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Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors

a technology of dipeptidyl peptidase and fluorinated cyclic amide, which is applied in the field of compound, can solve the problems of limiting their use, adding significantly to the overall morbidity and mortality attributable to those diseases, and few pharmacological agents available to reduce adiposity effectively and acceptably, and achieves increased in vivo half-life, increased metabolic stability, and easy preparation and detection.

Inactive Publication Date: 2004-07-08
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a new compound (Formula I) and its prodrug (Formula I') that can be used to treat Type 2 diabetes, metabolic syndrome, hyperglycemia, impaired glucose tolerance, and other related diseases. The compound has been found to have beneficial effects on insulin resistance, hypertension, hyperlipidemia, atherosclerosis, and obesity. It can be administered as a pharmaceutical composition or as a food additive to prevent disease progression and improve overall health. The compound has been found to have beneficial effects on various biomarkers associated with Type 2 diabetes, such as fasting blood glucose, insulin, and GLP-1. The compound can also be used to treat Type 1 diabetes, polycystic ovary syndrome, short bowel syndrome, and other metabolic disorders.

Problems solved by technology

The administration of an excess dose of insulin causes hypoglycemia, with consequences ranging from mild abnormalities in blood glucose to coma, or even death.
However, the clinically available hypoglycemics can have side effects which limit their use.
In addition, diabetes mellitus is a comorbid disease that frequently confounds hyperlipidemia, atherosclerosis and hypertension, adding significantly to the overall morbidity and mortality attributable to those diseases.
Currently few pharmacological agents are available that reduce adiposity effectively and acceptably.
Osteoporosis and the consequences of compromised bone strength are a significant cause of frailty, and of increased morbidity and mortality.
Heart disease is a major health problem throughout the world.
Myocardial infarctions are a significant source of mortality among those individuals with heart disease.

Method used

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  • Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
  • Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
  • Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

(2S, 3S)-2-amino-3-methyl-1-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-pentan-1--one

[0121] Step 1: [(1S, 2S)-2-Methyl-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-car-bonyl)-butyl]-carbamic Acid Tert-Butyl Ester.

[0122] To a mixture of (L)-Boc-isoleucine (322 mg, 1.30 mmol), 3,3,4,4-tetrafluoro-pyrrolidine hydrochloride (300 mg, 1.67 mmol), hydroxybenzotriazole (225 mg, 1.67 mmol) and triethylamine (0.23 mL, 1.67 mmol) in dichloromethane (10 mL) was added 1-(-3-dimethylaminopropyl)-3-e-thylcarbodiimide hydrochloride (319 mg, 1.67 mmol). The mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with 2 N HCl, saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (hex / ethyl acetate, 4:1) and isolated as a white solid (415 mg, 86%).

[0123] The 3,3,4,4-tetrafluoro-pyrrolidine hydrochloride utilized in Step 1 may be prepared according to Chaudhry et al. J.Chem.Soc.; 1964; 874...

example 2

(2S, 3S)-2-amino-1-(3-fluoro-azetidin-1-yl)-3-methyl-pentan-1-one.

[0126] Step 1: [(1S,2S)-1-(3-Hydroxy-azetidine-1-carbonyl)-2-methyl-butyl]--carbamic Acid Tert-Butyl Ester.

[0127] [(1S,2S)-1-(3-Hydroxy-azetidine-1-carbonyl)-2-methyl-butyl]-carbami-c acid tert-butyl ester was prepared as analogously described in Step 1 of Example 1 from a mixture of (L)-Boc-isoleucine and 3-hydroxyazetidine. 3-Hydroxyazetidine was prepared according to Lee, J. et al. (Bioorg.Med.Chem.Lett. 2000, 10, 1063).

[0128] Step 2: [(1S, 2S)-1-(3-Fluoro-azetidine-1-carbonyl)-2-methyl-butyl]--carbamic Acid Tert-Butyl Ester.

[0129] To a cooled (-78.degree. C.) solution of diethylaminosulfur trifluoride (0.46 mL, 3.5 mmol) in dichloromethane (6 mL), was added dropwise a solution of [(1S, 2S)-1-(3-hydroxy-azetidine-1-carbonyl)-2-met-hyl-butyl]-carbamic acid tert-butyl ester (1.0 g, 3.5 mmol) in dichloromethane (4 mL). The mixture was warmed to room temperature, stirred overnight, then diluted with ethyl acetate and p...

example 3

(S)-2-amino-2-cyclohexyl-1-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-ethanone

[0132] Step 1: (S)-[1-Cyclohexyl-2-oxo-2-(3,3,4,4-tetrafluoro-pyrrolidin-1--yl)-ethyl]-carbamic Acid Tert-Butyl Ester.

[0133] (S)-[1-Cyclohexyl-2-oxo-2-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-eth-yl]-carbamic acid tert-butyl ester was prepared from (L)-Boc-cyclohexylglycine and 3,3,4,4-tetrafluoropyrrolidine as analogously described in Step 1 of Example 1.

[0134] Step 2: (S)-2-amino-2-cyclohexyl-1-(3,3,4,4-tetrafluoro-pyrrolidin--1-yl)-ethanone.

[0135] (S)-2-amino-2-cyclohexyl-1-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-et-hanone was obtained by HCl treatment of (S)-[1-cyclohexyl-2-oxo-2-(3,3,4,4--tetrafluoro-pyrrolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester as analogously described in Step 2 of Example 1. (mp 278.degree. C.).

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Abstract

The invention relates to new therapeutically active and selective inhibitors of the enzyme dipeptidyl peptidase-IV, pharmaceutical compositions comprising the compounds and the use of such compounds for treating diseases that are associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes mellitus, hyperglycemia, impaired glucose tolerance, metabolic syndrome (Syndrome X or insulin resistance syndrome), glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, inflammatory bowel syndrome and to prevent disease progression in Type 2 diabetes. The invention also relates to a method of identifying an insulin secretagogue agent for diabetes.

Description

[0001] This application is filed claiming priority from co-pending U.S. Provisional Application No. 60 / 86157, filed Jun. 4, 2002.[0002] The present invention relates to new therapeutically active and selective inhibitors of the enzyme dipeptidyl peptidase-IV (hereinafter "DPP-IV"), pharmaceutical compositions comprising the compounds and the use of such compounds for treating diseases that are associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes, metabolic syndrome (Syndrome X or insulin resistance syndrome), hyperglycemia, impaired glucose tolerance, glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fa...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D205/04C07D207/08C07D211/38
CPCC07D205/04C07D211/38C07D207/08
Inventor HULIN, BERNARDPARKER, JANICE C.
Owner PFIZER INC
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