Pharmaceutical composition containing phenoxazinium compound as active ingredient

A technology for active ingredients and compositions, which is applied in the field of pharmaceutical compositions containing phenoxazine compounds as active ingredients, can solve the problems of high acute toxicity, difficult therapeutic effect, and is not suitable for large-scale administration, and achieves remarkable curative effect, Effects of high selective toxicity

Inactive Publication Date: 2008-02-27
JAPAN SCI & TECH CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The treatment drugs for some of the above diseases have the problem that they can cause the emergence and spread of resistant protozoa and their serious side effects
[0022] The above results teach that the compounds disclosed in Non-Patent Document 1 do not show a high growth-inhibiting effect in an in vivo assay system, and their actual therapeutic effects cannot be expected
Beyond that, animals treated with the compound lived only about 1 or 2 days longer than untreated animals
Due to high acute toxicity, they are not suitable for large dose administration and it will be difficult to achieve high therapeutic effect with these compounds

Method used

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  • Pharmaceutical composition containing phenoxazinium compound as active ingredient
  • Pharmaceutical composition containing phenoxazinium compound as active ingredient
  • Pharmaceutical composition containing phenoxazinium compound as active ingredient

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Synthesis of 3-Dibutylamino-7-diethylaminophenoxazinium Perchlorate (Compound A-8)

[0073] A mixture of 3-butylaminophenol (1.0 mL, 4.43 mmol) and N,N-diethyl-4-nitrosoaniline (790 mg, 4.43 mmol) was suspended in ethanol (55 mL) at room temperature, and 60% aqueous perchloric acid (0.5 mL) was added dropwise to the suspension. The resulting mixture was heated to reflux for 3 hours and cooled to room temperature. It was then concentrated under reduced pressure to half its starting volume of solvent and cooled to 0 °C. The resulting precipitate was removed by filtration and the filtrate was concentrated. The concentrated crude material was purified by silica gel chromatography (eluent: chloroform:ethyl acetate=9:1) to obtain a crude compound. The resulting crude compound was dissolved in methanol and cooled to 0°C, and a few drops of diethyl ether were added thereto for crystallization. The obtained dark blue crystals were filtered to obtain 3-dibutylamino-7-diethy...

Embodiment 2

[0076] Synthesis of 3-ethylmethylamino-7-dimethylaminophenoxazinium perchlorate (compound A-9)

[0077] A mixture of 3-methylethylaminophenol (300 mg, 1.98 mmol) and N,N-dimethyl-4-nitrosoaniline (298 mg, 1.98 mmol) was suspended in ethanol (15 mL) at room temperature, And 70% aqueous perchloric acid (0.5 mL) was added dropwise to the suspension. The resulting mixture was heated to reflux for 6 hours, cooled to room temperature and distilled under reduced pressure to remove the solvent. The resulting crude material was purified by silica gel chromatography (eluent: chloroform:ethyl acetate=9:1) to obtain a crude compound (216 mg, crude yield 27%). The resulting crude compound was dissolved in methanol and cooled to 0°C for crystallization. The resulting dark blue crystals were filtered to obtain 3-ethylmethylamino-7-dimethylaminophenoxazinium perchlorate (13.3 mg, isolated yield 2%).

[0078] 1H-NMR (400MHz, CDCl3) δ: 7.80(s, 1H), 7.78(s, 1H), 7.41(dd, 1H, J=6.8, 2.8Hz), ...

Embodiment 3

[0080] Synthesis of 3-dimethylamino-7-(1-piperazinyl) phenoxazinium chloride monohydrochloride (compound A-11) become

[0081]A mixture of 3-(1-piperazinyl)phenol (165 mg, 0.92 mmol) and N,N-dimethyl-4-nitrosoaniline (139 mg, 0.92 mmol) was suspended in ethanol (50 mL) at room temperature , and 70% aqueous perchloric acid (0.5 mL) was added dropwise to the suspension. The resulting mixture was heated to reflux for 6 hours, cooled to room temperature and distilled under reduced pressure to remove the solvent. The obtained crude material was purified by silica gel chromatography (eluent: chloroform:ethyl acetate=9:1) to obtain a crude compound (65 mg). The obtained crude compound was dissolved in methanol, mixed with ion exchange resin Amberlyte IRA-400 (C1) and left at room temperature for 2 hours. The resulting mixture was then filtered, and the resin was further washed with methanol. The collected filtrate was concentrated under reduced pressure for crystallization. T...

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Abstract

A pharmaceutical composition, especially therapeutic and/or preventive pharmaceutical composition that has high therapeutic effect and selective toxicity on parasitic protozoa infections, exhibiting life-extending effectiveness, etc. There is provided a pharmaceutical composition, especially therapeutic and/or preventive agent for protozoa infections comprising a compound of the general formula (1) and provided a novel compound contained therein as an active ingredient.

Description

technical field [0001] The present invention relates to pharmaceutical compositions and novel compounds for use as active ingredients of pharmaceutical compositions. The compositions of the present invention are useful for the treatment and / or prevention of, for example, malaria including drug-resistant malaria, leishmaniasis, trypanosomiasis including African sleeping sickness and Chagas' disease, toxoplasmosis and cryptosporidiosis, etc. It is especially useful for diseases associated with infection with parasites. Background of the invention [0002] Parasitic protozoan infections are still frequently found today mainly in tropical and subtropical regions, including, for example, malaria, leishmaniasis, African trypanosomiasis (African sleeping sickness), American trypanosomiasis (Chagas disease), toxoplasmosis Lymphatic filariasis, babesiosis and cryptosporidiosis. They are divided into diseases affecting only humans and diseases affecting both humans and domestic anim...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/538A61P33/06A61P33/02C07D265/38
CPCC07D265/38A61K31/538A61P33/02A61P33/06Y02A50/30
Inventor 井原正隆高须清诚川上雅之北口博司佐藤幸藏
Owner JAPAN SCI & TECH CORP
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