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Folacin analogue, and salt of folacin analogue in use for medical treatment

An analogue, folic acid technology, applied in the field of chemistry, can solve the problems of solid tumors with little effect, strong, unable to obtain satisfactory therapeutic effect, etc., and achieve the effect of strong growth inhibitory activity

Inactive Publication Date: 2011-04-27
SHANGHAI GOLDEN PHARMATECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] MTX mainly fights cancer through folic acid antagonism, has strong toxicity, and has little effect on solid tumors. There is also resistance of tumor cells to this drug, so satisfactory therapeutic effects cannot be obtained.

Method used

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  • Folacin analogue, and salt of folacin analogue in use for medical treatment
  • Folacin analogue, and salt of folacin analogue in use for medical treatment
  • Folacin analogue, and salt of folacin analogue in use for medical treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Synthesis of 4-chloro-2-amino-6-(3-hydroxy-4-enyl-1-pentylamino)-pyrimidine (1)

[0041] 50mmol 4,6-dichloro-2-amino-pyrimidine and 5mmol~60mmol 3-hydroxyl-4-en-1-pentylamine were dissolved in 200ml ethanol and 51mmol triethylamine was added, N 2 Reflux under protection for 4h. Remove the solvent and add CH to the residual solid 2 Cl 2 The solvent was dissolved, and the insoluble matter was removed by filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography. EluentMeOH / CH 2 Cl 2 = 2 / 98. 8.31 g of the product was obtained with a yield of 73%.

[0042] 1 H NMR (CDCl 3)δ: 1.65~1.85(2H,dm), 3.30-3.63(m,2H), 4.2(1H,dm), 4.97(2H,sb), 5.03(1H,d), 5.27(1H,d), 5.80 (1H, s), 5.91 (1H, m).

Embodiment 2

[0044] Synthesis of 2-amino-4-methoxy-6-(3-hydroxy-4-enyl-1-pentylamino)-pyrimidine (2)

[0045] In 100ml methanol, add 6.48g (120mmol) sodium methylate and 5g (22mmol) 4-chloro-2-amino-6-(3-hydroxyl-4-enyl-1-pentylamino)-pyrimidine, N 2 Reflux for 48h under protection, remove most of the solvent under reduced pressure, add 100ml saturated NH 4 Cl aqueous solution with CH 2 Cl 2 Extraction (100mlx3), organic layer with anhydrous Na 2 SO 4 dry. Concentration gave 3.13 g of a light yellow solid, with a yield of 63.6%.

[0046] 1 H NMR (CDCl 3 )δ: 1.61-1.80 (2H, dm), 3.21-3.62 (2H, dm), 3.80 (3H, S), 4.19 (1H, d), 4.73 (2H, S, NH 2 ), 4.88 (1H, S, NH), 5.09 (1H, d), 5.25 (1H, d), 5.14 (1H, s), 5.88 (1H, m).

Embodiment 3

[0048] 4-[5-(2-Amino-4-methoxy-pyrimidine-6-amino)-3-oxo-pentyl]-benzoic acid methyl ester (3)

[0049] 560mg (2.5mmol) 2-amino-4-methoxy-6-(3-hydroxy-4-enyl-1-pentylamino)-pyrimidine, 720.5mg (2.75mmol) methyl 4-iodobenzoate, 577.5 mg(6.87mmol)NaHCO 3 , 28 mg (0.125 mmol) Pd (AcO) 2 , 885.5 mg (2.75 mmol) Bu 4 NBr and 0.5 g of crushed 4A molecular sieves, dissolved in 20 ml of anhydrous DMF, N 2 Stir at room temperature under protection for 72h, filter, and remove the solvent from the filtrate under reduced pressure to obtain a brownish-red solid, which is eluted by gradient elution of silica gel column chromatography 1.CH 2 Cl 2 , 2. CH 2 Cl 2 / MeOH (98:2) gave 0.77g of slightly light brown solid, yield 86%, mp110-113℃, R f =0.489(CH 2 Cl 2 / MeOH=20:1).

[0050] 1 H NMR (CDCl 3 )δ: 2.66(2H, t), 2.74(2H, t), 2.93(2H, t), 3.46(2H, m), 3.77(3H, s), 3.88(3H, s), 4.67(2H, s , NH 2 ), 4.95 (1H, s, NH), 5.09 (1H, s), 7.21 (2H, d), 7.92 (2H, d).

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PUM

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Abstract

This invention discloses folic acid analogues as shown in general chemical formula (I), and their salts used in therapy. In general chemical formula (I), R is OH, Cl, NH2, OCH3 or OCH2CH3. This invention also discloses the application of the folic acid analogues and their salts in drugs for treating cancers. The folic acid analogues and their salts have strong inhibitive activity on the growth of multiple cancer cells.

Description

Technical field: [0001] The invention relates to the field of chemistry, in particular to medicine, in particular to a folic acid analogue and a salt of the folic acid analogue used for medical treatment. Background technique: [0002] Reduced folic acid (FH 4 ) is an essential one-carbon unit transporter in the biosynthesis of purines and the conversion of deoxyuridine monophosphate (dUMP) to thymidylate (dTMP). In these biochemical reactions, reduced folic acid is oxidized and regenerated into active reduced folic acid by dihydrofolate reductase (DHFR). [0003] Methotrexate (MTX) and similar compounds are known to bind strongly to DHFR, and these drugs inhibit the reduction of dihydrofolate to tetrahydrofolate, resulting in dTMP and / or purine deficiency, disruption of DNA synthesis, and subsequent cytotoxicity effect, leading to cell death. These drugs have been developed into anticancer drugs, and currently occupy a very important position as clinical drugs. Pemetrex...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/551A61P35/00C07D239/00C07D243/00
Inventor 毛振民刘增路朱高军
Owner SHANGHAI GOLDEN PHARMATECH
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