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Use of bioactive metabolites of gepirone for the treatment of psychological disorders

A technology for mammals and psychological states, which can be used in drug combinations, medical preparations containing active ingredients, pharmaceutical formulations, etc., and can solve problems such as lack of biological activity.

Inactive Publication Date: 2006-01-04
FABRE KRAMER PHARMA INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For 6'-Hydroxy-Bu, no significant biological activity is disclosed

Method used

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  • Use of bioactive metabolites of gepirone for the treatment of psychological disorders
  • Use of bioactive metabolites of gepirone for the treatment of psychological disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the preparation of 3-hydroxy gepirone (I)

[0047] A. Di-4-nitrobenzyl peroxydicarbonate (III)

[0048] Di-4-nitrobenzyl peroxydicarbonate can be prepared using a modification of a documented procedure (Strain et al., "Japan American Chemical Science", 1950, 72: 1254; incorporated herein by reference ). Thus, a cold solution of 4-nitrobenzyl chloroformate (10.11 g, 4.7 mmol) in acetone (20 mL) was added dropwise over a period of 30 minutes from 30% H 2 o 2 (2.7mL, 24mmol) and 2.35N NaOH (20mL, 47mmol) in a cold mixture. The mixture was stirred well for 15 minutes, then filtered, and the filter cake was rinsed first with water and then with hexane. The resulting wet solid was dissolved in dichloromethane, and the solution was dried over Na2SO4 and diluted with an equal amount of hexane. Concentration of the solution on a rotary dehydrator at 20°C resulted in the precipitation of crystals, which were filtered and rinsed with hexane, and dried in vacuo t...

Embodiment 2

[0057] Example 2: Comparison of 3-hydroxygepirone, gepirone metabolites and gepirone

[0058]

compound

Log ρ ow octanol-water partition coefficient

Crippen fraction

Viswanadhan fraction

Broto fraction

Gepirone

1.38±0.47

1.32±0.49

1.13±0.97

3-Hydroxygepirone

0.73±0.47

0.89±0.49

-0.23±1.11

[0059] In all methods, 3-hydroxygepirone has higher water solubility (low log ρ ow ) and have lower ester solubility compared with gepirone.

[0060] The short half-life of gepirone is attributed to its high oil solubility, which makes it more susceptible to first-pass degradation in the liver. Because 3-hydroxygepirone has little solubility in esters, its first-pass degradation profile results in a long half-life in plasma. In addition, the ester solubility range of 3-hydroxygepirone (approximately 5:1 to 8:1) is generally within the acceptable range for psychoactive drugs acting on brain recept...

Embodiment 3

[0061] Embodiment 3: 3-hydroxygepirone preparation

[0062] The 3-hydroxygepirone compositions and formulations of the present invention are designed to administer to mammals, preferably humans, an effective amount of an anxiolytic, antidepressant, psycho-altering 3-hydroxygepirone, or a pharmacologically acceptable form thereof. its salts. Effective formulations of about 0.01 to 40 mg / kg body weight are envisioned, with a preferred range of about 0.1-0.2 mg / kg body weight. For some central nervous disorders, it is recommended to take 15-90mg per day, preferably 30-60mg per day. (See US Patent 4,771,053 to Cott et al., incorporated herein by reference). The administration of the biologically active gepirone metabolite according to the present invention can be through injection, oral administration, buccal administration, rectal administration, external application, etc., but oral administration is preferred. For alleviating severe depression, the clinical dose range is less...

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Abstract

Bioactive gepirone metabolites, such as 3-OH gepirone (4,4,-dimethyl-3-hydroxy-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6-piperidinedione), and their pharmaceutically acceptable salts and hydrates, can be used to alleviate psychological disorders or the symptoms thereof. The use of these compounds provides advantages over other therapeutic azapirones as they possess superior bioavailability, faster onset of action, and more stable plasma levels when administered to a mammal.

Description

[0001] This application is a divisional application of the Chinese patent application with the application number 00817455.5 and the title of the invention "Application of Gepirone Metabolites in the Preparation of Compositions for Treating Psychological Disorders". technical field [0002] The present invention relates to the alleviation of depression, anxiety and other psychological or psychiatric disorders by administering certain biologically active metabolites of the known antidepressant compound gepirone. In a preferred example, the compound is 4,4,-dimethyl-3-hydroxyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6 -piperazinediketone (3-hydroxygepirone), however, other gepirone metabolites and compounds thereof are also possible and foreseeable. Surprisingly, these bioactive metabolites of gepirone showed an improved bioavailability profile and improved potential for immediate action and long-term therapy compared to gepirone and other azapirone therapeutics. Accordi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/506A61P25/22A61P25/24A61P25/32A61P25/36A61KA61P
Inventor 斯蒂芬·J·克雷默路易斯·F·法布里爱德华·H·鲁迪格约瑟夫·P·耶维克
Owner FABRE KRAMER PHARMA INC
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