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Use of bioactive metabolites of gepirone for treatment of psychological disorders

A technology of biological activity and metabolites, which is applied in the field of using gepirone bioactive metabolites to treat psychological disorders, and can solve problems such as no biological activity

Inactive Publication Date: 2003-04-16
FABRE KRAMER PHARMA INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The methods of use and preparation of the compounds making up the present invention will become clearer in the following examples. These examples are for the purpose of illustrating the invention and not limiting the invention thereto, and all references cited in this specification for any purpose can be utilized and believed and can be used as specific examples of the present invention. Example. All references cited are incorporated herein by reference. Embodiment 1: Preparation of 3-OH gepirone (I) A. two-4-nitrobenzyl peroxydicarbonate (III) two-4-nitrobenzyl peroxydicarbonate can utilize (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 2.35 N NaOH (20mL, 47mmol) in a cold mixture. The mixture was stirred well for 15 minutes, then filtere...

Embodiment 2

[0040] Experimental results: C, 60.21; H, 7.79; N, 18.32 Example 2: Comparison of 3-OH gepirone, gepirone metabolites and gepirone

[0041] compound

[0042] 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-OH gepirone has little solubility in esters, its first-pass degradation profile results in a long half-life in plasma. Furthermore, the ester solubility range of 3-OH gepirone (approximately 5:1 to 8:1) is generally within the acceptable range for psychoactive drugs acting on brain receptors, while Broto's calculation method is not considered because of high standard deviation. within range. Therefore, 3-OH gepirone has excellent properties from the point of view of an immediate acting pharmacological compound avoiding first pass degradation in the liver. Embodiment 3: 3-OH gepirone preparation

Embodiment 3

[0043] The 3-OH gepirone compositions and formulations of the present invention are designed to administer to mammals, preferably humans, an effective amount of an anxiolytic, antidepressant, psychotropic 3-OH gepirone, 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 than 100 mg / day, generally 15-90 mg / day, preferably 30-60 mg / day...

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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

technical field [0001] 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-OH gepirone), 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. Accordingly, the present invention provides new and improved methods and conditions for the treatment of various psychological disorders. Background technique [0002] The use, preparation and properties of azapirone compound therapeutic agents are disclosed in many documents ...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/506A61P25/22A61P25/24A61P25/28A61P25/32
CPCA61K31/506A61P25/00A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32
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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