors and other agents, said combinations being useful in treating type 2 diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, type 1 diabetes and / or insulin resistance syndrome. BACKGROUND OF THE INVENTION IRS, as defined herein, means the concomitant existence in a subject of two or more of: hyperinsulinemia, dyslipidemia, hypertension, type 2 diabetes or impaired glucose tolerance, hyperuricemia or gout, a pro-coagulant state, atherosclerosis and / or truncal obesity. At the center of IRS, also known as “Syndrome X” and “Metabolic Syndrome” in the biomedical literature, is the common feature of tissue resistance to the action of insulin. This impaired biological respo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/437C07D487/04A61K31/505A61K31/519A61K31/5377A61K31/541A61K45/00A61K45/06A61P3/04A61P3/06A61P3/08A61P3/10A61P5/50A61P7/02A61P9/10A61P9/12A61P19/06A61P43/00
CPCA61K31/437A61K31/505A61K31/519A61K31/5377A61K31/541A61K45/06A61K2300/00A61P19/06A61P3/04A61P3/06A61P3/08A61P43/00A61P5/50A61P7/02A61P9/10A61P9/12A61P3/10
Inventor FRYBURG, DAVID A.GIBBS, EARL MICHAEL
Owner PFIZER INC
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