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Triazinyl nitroxide and its synthesis and use

A technology of oxides and dioxides, applied in the directions of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc., can solve the problems of limited, toxic and side effects diffusion capacity

Inactive Publication Date: 2007-01-03
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although tirapazamine has higher activity, there are also some toxic and side effects such as finding that the diffusion ability in the body is limited in clinical trials, and can cause muscle spasms in patients etc. (Senan S.et al, Int.J.Radiat.Oncol. Biol.Phys., 1994, 29 (2), 379-82.; Luo, Chuanhuan et al, Faming ZhuanliShenqing Gongkai Shuomingshu, 2003, 6pp), therefore aiming at its existing problems, introducing some lipophilic groups to improve its diffusion ability , it is very important to obtain low-toxicity and high-efficiency N-oxygen bioreduction reagents

Method used

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  • Triazinyl nitroxide and its synthesis and use
  • Triazinyl nitroxide and its synthesis and use
  • Triazinyl nitroxide and its synthesis and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] The detailed steps of object compound: triphosgene 39.6g (0.13mol) is dissolved in 30ml toluene, drips under room temperature nitrogen protection containing substituted o-nitroaniline (I 1-4 ) 0.2mol and triethylamine 27.6ml (0.2mol) toluene solution, dropwise in 30min, be warming up to toluene reflux temperature, obtain o-nitroisocyanate (II 1-4 ), cooling, without separation, directly feed anhydrous ammonia for 30min, filter, wash with petroleum ether and hot water successively to obtain the substituted o-nitrourea (III 1-4 ), with 30% sodium hydroxide cyclization to obtain 3-hydroxyl-1,2,4-substituted benzotriazine-1-oxide (IV 1-4 ), 3-hydroxy-1,2,4-substituted benzotriazine-1-oxide (IV 1-4 ) and POCl 3 Substitution gives 3-Cl-1,2,4-substituted benzotriazine-1-oxides (V 1-4 ), V and C 4 -C 10 fatty amine, C 3 -C 6 Condensation of cycloalkylamines, substituted aromatic amines and substituted benzylamines to give 3-substituted amino-1,2,4-substituted benzotriazi...

Embodiment 2

[0048] The synthetic steps of the target product containing nitro substitution: in 3-hydroxyl-1,2,4-benzotriazine-1-oxide (IV 1 ) 2.5g (15.34mmol), add 50ml of mixed acid dropwise, stir at room temperature for 2 hours, heat to 60°C or 100°C, heat for 4 hours, cool, add a large amount of ice water, solids are generated, filter, wash with water, and dry to obtain 3-hydroxy -1,2,4-Nitro-substituted benzotriazine-1-oxide (IV 5，6 ). 3-Hydroxy-1,2,4-6 or 7-nitro-benzotriazine-1-oxide (IV 5，6 )0.5g (2.40mmol) by adding 5ml POCl 3 , heated to reflux for 6h, evaporated to remove unreacted POCl 3 , add ice water, dichloromethane extraction, petroleum ether / ethyl acetate=4:1 is the eluent column chromatography to obtain the product 3-chloro-1,2,4-6 or 7-nitro-benzotriazine -1-Oxide (V 5，6 ). Take 0.5g (2.21mol) 3-chloro-1,2,4-7-nitro substituted benzotriazine-1-oxide (V 6 ) and C 4 -C 10 fatty amine, C 3 -C 6 Cycloalkylamine, substituted arylamine and substituted benzylamine a...

Embodiment 3

[0050] 3-Hydroxy-1,2,4-benzotriazine-1-oxide (IV 1 ): Prepared by referring to literature method (F.J.Wolf et al, J.Amer.Chem.Soc., 1954, 4611-4613).

[0051] MS(EI): 164(M+1); 1 H NMR (DMSO, 400MHz): δ8.08(d, 1H, J=8.4Hz), 7.78(t, 1H, J=7.8Hz), 7.28~7.34(m, 2H), 3.34(s, 1H); IR (KBr): 3421, 2814, 1681, 1615, 1483, 1419, 1344, 1309, 1137, 778.

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Abstract

The present invention provides 3-substituted amino-1, 2, 4-substituted phentriazine-1, 4-dioxides in the general expression as shown. The compounds are prepared with substituted one-nitroaniline as main material and through acylation to produce urea, cyclization, chlorination, amino substitution, oxidation and other steps. The tests show that the compounds of the present invention have anticancer activity and hypoxia selectivity higher than those of TPZ and may be used in preparing hypoxia selective anticancer medicine.

Description

technical field [0001] The invention belongs to the preparation method of compounds, relates to the preparation of triazine nitrogen oxides, mainly relates to a preparation method of a class of 3-substituted amino-1,2,4-substituted benzotriazine-1,4-dioxide, and It is used in hypoxic selective antitumor drugs. Background technique [0002] Malignant tumors are an important class of diseases that affect human life and health. Among all tumors, solid tumors (solid tumors) account for more than 90%. Studies have shown that hypoxia is a necessary process in the development of tumors, and it is also one of the important reasons why solid tumors are resistant to radiotherapy and chemotherapy, and it is closely related to tumor metastasis (Shannon A.M., et al, Cancer Treat.Rev. , 2003, 29(4), 297-307), and is an independent indicator of the prognosis of cancer patients. Although hypoxia is one of the basic characteristics of the microenvironment of most solid tumors and one of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D253/10A61K31/53A61P35/00
Inventor 胡永洲姜发琴杨波何俏军盛荣
Owner ZHEJIANG UNIV
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