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Animal and human Anti-trypanosomonal and Anti-leishmania agents

A compound, aminopurine technology, applied in the field of trypanosomiasis or leishmaniasis, treatment or prevention of trypanosomiasis, can solve the problems of long duration of treatment, lack of compliance, difficulty in administration, etc.

Active Publication Date: 2019-03-15
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current treatments have safety / toxicity issues (including cardiotoxicity), incomplete cure rates, difficult administration, long treatment duration, lack of adherence and development of resistance

Method used

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  • Animal and human Anti-trypanosomonal and Anti-leishmania agents
  • Animal and human Anti-trypanosomonal and Anti-leishmania agents
  • Animal and human Anti-trypanosomonal and Anti-leishmania agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0244] Example 1: N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1S,4S)-4-(piperidine-1 -ylmethyl)cyclohexyl)-9H-purine-2,8-diamine

[0245]

[0246] ((1S,4S)-tert-butyl 4-(piperidine-1-carbonyl)cyclohexyl)carbamate. To a stirred solution of (1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (1.5 g, 6.0 mmol) in DMF (20 mL) was added DIPEA ( 2 mL, 12.5 mmol), piperidine (0.63 g, 7.5 mmol), EDCI (2.35 g, 12.5 mmol) and HOBT (1.88 g, 12.5 mmol). The reaction mixture was stirred for 16h. Reaction completion was confirmed by UPLC. The product was isolated and triturated with petroleum ether to give tert-butyl ((1S,4S)-4-(piperidine-1-carbonyl)cyclohexyl)carbamate (1.9 g) as an off-white solid. MS(ESI)m / z 311[M+1] + .

[0247] ((1S,4S)-4-Aminocyclohexyl)(piperidin-1-yl)methanone. To a stirred solution of ((1S,4S)-4-(piperidine-1-carbonyl)cyclohexyl)carbamate tert-butyl ester (1.9 g, 6.5 mmol) in DCM (20 mL) was added di HCl in oxane (2 mL). ...

Embodiment 2

[0253] Example 2: N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1S,4S)-4-(morpholinemethyl )cyclohexyl)-9H-purine-2,8-diamine

[0254]

[0255] ((1S,4S)-tert-butyl 4-(morpholine-4-carbonyl)cyclohexyl)carbamate. To a stirred solution of (1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (3 g, 12 mmol) in DMF (30 mL) was added DIPEA (4.5 mL) at ambient temperature , 24mmol), morpholine (1.28g, 14.76mmol), EDCI (4.70g, 24.6mmol) and HOBT (3.76g, 24.6mmol). The reaction mixture was stirred for 16h. Reaction completion was confirmed by UPLC. The product was isolated and triturated with petroleum ether to afford tert-butyl ((1S,4S)-4-(morpholine-4-carbonyl)cyclohexyl)carbamate (2.65 g, 75%) as an off-white solid. MS(ESI)m / z 313[M+1] + .

[0256] ((1S,4S)-4-Aminocyclohexyl)(morpholino)methanone. To a stirred solution of ((1S,4S)-4-(morpholine-4-carbonyl)cyclohexyl)carbamate tert-butyl ester (2.65 g, 8.5 mmol) in DCM (50 mL) was added di HCl...

Embodiment 3

[0262] Example 3: (1S,4S)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

[0263]

[0264] cis-(4-carbamoyl-cyclohexyl)-carbamate tert-butyl ester. cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1 equiv) and TEA (1.1 equiv) were dissolved in 0.3M THF, and the mixture was cooled to 0°C. Ethyl chloroformate (1.1 equiv) was added dropwise. After stirring at 0 °C for 30 min, NH in THF was added 3 . The mixture was stirred at -78 °C for 2 h. The mixture was diluted with water, and the solvent was evaporated until only water remained. The resulting precipitate was collected by filtration and dried under vacuum to afford cis(4-carbamoyl-cyclohexyl)-carbamate tert-butyl ester (45%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δppm 7.10(brs,1H),6.69(brs,2H),3.41(brs,1H),2.10(m,1H),1.72(m,2H),1.53(m,2H),1.42(m,4H) ,1.36(s,9H).

[0265] cis-4-amino-cyclohexanecarboxylic acid amide hydrochloride. To a solution of cis-(4-carbamoyl-cyclohexyl)-car...

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PUM

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Abstract

Provided herein are Aminopurine compounds of Formula (I) or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof, wherein R1, R2, and R3 are as defined herein, compositions comprising an effective amount of an Aminopurine Compound, and methods for treating or preventing animal and human protozoal infections.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 344,759, filed June 2, 2016, which is hereby incorporated by reference in its entirety. technical field [0002] Provided herein are certain aminopurine compounds, compositions comprising effective amounts of such compounds, and methods of treating or preventing trypanosomosis, trypanosomiasis, or leishmaniasis comprising administering An effective amount of such aminopurine compounds is administered to a subject in need thereof. Accordingly, also provided herein are such compounds for use in said methods of treating or preventing trypanosomiasis, trypanosomiasis, or leishmaniasis. Background technique [0003] Protozoa of the genera Trypanosoma and Leishmania are known to cause many diseases in animals and humans. These protozoa can be transmitted by blood-sucking invertebrates, by mechanical vectors, or sexually, and are responsible for a number of diseases known as trypanosomiasis or trypan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H21/02C12N15/11
CPCA61K45/06C07D413/02C07D473/32A61P33/02A61P43/00A61K31/52C07C13/06C07C13/10C07C211/36C07C211/57C07C217/02G01N33/56905
Inventor 史黛西·S·卡南纳塔利·安妮·哈夫雷拉克迈克尔·约翰·威蒂
Owner CELGENE CORP
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