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Treatment of insulin resistance with growth hormone secretagogues

A technology for insulin resistance and medicinal salts, applied to endocrine system diseases, dipeptide components, organic active ingredients, etc., can solve problems such as insulin and glucose monitoring

Inactive Publication Date: 2000-07-05
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Single-dose studies of GHRP demonstrated no acute effects on circulating insulin or glucose levels; generally in chronic studies other than few adverse changes have been documented (Jacks, T., et al., J Endocrinol, 143:399 (1993)) Insulin and glucose not yet monitored

Method used

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  • Treatment of insulin resistance with growth hormone secretagogues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0168] Example 12-amino-N-{1(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2, 3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}isobutyramide hydrochloride and 2-amino-N- {1(R)-Benzyloxymethyl-2-[3a-(S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3.3a.4.6.7-hexa Hydrogen pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}isobutyramide hydrochloride A.4-oxo-piperidine-1,3-dicarboxylic acid 1- tert-butyl 3-ethyl ester

[0169] At room temperature, by 8.00g (38.5mmol) 4-oxo-piperidine-3-formic acid ethyl ester hydrochloride, 9.23g (42.4mmol) di-tert-butyl dicarbonate and 3.89g (38.5mmol) triethylamine The resulting mixture was stirred in 150 ml THF for about 72 hours. After concentrating the mixture, the residue was dissolved in ethyl acetate and washed three times (each with 10% aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine), dried over magnesium sulfate and concentrated to give 10.0 g of 1A white solid MS (Cl , NH ...

Embodiment 22

[0181] Example 22-amino-N-[2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7 -Hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl}isobutyl Amide Hydrochloride A. Methyl (R)-2-amino-3-(1H-indol-3-yl)propionate

[0182] First add 2.46g (17.8mmol) of potassium carbonate and then 2.4lg (17.0mmol) of iodomethane into a solution formed by 4.92g (16.2mmol) of N-α-t-BOC-D-tryptophan in 100mL of DMF; And, the mixture was stirred at about 24° C. overnight under nitrogen atmosphere. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed 5 times with 500 mL of water and once with brine, dried over magnesium sulfate and concentrated to give 4.67 g of a white solid. At about 0°C, 15 mL of cold trifluoroacetic acid was added to crude (R)-2-tert-butoxycarbonylamino-3-(1H-indol-3-yl)propionic acid methyl ester, and the mixture was stirred for about 2 Hour. After ...

Embodiment 32

[0187] Example 32-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazole And[4,3-c]pyridin-5-yl]-1(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl}isobutyramide A.4-oxo -Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

[0188] To 7.00 g (36.2 mmol) 4-oxo-piperidine-3-carboxylic acid methyl ester and 8.82 g (72.3 mmol) 4,4- To the mixture of dimethylaminopyridine was added a solution of 7.88 g (36.2 mmol) of di-tert-butyl dicarbonate in 150 mL of dichloromethane. The mixture was warmed to room temperature and then stirred for about 17 hours. After concentrating the mixture, the residue was diluted with chloroform and washed three times (each with 10% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine), dried over magnesium sulfate and concentrated to give 9.18 g of a clear yellow oil. B. 1-tert-butyl 3-methyl 3-(R,S)-benzyl-4-oxo-piperidine-1,3-dicarboxylate

[0189] 745 mg (7.4 mmol) of sodi...

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PUM

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Abstract

This invention is directed to methods of treating insulin resistance in a mammal which comprise administering an effective amount of a compound of formula I, where the variables are defined in the specification, or the stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers, or the pharmaceutically acceptable salts and prodrugs thereof to said mammal. The compounds of formula I are growth hormone secretagogues and as such are useful for increasing the level of endogenous growth hormone. In another aspect this invention provides certain intermediates which are useful in the synthesis of the foregoing compounds and certain processes useful for the synthesis of said intermediates and the compounds of formula I. This invention is further directed to methods comprising administering to a human or other animal a combination of a functional somatostatin antagonist such as an alpha-2 adrenergic agonist and a compound of formula I.

Description

Background technique [0001] Growth hormone (GH) secreted by the pituitary gland stimulates the growth of all growth-capable tissues in the body. In addition, growth hormone is known to have the following basic effects on the body's metabolic processes: 1. Increase the synthesis rate of proteins in almost all body cells ; 2. Reduce the utilization rate of carbohydrates in body cells; 3. Promote the metabolism of free fatty acids and the role of fatty acids in providing energy. [0002] Growth hormone deficiency leads to a variety of disorders, in children it causes short stature, while in adults the consequences of acquired GH deficiency include a profound loss of lean body mass with increased body fat, especially in the trunk. Decreased skeletal and cardiac muscle mass and reduced muscle strength lead to a marked reduction in exercise capacity; bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse a variety of metabolic changes, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60A61K38/00A61K38/05A61K38/25A61P3/04A61P5/02A61P9/04A61P25/00A61P25/20A61P43/00C07DC07D211/74C07D211/78C07D471/04C07KC07K1/02C07K1/06C07K5/04C07K5/06
CPCC07D471/04A61K38/05C07D211/78A61K38/25Y02P20/55A61P25/00A61P25/20A61P3/04A61P43/00A61P5/02A61P5/48A61P5/50A61P9/04A61P3/10A61K31/437
Inventor P·A·卡皮诺C·国锋·赵B·A·勒夫克L·C·潘J·L·特勒拉德瓦M·P·萨威斯托斯基
Owner PFIZER PRODS ETAT DE CONNECTICUT
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