Dipeptide derivatives as growth hormone secretagogues

a technology of growth hormone and dipeptide, which is applied in the direction of peptides, drug compositions, metabolic disorders, etc., can solve the problems of high price, disease associated with the source of pituitary gland could be transmitted to the recipient of growth hormone, and still a very expensive product, so as to promote the release of endogenous growth hormone, improve muscle strength, and maintain skin thickness.

Inactive Publication Date: 2004-06-01
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

In yet another aspect, this invention provides methods for improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis and renal homeostasis, which comprise administering to a human or other animal especially dogs, cats and horses, in need of such treatment an amount of a compound of claim 1 which is effective in promoting release of endogenous growth hormone.

Problems solved by technology

In children, it causes dwarfism.
This resulted in an expensive product, and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone (e.g., Jacob-Creutzfeld disease).
Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or nasal spray.
These peptides, while considerably smaller than growth hormones, are still susceptible to various proteases.
As with most peptides, their potential for oral bioavailability is low.

Method used

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  • Dipeptide derivatives as growth hormone secretagogues
  • Dipeptide derivatives as growth hormone secretagogues
  • Dipeptide derivatives as growth hormone secretagogues

Examples

Experimental program
Comparison scheme
Effect test

example 1

2-Amino-N-[2-(8a(S)-benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1(R )-(3,5-dichloro-benzyloxymethyl)-2-oxo-ethyl]-2-methyl-propionamide, hydrochloride

##STR85##

A. 2-Benzyl-piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester

To a stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (20.0 g, 53 mmol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (500 mL) was added N,N-dimethylformamide (50 mL). The reaction was cooled to about -78.degree. C., and a 1M solution of sodium bis (trimethylsilyl)amide in tetrahydrofuran (80 mL) was added. The reaction was stirred at about -78.degree. C. for about 1 hour, and then benzyl bromide (9.4 mL, 79 mmol) was added. The reaction was stirred for about 30 minutes more at about -78.degree. C., then warmed to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution, a...

example 2

2-Amino-N-[2-(8a(S)-benzyl-2-methyl-3-oxo-hexahydro-imidazol[1,5-a]pyrazin- 7-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide, hydrochloride

##STR86##

A. 3-Benzyl-piperzaine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

The title compound of part 1-A (2.80 g, 5.98 mmol) was deprotected according to the method described in General Procedure F to give the title compound of part 2-A as a white foam (1.89 g, 95%): +APcl MS (M+1).sup.+ 335, (M-55).sup.+ 279, (M-99).sup.+ 235; .sup.1 H NMR=400 MHz (CDCl.sub.3) .delta.: 7.28-7.18 (arom, m, 5H), 3.66 (Me, s, 3H), 1.40 (BOC, s, 9H).

B. 3,4-Dibenzyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

To a solution of the title compound of part 2-A (1.22 g, 3.65 mmol) and diisopropylamine (0.63 mL, 3.65 mmol) in acetonitrile (18 mL) was added benzyl bromide (0.45 mL, 3.83 mmol), and the reaction was stirred at room temperature overnight. The reaction was then heated to reflux for about 5 hours. The solvent was t...

example 3

2-Amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2, 2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7yl]-2-oxo-ethyl}-2-me thyl-propionamide, hydrochloride

##STR87##

A. 2-Pyridin-2-ylmethyl-piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester:

A stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (200 g, 529 mol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (200 mL) and DMF (1.5 L) was cooled to about -78 C., and a 0.5M solution of potassium bis(trimethylsilyl)amide in THF (1.27 L) was added. After the above solution had stirred for about one hour, the free base of 2-picolyl chloride was generated by extracting the corresponding hydrochloride salt (217 g, 1.32 mol) from saturated sodium bicarbonate solution with methylene chloride. The combined organic extracts were dried (MgSO.sub.4), concentrated, immediately dissolved in DM...

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Abstract

This invention is directed to compounds of the formula ##STR1## and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis and/or frailty, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis and/or frailty when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of Formula I.

Description

This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis and / or frailty.BACKGROUND OF THE INVENTIONGrowth hormone (GH), which is secreted from the pituitary gland, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects of the metabolic processes of the body: 1. Increased rate of protein synthesis in substantially all cells of the body; 2. Decreased rate of carbohydrate utilization in cells of the body; and 3. Increased mobilization of free fatty acids and use of fatty acids for energy.Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle m...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D513/04C07D513/00C07D471/00C07D471/04C07D487/04C07D487/00C07D491/04C07K5/00C07D498/00C07D498/04C07D491/00C07K5/06C07K5/02A61K38/00A61K31/138A61K31/40A61K31/4168A61K31/4174A61K31/437A61K31/4439A61K31/4453A61K31/4535A61K31/4725A61K31/4985A61K31/565A61K31/663A61K38/04A61K38/22A61K38/23A61K38/27A61K45/00A61P3/00A61P3/02A61P3/04A61P3/08A61P3/10A61P5/06A61P5/10A61P7/00A61P9/04A61P13/12A61P15/00A61P15/14A61P17/00A61P17/02A61P19/00A61P19/08A61P19/10A61P21/00A61P25/02A61P25/20A61P43/00C07K1/02C07K5/023C07K5/062
CPCA61K38/00A61P3/00A61P3/02A61P3/04A61P3/08A61P3/10A61P5/06A61P5/10A61P7/00A61P9/04A61P13/12A61P15/00A61P15/14A61P17/00A61P17/02A61P19/00A61P19/08A61P19/10A61P21/00A61P25/02A61P25/20A61P43/00C07D471/04C07D487/04C07D491/04C07D513/04C07K5/0202C07K5/0205C07K5/0207C07K5/021C07K5/06026
Inventor CARPINO, PHILIP ALBERTGRIFFITH, DAVID ANDREWLEFKER, BRUCE ALLEN
Owner PFIZER INC
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