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Solanesol phosphamide derivatives and their preparation method and use

A technology for solanesphosphamide and its derivatives, which is applied in the field of solanesphosphamide derivatives and their preparation and application, can solve the problems of poor selectivity and high toxicity, and achieve low toxicity and significant anticancer effects

Inactive Publication Date: 2015-07-15
SHIJIAZHUANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because many nitrogen mustard antineoplastic drugs currently used still have the disadvantages of high toxicity and poor selectivity, new nitrogen mustard antineoplastic drugs with high efficiency and low toxicity have always been a research hotspot in the world; and looking for various new types of nitrogen mustards carrier to improve its pharmacokinetic properties such as absorption and distribution in the body is an important way to discover new nitrogen mustard drugs (Parker L L, Lacy S M, Farrugla L J, et al. J Med Chem, 2004, 47: 5 683 ; Jain M, Kwon C-H. J Med Chem, 2003, 46:5 428)

Method used

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  • Solanesol phosphamide derivatives and their preparation method and use
  • Solanesol phosphamide derivatives and their preparation method and use
  • Solanesol phosphamide derivatives and their preparation method and use

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Preparation of [(3,4-dimethoxy)benzyl]-N-solanyl-N',N'-bis(2-chloroethyl)diaminophosphate (1) Structure of (1) See Figure 4 , under the protection of nitrogen, add 20mL of dichloromethane and 1.68g (10mmol) of 3,4-dimethoxybenzyl alcohol into the reactor, cool to 0°C, add PCl 3 1.49g (11mmol) and Et 3 N1.01g (10mmol), stirred and reacted for 20 minutes, then added 6.3g (10mmol) of solanesamine, kept the reaction for 60 minutes, then added 1.77g (10mmol) of nitrogen mustard hydrochloride and Et 3 N 1.51 g (15 mmol), continue to keep warm for 60 minutes, then naturally rise to room temperature, and react for 30 minutes. Then cool to -20°C, add 1.9 mL (10 mmol) of 5.2 mol / L decane solution of tert-butanol peroxide, react for 1.5 hours, filter, wash the filter cake with an appropriate amount of water, dry, and purify by silica gel chromatography. Get [(3,4-dimethoxy)benzyl]-N-solanyl-N',N'-bis(2-chloroethyl)diaminophosphate (1); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm): 1...

Embodiment 2

[0026] Preparation of [(3,4,5-trimethoxy)benzyl]-N-solanyl-N',N'-bis(2-chloroethyl)diaminophosphate (2):

[0027] (2) structure see Figure 5 , replace the 3,4-dimethoxybenzyl alcohol in Example 1 with 3,4,5-trimethoxybenzyl alcohol, and keep the other things unchanged, prepare [(3,4,5-trimethoxy)benzyl ]-N – solanyl-N', N'-bis(2-chloroethyl) diaminophosphate (2); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm): 1.26-1.75 (m, 30H, CH 3 ), 1.96-2.08 (m, 32H, CH 2 ), 2.85-3.38 (m, 7H, NCH 2 , NH), 3.51-3.59 (m, 4H, CH 2 C1), 3.75 (s, 9H, OCH 3 ), 5.10-5.20 (m, 9H, C=CH), 5.28 (s, 2H, CH 2 ), 6.11-6.56 (m, 2H, Ar-H). Anal Calcd for C 59 h 95 Cl 2 N 2 o 5 P : C, 69.87; H, 9.44 N, 2.76. Found: 69.75; H, 9.43; N, 2.76.

Embodiment 3

[0029] Preparation of [[(3-methoxy-4-hydroxy)phenyl]propenyl]-N-solanyl-N',N'-bis(2-chloroethyl)diaminophosphate (3) :

[0030] (3) structure see Image 6 , the 3,4-dimethoxybenzyl alcohol in Example 1 is replaced with 3,4-dimethoxyphenyl propylene alcohol, and other changes are made, and [(3-methoxyl-4-hydroxyl )phenyl]propenyl]-N-solanyl-N',N'-bis(2-chloroethyl)diaminophosphate (3); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm): 1.25-1.76 (m, 30H, CH 3 ), 1.96-2.08 (m, 32H, CH 2 ), 2.85-3.38 (m, 7H, NCH 2 , NH), 3.52-3.58 (m, 4H, CH 2 C1), 3.68 (s, 3H, OCH 3 ), 3.74 (s, 3H, OCH 3 ), 5.03-5.20 (m, 9H, C=CH), 5.27 (s, 2H, CH 2 ), 6.58-6.69 (m, 3H, Ar-H). Anal Calcd for C 58 h 93 Cl 2 N 2 o 4 P : C, 70.80; H, 9.46 N, 2.85. Found: 70.73; H, 9.44; N, 2.86.

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Abstract

The invention discloses solanesol phosphamide derivatives or their pharmaceutically acceptable salts shown in the formula (I). The solanesol phosphamide derivatives or their pharmaceutically acceptable salts comprise stereoisomers or tautomers. In the formula (I), R represents 4-hydroxybenzyl, 4-methoxybenzyl, 4-acetoxybenzyl, 3,4-dihydroxybenzyl, 3,4,5-trihydroxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 3,4-dihydroxyphenyl allyl, 3-methoxy-4-hydroxyphenyl allyl, 3,4-dimethoxyphenyl allyl, 3,4-diacetoxyphenyl allyl or 3-methoxy-4-acetoxyphenyl allyl; and Y represents NH or piperazinyl. The invention also relates to a preparation method of the solanesol phosphamide derivatives or their pharmaceutically acceptable salts, and a use of the solanesol phosphamide derivatives or their pharmaceutically acceptable salts in tumor therapy.

Description

technical field [0001] The invention relates to a solanisfamide derivative, a preparation method thereof and an application as an anticancer drug. Background technique [0002] Nitrogen mustard is an anti-tumor group without structural specificity, whether it is free or connected with various carriers, it has anti-tumor effect. Because many nitrogen mustard antineoplastic drugs currently used still have the disadvantages of high toxicity and poor selectivity, new nitrogen mustard antineoplastic drugs with high efficiency and low toxicity have always been a research hotspot in the world; and looking for various new types of nitrogen mustards carrier to improve its pharmacokinetic properties such as absorption and distribution in the body is an important way to discover new nitrogen mustard drugs (Parker L L, Lacy S M, Farrugla L J, et al. J Med Chem, 2004, 47: 5 683 ; Jain M, Kwon C-H. J Med Chem, 2003, 46:5 428). In recent years, there have been a large number of literatur...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/24C07F9/6509A61P35/00
Inventor 史兰香刘斯婕何敬宇张宝华
Owner SHIJIAZHUANG UNIVERSITY