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Anticancer compound, preparation method and use thereof, and composition containing the compound

A compound and composition technology, applied in the field of medicine, can solve the problems of large oral dose, inconvenient use, and instability of temozolomide

Active Publication Date: 2008-06-04
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Preclinical studies have shown that temozolomide has good fat solubility and can pass through the blood-brain barrier. It has a good curative effect on glioma, but the half-life is only 1.7-1.9 hours. In clinical treatment, temozolomide has a large oral dose and has bone marrow Inhibition, nausea, vomiting and other adverse reactions, and it was found that temozolomide did not significantly prolong the life of brain cancer patients, and the average survival time was still less than one year, and even about half of the patients did not respond to temozolomide treatment (see: Zeng Xianqi, Yang Shuyuan. Clinical Observation on Chemotherapy of Postoperative Primary Malignant Glioma Patients Using Temozolomide Alone [J]. Modern Journal of Neurological Diseases, 2003, 3(5): 270-273), these shortcomings limit the application of Temozolomide
Since NO is a gaseous substance, its half-life in the body is relatively short, unstable in aqueous solution, and inconvenient to use, etc., so far no reports have been seen. See the report on the coupling of NO or its donor with Temozolomide

Method used

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  • Anticancer compound, preparation method and use thereof, and composition containing the compound
  • Anticancer compound, preparation method and use thereof, and composition containing the compound
  • Anticancer compound, preparation method and use thereof, and composition containing the compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1I 1 Compound preparation

[0054] 1) 3,4-dihydro-3-methyl-4-oxoimidazol[5,1-d]bromoethyl 1,2,3,5-tetrazine-8-carboxylate (Ia 1 )

[0055] Dissolve 1.95 g (10 mmol) of 3,4-dihydro-3-methyl-4-oxoimidazol[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid in 15 ml of acetone , add 1,2-dibromoethane and triethylamine (3ml) under stirring, react at room temperature for 3 hours, filter off insoluble matter, concentrate the filtrate, column chromatography [ethyl acetate:petroleum ether=1:6(V: V)], 1.74g of white solid was obtained, the yield was 57.6%, mp: 102.7~104.5°C; the same method could be obtained by 3,4-dihydro-3-methyl-4-oxoimidazole [5,1-d] And 1,2,3,5-tetrazine-8-carboxylic acid and 1,4-dibromobutane, 1,5-dibromopentane can prepare other two intermediate compounds Ia 2 and Ia 3 .

[0056] 2) 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]1,2,3,5-tetrazine-8-carboxylate nitroethyl ester (I1)

[0057] Ia 1 0.5g (1.66mmol) was dissolved in tetrahydrofuran solvent, 0....

Embodiment 2

[0063] Example 2I 2 Compound preparation

[0064] 1) 3,4-dihydro-3-methyl-4-oxoimidazol[5,1-d]bromobutyl 1,2,3,5-tetrazine-8-carboxylate (Ia 2 )

[0065] Refer to Ia 1 The preparation method, by 3,4-dihydro-3-methyl-4-oxoimidazol[5,1-d] and 1,2,3,5-tetrazine-8-carboxylic acid and 1,4-two Bromobutane reaction preparation, yield 43.6%,

[0066] mp: 73.5~75.6℃

[0067] 2) 3,4-dihydro-3-methyl-4-oxoimidazo [5,1-d] and 1,2,3,5-tetrazine-8-carboxylate nitrobutyl ester (I 2 ) refer to I 1 The preparation method is prepared by reacting Ia2 with silver nitrate, the yield is 55.8%, mp: 82.8~84.5°C

[0068] ESI-Ms: 334.8[M+Na] +

[0069] IR (KBr, v (cm -1 )): 3100(O-H); 2959(C-H); 1734(C=O); 1606(C=N); 1456(N=O); 1252, 1052(C-O);

[0070] 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 1.97 (m, 4H, CH 2 ), 4.07 (s, 3H, CH 3 ), 4.52(t, 2H, OCH 2 ), 4.56(t, 2H, CH 2 O), 8.47 (s, H, CH)

[0071] Elemental Analysis C 10 h 12 o 6 N 6 Found: (%)N 26.98 C 38.60 H 3.91

[0072] ...

Embodiment 3

[0073] Example 3I 3 Compound preparation

[0074] 1) 3,4-dihydro-3-methyl-4-oxoimidazol[5,1-d]bromopentyl 1,2,3,5-tetrazine-8-carboxylate (Ia 3 )

[0075] Refer to Ia 1 The preparation method, by 3,4-dihydro-3-methyl-4-oxoimidazol[5,1-d] and 1,2,3,5-tetrazine-8-carboxylic acid and 1,5-bromo Prepared by pentane reaction, yield 56.7%,

[0076] mp: 80.5~82.7℃

[0077] 2) 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d] and 1,2,3,5-tetrazine-8-carboxylate nitropentyl ester (I 3 )

[0078] Refer to I 1 The preparation method of Ia 3 Prepared by reacting with silver nitrate, the yield is 47.6%, mp: 74.6~76.8℃

[0079] ESI-Ms: 348.8[M+Na] +

[0080] IR (KBr, v (cm -1 )): 3090(O-H); 2953(C-H); 1752(C=O); 1636(C=N); 1459(N=O); 1257, 1054(C-O); .

[0081] 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 1.67 (m, 2H, CH 2 ), 1.80 (m, 2H, CH 2 ), 1.92 (m, 2H, CH 2 ), 4.06 (s, 3H, CH 3 ), 4.46(t, 2H, OCH 2 ), 4.52(t, 2H, CH 2 O), 8.47 (s, H, CH)

[0082] Elemental Analysis C 11 h 14 o ...

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PUM

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Abstract

The invention provides compounds of the same class with anticancer activity and purposes thereof. In particular, the invention solves the current defects of temozolomide and can significantly prolong the lives of patients with brain cancer and strengthen the treatment responses of the patients to the temozolomide. The invention combines the effect of inducing apoptosis of tumor cells of NO based on the anti-tumor effect of the temozolomide and applies the basic theories of drug design so as to design and synthesize NO-donating temozolomide nitrate esters derivatives with novel structure and NO releasing activity, namely the synthesis and anti-tumor activity of 3,4-dihydro-3-Methyl-4-oxoimidazo (5,1-d) 1,2,3,5 tetrazine-8-carboxylic carbonate.

Description

technical field [0001] The invention relates to the field of medicine, in particular to an anticancer active ingredient compound and the application of the compound. Background technique [0002] Temozolomide (TM) was developed by Schering-plough Company. It was approved by the FDA on August 11, 1999 and launched in the United States. It was launched in many countries at the same time. It is a new anticancer drug for the treatment of glioma and malignant melanoma. This oral cytotoxic alkylating agent represents an important step in glioblastoma therapy due to its low toxicity and good tolerability. It can be completely absorbed after oral administration, has high bioavailability, good tissue distribution, and can pass through the blood-brain barrier. Reaching an effective drug concentration in the central system has a remarkable effect on the treatment of glioma. Clinical studies have found that about 50% of patients with cell tumors have significantly improved CT scans af...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4162A61P35/00C07D233/00C07D257/00
Inventor 王兰周微张广明
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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