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N4-substited pyrazolyl [4,5-e][1,2,4] thiadiazine derivative and its preparation process and medicine composition

A technology of thiadiazine and derivatives, applied in the field of derivative drugs

Inactive Publication Date: 2009-05-06
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although an overall structure-activity relationship has been established, N 4 Whether the single substitution is active, and it is N 2 bit or N 4 The formation of the "butterfly" configuration with the thienothiadiazine moiety still needs further study

Method used

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  • N4-substited pyrazolyl [4,5-e][1,2,4] thiadiazine derivative and its preparation process and medicine composition
  • N4-substited pyrazolyl [4,5-e][1,2,4] thiadiazine derivative and its preparation process and medicine composition
  • N4-substited pyrazolyl [4,5-e][1,2,4] thiadiazine derivative and its preparation process and medicine composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1. Preparation of intermediate 7-methyl-1,1,3-trioxy-2,4-dihydropyrazol[4,5-e][1,2,4]thiadiazine (4)

[0040] Add 5.1g (22mmol) of 1-methyl-5-sulfonamido-4-pyrazolecarboxylic acid ethyl ester (1), 3.8g (66mmol) of 85% hydrazine hydrate and 25ml of ethanol in a 100ml flask, heat and stir to reflux for 10h , the solvent and unreacted hydrazine hydrate were distilled off under reduced pressure, and the residual oil was recrystallized from absolute ethanol to obtain a white solid (2). Dissolve 2.19g (10mmol) (2) in 50ml 2N HCl, slowly add 2ml of NaNO 2 (0.85g, 12mmol) aqueous solution, the temperature was kept below 10°C, the mixture was stirred at this temperature for about 2h, a white solid (3) was precipitated, filtered and washed with water. The product was not further purified due to its instability, but was pure enough for the next step. Add 8.8g (40mmol) (3) into 100ml of toluene, heat and stir to reflux for 7h, after the reaction is complete, filter the pr...

Embodiment 2

[0041] Example 2. 2-benzyl-7-methyl-1,1,3-trioxy-2,4-dihydropyrazol[4,5-e][1,2,4]thiadiazine (5a ) preparation

[0042] 1 equivalent of the intermediate 7-methyl-1,1,3-trioxo-2,4-dihydropyrazol[4,5-e][1,2,4]thiadiazine prepared in Example 1 , dissolved in dry dimethylformamide (DMF), under N 2 Under protection, slowly add 2 equivalents of sodium hydride containing 60% mineral oil, keep the temperature below 10°C, after the addition is complete, stir for 15-20min, then slowly add 1 equivalent of benzyl bromide. The reaction mixture was stirred for an additional 10 h at 28 °C. After cooling, the solvent was evaporated under reduced pressure. The residue was separated and purified by flash column chromatography. Eluent: dichloromethane:methanol (4:1), recrystallized from an organic solvent to obtain crystals. Yield 65%, white solid, mp 187°C (dec) (ethanol). The product spectrum data are as follows:

[0043] IR (KBr, cm -1 ): 3430 (NH), 3032 (Py-CH), 1594 (C=O), 1342, 114...

Embodiment 3

[0044] Example 3. 2-(p-cyanobenzyl)-7-methyl-1,1,3-trioxy-2,4-dihydropyrazol[4,5-e][1,2,4] The preparation of thiadiazine (5b), preparation method is as embodiment 2, difference is:

[0045] The 7-methyl-1,1,3-trioxy-2,4-dihydropyrazol[4,5-e][1,2,4]thiadiazine and p-cyanochloride prepared in Example 1 Benzyl was reacted at 30-40°C for 12h, eluent: dichloromethane:methanol (4:1), yield 55%, white solid, mp 244°C (dec) (ethanol). The product spectrum data are as follows:

[0046] IR (KBr, cm -1 ): 3461 (NH), 2236 (CN), 1598 (C=O); 1338, 1143 (SO 2 ). 1 H-NMR (DMSO-d 6 )δ: 7.74(d, 2H, J=8.0Hz, Ar-H); 7.41(d, 2H, J=8.0Hz, Ar-H); 7.12(s, 1H, Py-H); 4.97(s, 2H, CH 2 ); 3.84 (s, 3H, CH 3 ). 13 C-NMR (DMSO-d 6 )δ: 152(C 3 =O), 144(C-1'), 132(2C, C-3', 5'), 128(C-7a), 127(2C, C-2', 6'), 125(C-4a ), 123(C-5), 118(C-4'), 109(CN), 46(CH 2 ), 37 (CH 3 ). MS (EI) m / z 318 (M+1).

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Abstract

The present invention is N4-substituent-7-methyl-1, 1, 3-trioxy-2, 4-dihydropyrazolyl[4, 5-e][1, 2, 4] thiadiazine derivative as HIV-1 non-nucleoside reverse transcriptase inhibitor and its preparation process and medicine composition, and belongs to the field of derivative medicine technology. The preparation process of N4-substituent-7-methyl-1, 1, 3-trioxy-2, 4-dihydropyrazolyl[4, 5-e][1, 2, 4] thiadiazine derivative includes the following steps: synthesizing intermediate, dissolving the intermediate in dimethyl formamide, adding sodium hydride, stirring at temperature lower than 10 deg.c, adding alkyl halide, stirring the mixture at 25-60 deg.c, cooling, separating and purifying and re-crystallizing in organic solvent. The derivative is one heterocyclic system in novel structure, has HIV-1 reverse transcriptase inhibiting activity and may be used as precursor compound for preparing medicine to resist AIDS.

Description

(1) Technical field [0001] The present invention relates to a kind of HIV-1 non-nucleoside reverse transcriptase inhibitor N 4 - substituted-7-methyl-1,1,3-trioxo-2,4-dihydropyrazol[4,5-e][1,2,4]thiadiazine derivatives and their preparation methods, and The pharmaceutical composition composed of the derivative and auxiliary materials belongs to the technical field of derivative drugs. (2) Background technology [0002] Acquired immunodeficiency syndrome, commonly known as AIDS (Acquried immunodeficiency syndrome AIDS), is a serious infectious disease caused by human immunodeficiency virus (Human immunodeficiency virus HIV). HIV is a retrovirus, divided into two types, HIV-1 and HIV-2. HIV-1 reverse transcriptase (reverse transcriptase RT) plays an important role in the virus life cycle. The virus reverse-transcribes single-stranded RNA into double-stranded DNA through reverse transcriptase, and then the viral DNA is quickly integrated into the host RNA, thereby completing...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04C07D231/00C07D285/00A61K31/549A61P31/18
Inventor 刘新泳陈年根徐文方
Owner SHANDONG UNIV