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Tetrahydropyridine [3,2-d] pyridine compound and its uses for preparing antineoplastic drug

A technology of tetrahydropyridine and compounds, applied in the field of tetrahydrofolate derivatives, can solve the problems of inability to speculate on the selectivity and effect of different tumors, and the inability to be applied industrially

Inactive Publication Date: 2007-05-16
PEKING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] N-(N-{4-[2-(2-amino-4-hydroxyl-5,6,7 8-tetrahydropyrido[2,3-d]pyrimidine-6-)ethyl]- Benzoyl}-L-γ-glutamyl)-D-aspartic acid, the target of this compound is glycosylamide ribonucleotide formyltransferase (GARFT), it is only speculated that this type of compound has anti- Tumor effect, but there is no biological or cytological experiment to confirm, so those in the field cannot speculate on the mode of action, selectivity and effect on different tumors, and cannot be applied in industry

Method used

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  • Tetrahydropyridine [3,2-d] pyridine compound and its uses for preparing antineoplastic drug
  • Tetrahydropyridine [3,2-d] pyridine compound and its uses for preparing antineoplastic drug
  • Tetrahydropyridine [3,2-d] pyridine compound and its uses for preparing antineoplastic drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: N-[4-[[(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-6-)methylene]amino]benzene Formyl]-L-glutamic acid diethyl ester

[0070] Diethyl N-[4-[[(2,4-diaminopyrido[3,2-d]pyrimidine-6-)methylene]amino]benzoyl]-L-glutamate (600 mg, 1.2mmol) and PtO 2 (60mg) was placed in a reaction flask, added 90ml ethanol, 12ml acetic acid (0.5N), catalytic hydrogenation at 40°C and 0.3Kpa pressure for 48-96h, suction filtered, and the filtrate was washed with 5% NaHCO 3 Adjust the pH value to 7-8, and evaporate the solvent to dryness under reduced pressure to obtain a light yellow solid, which is vacuumed to complete dryness. Add 10ml of chloroform, stir well and then filter, the filtrate is concentrated to a viscous liquid, separated by silica gel column chromatography to obtain 409mg of the title compound as a white solid, yield 68%.

[0071] 1 H NMR (500MHz, DMSO-d 6 ): δ1.15~1.20(m, 6H), 1.59~1.64(m, 1H), 1.97~2.01(m, 2H), 2.05~2.11(m, 1H), 2.41~2.44(t, 2H, J=...

Embodiment 2

[0074] Example 2: N-[4-[[(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-5,6-)dimethylene] Amino]benzoyl]-L-glutamic acid diethyl ester

[0075] N-[4-[[(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-6-)methylene]amino]benzoyl] - Diethyl L-glutamate (400mg, 0.8mmol) was placed in a reaction flask, 1.2ml of water was added, THF was added dropwise to dissolve the solid, 120mg of paraformaldehyde was added, ultrasonication was performed at room temperature for 4 hours, and the reaction solution was evaporated to dryness under reduced pressure. Add 10 ml of water to the residue, extract with chloroform, combine the chloroform layers, and perform silica gel column chromatography to obtain 317 mg of the title compound as a pale yellow solid, yield 77.4%.

[0076] 1 H NMR (500MHz, DMSO-d 6 ): δ1.15~1.24(m, 6H), 1.72~1.87(m, 2H), 1.97~2.11(m, 2H), 2.41~2.46(m, 2H), 2.58~2.60(m, 2H), 3.33 ~3.34(m, 1H), 3.63~3.69(m, 2H), 3.78~3.79(d, 1H), 4.03~4.13(m, 4H), 4.38~4.43(m,...

Embodiment 3

[0079] Example 3: N-[4-[[(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-5,6-)dimethylene] Amino]benzoyl]-L-glutamic acid

[0080] N-[4-[[(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-5,6-)dimethylene]amino]benzene Formyl]-L-glutamate diethyl ester (23mg, 0.05mmol) was placed in a round bottom flask, 1.15ml THF and 0.79ml NaOH aqueous solution (0.3N) were added, stirred at room temperature for 2h, THF was distilled off under reduced pressure, and the remaining The pH of the liquid was adjusted to 5 with 0.5N hydrochloric acid, a large amount of white solid appeared, filtered, the filter cake was washed twice with a small amount of water, and fully dried to obtain 14 mg of the title compound as a white solid, with a yield of 68%.

[0081] 1 H NMR (300MHz, DMSO-d 6 ): δ1.76~2.1(m, 4H), 2.29~2.34(m, 2H), 2.49~2.73(m, 2H), 3.33~3.90(m, 1H), 3.66~3.70(m, 2H), 3.79 ~3.80(d, 1H, J=3.9Hz), 4.43~4.36(m, 1H), 4.92~4.93(d, 1H, J=3.9Hz), 6.48(bs, 2H), 6.54(d, 4H, J =8...

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Abstract

The invention discloses a tetrahydrochysene folacin derivant substituted by 8-aza, N5-alkyl and optical pure isomer or diastereoisomer and medical composition, wherein each group in the formula is defined as introduction, which possesses anti-folacin proteinase in the tumour-resistance drug.

Description

technical field [0001] This patent involves a new 8-position deaza, N 5 Alkyl-substituted tetrahydrofolate derivatives, optically pure isomers or diastereomer mixtures, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the compounds. The present invention also relates to the use of these compounds in preparing antitumor drugs that have anti-folate protease effects and induce tumor cell apoptosis. Background technique [0002] Cancer is a major disease that endangers human life and health. The number of deaths from cancer worldwide is more than 5 million every year, and it has become the second largest killer after cardiovascular disease. In my country, more than 1.7 million cancer patients are newly discovered every year, and about 1.4 million die, making it the disease with the highest fatality rate. Due to the lack of in-depth understanding of the pathogenesis of different cancers over the years, there are currently no effective method...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D471/12
Inventor 刘俊义张志丽
Owner PEKING UNIV
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