Dihydropyridine type tumor chemotherapeutic sensitizer and application thereof

A dihydropyridine and compound technology, applied in the field of dihydropyridine tumor chemotherapy sensitizers, can solve the side effects of cardiovascular system and other problems

Inactive Publication Date: 2012-11-21
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

1,4-dihydropyridine compounds such as nifedipine and nicardipine have been used clinically as chemosensitizers, but these calcium antagonists still have side effects on the cardiovascular system (Tasaka S, Ohmori H, et al .Synthesis and Structure-Activity Analysis of Novel Dihydro-pyridine Derivatives to Overcome Multidrug Resistance[J].Bioorg.Med.Chem.Lett, 2001, 11:275-277)

Method used

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  • Dihydropyridine type tumor chemotherapeutic sensitizer and application thereof
  • Dihydropyridine type tumor chemotherapeutic sensitizer and application thereof
  • Dihydropyridine type tumor chemotherapeutic sensitizer and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: 2,6-Dimethyl-4-(3-nitrophenyl)-1-[(oxiranyl)methyl]-1,4-dihydropyridine-3,5-dicarboxy Acid dimethyl ester (intermediate)

[0064] Add 2.31g (57.8mmol) 60% sodium hydrogen and 50mL anhydrous tetrahydrofuran to the reaction flask, stir, and add 10g (28.9mmol) 2,6-dimethyl-4-(3-nitrophenyl) at 0°C -Dimethyl 1,4-dihydropyridine-3,5-dicarboxylate, after no gas is released, add 7.98g (86.7mol) of epichlorohydrin dropwise. After the addition, continue to stir for 0.5h, and react at room temperature for 24h. Slowly add 5 mL of water dropwise, concentrate under reduced pressure, add 20 mL of dichloromethane and 10 mL of water to the residue, stir for 10 min, separate the layers, extract the aqueous layer with 2×5 mL of dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, and filter. Concentration under reduced pressure, the residue was separated by column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain 5.30 g of light yello...

Embodiment 2

[0065] Example 2: 1-[3-(2-hydroxyethylamino)-2-hydroxypropyl]-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro Dimethyl pyridine-3,5-dicarboxylate (I 1 )

[0066] Add 0.5g (1.25mmol) 2,6-dimethyl-4-(3-nitrophenyl)-1-[(oxiranyl)methyl]-1,4-dihydropyridine to the reaction flask -Dimethyl 3,5-dicarboxylate, 0.23g (3.75mmol) ethanolamine and 10mL methanol, stirred and refluxed for 5h, concentrated under reduced pressure, and the residue was column chromatographed (petroleum ether: ethyl acetate: triethylamine=30: 6:1) to obtain 500 mg of pale yellow oil, with a yield of 86.8%.

[0067] 1 HNMR (CDCl 3 )δ: 2.43~2.74(m, 4H, CHC H 2 NHC H 2 CH 2 OH), 2.50, 2.55 (2×s, 6H, C 2，6 -CH 3 ), 3.65(t, J=5.1Hz, 2H, CH 2 C H 2 OH), 3.69~3.74 (m, 1H, C H OH), 3.71, 3.73 (2×s, 6H, C 3，5 -COOCH 3 ), 3.84 (m, 2H, NC H 2 CH), 5.21(s, 1H, C 4 -H), 7.39(m, 1H, nitrogenyl 5-H), 7.69(m, 1H, nitrogenyl 6-H), 7.98~8.00(m, 1H, nitrogenyl 4-H), 8.15(m, 1H, nitrogenyl 2 -H)

[0068] ESI-MS(m / ...

Embodiment 3

[0071] Example 3: 1-[(2-Hydroxy-3-n-butylamino)propyl]-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine- 3,5-dicarboxylic acid dimethyl ester (I 2 )

[0072] Refer to I 1 Synthetic method, a light yellow oily substance was obtained with a yield of 90.3%.

[0073] 1 HNMR (CDCl 3 )δ: 0.90 (t, J=7.1Hz, 3H, CH 2 CH 2 CH 2 C H 3 ), 1.30~1.43 (m, 4H, CH 2 C H 2 C H 2 CH 3 ), 2.27~2.55(m, 4H, CHCH 2 NHC H 2 CH 2 CH 2 CH 3 ), 2.49, 2.55 (2×s, 6H, C 2，6 -CH 3 ), 3.57~3.62 (m, 1H, C H OH), 3.71, 3.72 (2×s, 6H, C 3，5 -COOCH 3 ), 3.82 (d, J=5.4Hz, 2H, NC H 2 CH), 5.21(s, 1H, C 4 -H), 7.37(m, 1H, nitrogenyl 5-H), 7.70(m, 1H, nitrogenyl 6-H), 7.97~8.00(m, 1H, nitrogenyl 4-H), 8.15(m, 1H, nitrogenyl 2 -H)

[0074] ESI-MS(m / z): 476[M+H] +

[0075] IR: 3400, 3032, 2948, 1692, 1636, 1577, 1571, 1527, 1430, 1386, 1349, 1203, 1157, 772

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Abstract

The invention relates to compounds with a general formula (I), a general formula (II) and a general formula (III) and addition salts of acids for pharmaceutical purposes of compounds with the general formula (I) and (II) which can be accepted in pharmacy, wherein the definitions of R1, R2, R3, R4, R5, R6, R7 and R8 are the same as that in the patent specification. The invention also discloses a preparation method of the compounds and the hypersensitivity effect of the compounds in tumor chemotherapy.

Description

technical field [0001] The invention relates to dihydropyridine tumor chemotherapeutic sensitizers, and provides their preparation method and their sensitizing effect in tumor chemotherapy. Background technique [0002] Chemotherapy is one of the main treatment methods for cancer, but in the process of cancer chemotherapy, it is often observed that some drugs have a good therapeutic effect on cancer in the early stage of treatment, but as the treatment progresses, cancer cells quickly develop drug resistance , leading to treatment failure. Therefore, at present, in order to suppress the drug resistance of cancer cells, drug combination is an important method (Tsuruo T, Lida H, et al. Circumvention of Vincristine and Adriamycin Resistance in Vitro and in Vivo by Calcium InfluxBlockers [J]. Cancer Res, 1983, 43 : 2905-2910.). [0003] Chemosensitizer refers to no anti-tumor effect or little anti-tumor effect at the concentration or dose used, but it can affect the cytotoxici...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90C07D413/06A61K31/4422A61K31/496A61K31/4439A61P35/00A61P35/02
Inventor 陈国华张明亮李昂
Owner CHINA PHARM UNIV
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