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Novel beta-chloroethylnitrosourea compounds, and synthesis method and application thereof

A technology of chloroethyl nitroso compounds, which is applied in the fields of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc., can solve the problem that the inhibitory effect is not targeted, no related reports of compounds have been found, and damage to DNA damage repair mechanism And other issues

Active Publication Date: 2014-09-10
BEIJING UNIV OF TECH
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  • Abstract
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Problems solved by technology

However, the study found that due to O 6 AGT inhibition by benzylguanine is not on-target
In combination with CENU, O 6 -Benzylguanine can not selectively target tumor cells to exert its inhibitory effect on AGT, but simultaneously acts on normal cells non-targetedly, causing AGT in normal cells to be inhibited, thus destroying the DNA damage of normal cells Repair mechanism that increases the risk of DNA damage in normal cells, ultimately leading to increased toxicity of chemotherapy drugs
[0008] After searching, no related reports of the compounds provided by the invention have been found

Method used

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  • Novel beta-chloroethylnitrosourea compounds, and synthesis method and application thereof
  • Novel beta-chloroethylnitrosourea compounds, and synthesis method and application thereof
  • Novel beta-chloroethylnitrosourea compounds, and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Embodiment 1:1-(O 6 -Synthesis of [2-(aminomethyl)benzyl]guanine)-3-(2-chloroethyl)-1-nitrosourea (Compound 1).

[0087] (1) Synthesis of 1-(2-amino-9-hydrogen-purine-6-)-1-methylpyrrolidine chloride

[0088] Dissolve 2g of 2-amino-6-chloropurine (11.8mmol) in 40mL of N,N-dimethylformamide, add 2.8mL of 1-methylpyrrolidine (26.4mmol), mix and stir at 25°C for 18 hours, and the reaction is complete. After adding 4 mL of acetone, a precipitate appeared, filtered, and the collected solid was washed twice with ether and dried in vacuo to obtain 1-(2-amino-9-hydrogen-purine-6-)-1-methylpyrrolidine chloride (2.6 g, 8.2 mmol), 66% yield.

[0089] UV lambda: 289nm;

[0090] IR (KBr tablet) v / cm -1 : 3445.4(NH), 3274.9(NH 2 ), 2974.9(C-H), 1719.3(C=N), 1552.7(C=C);

[0091] 1 H-NMR (DMSO-d 6 )δ: 2.04(m,2H,CH 2 ),2.23(m,2H,CH 2 ),3.64(s,3H,CH 3 ),3.94(m,2H,CH 2 N + ),4.58(m,2H,CH 2 N + ),7.13(s,2H,NH 2 ),8.31(s,1H,H8),12.99(s,1H,H9);

[0092] ESI-MS: 255[M+H] + ...

Embodiment 2

[0126] Embodiment 2:1-(O 6-Synthesis of [3-(aminomethyl)benzyl]guanine)-3-(2-chloroethyl)-1-nitrosourea (Compound 2).

[0127] (1) Synthesis of 1-(2-amino-9-hydrogen-purine-6-)-1-methylpyrrolidine chloride: the method is the same as step (1) in Example 1.

[0128] (2) 3-[(trifluoroacetamido)methyl]-benzyl alcohol

[0129] Dissolve 3.4g of 3-(aminomethyl)-benzyl alcohol (24.8mmol) and 3.52mL of triethylamine (24.8mmol) in 50mL of anhydrous methanol, and add 3.92mL of ethyl trifluoroacetate (32.8mL) dropwise under argon protection. mmol), stirred and reacted at 25° C. for 2 hours, after the reaction was finished, 50 mL of ethyl acetate and 50 mL of water were added for extraction, the ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 3 -[(trifluoroacetamido)methyl]-benzyl alcohol crude product, the crude product was purified by silica gel column chromatography, the...

Embodiment 3

[0161] Example 3: 1-(O 6 Synthesis of -[4-(aminomethyl)benzyl]guanine)-3-(2-chloroethyl)-1-nitrosourea (compound 3)

[0162] (1) Synthesis of 1-(2-amino-9-hydrogen-purine-6-)-1-methylpyrrolidine chloride: the method is the same as step (1) in Example 1.

[0163] (2) 4-[(trifluoroacetamido)methyl]-benzyl alcohol

[0164] 2.55g of 4-(aminomethyl)-benzyl alcohol (18.6mmol) and 2.64mL of triethylamine (18.6mmol) were dissolved in 25mL of anhydrous methanol, and 2.94mL of ethyl trifluoroacetate (24.6 mmol), stirred at 25°C for 2 hours. After the reaction was completed, 35 mL of ethyl acetate and 35 mL of water were added for extraction, the ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 4-[(trifluoroacetamido)formazan base]-benzyl alcohol crude product. The crude product was purified by silica gel column chromatography, and the eluent was ethyl acetate / cyclohexan...

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Abstract

The invention relates to novel beta-chloroethylnitrosourea compounds, and a synthesis method and application thereof. The structure of the beta-chloroethylnitrosourea compounds is disclosed as general formula (II). The in-vitro antitumor screening test on the compounds disclosed as general formula II proves that the compounds disclosed as general formula I have obvious inhibiting action on human cerebral nerve glioma cells SF763, SF767, SF126 and SF188, human colon cancer cell HT29, mouse leukaemia cell L1210 and many other tumor cell lines and have higher tumor inhibiting activity than the existing CENU and CENU / O6-benzylguanine combined medicine.

Description

technical field [0001] The present invention relates to a nitrosourea compound and its synthesis method and use, in particular to a novel β-chloroethyl nitrosourea compound, its synthesis method and its use in the preparation of antitumor drugs. Background technique [0002] Nitrosourea compounds are antitumor drugs widely used clinically. In the 1960s, the American Cancer Research Center found that N-methyl-N-nitrosourea was effective for transplantation of L1210 leukemia (Schepartz, S.A. Cancer Treat. Rep. 1976, 60, 647-649.), and then worked on the structure of this type of drug During the transformation process, it was found that when the methyl group at the β position was replaced by a chloroethyl group, the anticancer activity of the drug increased significantly, and a series of β-chloroethylnitrosourea (CENU) compounds (such as formula Ⅰ) (Gnewuch, C.T.; Sosnovsky, G. Chem. Rev. 1997, 97, 829-1013.). [0003] [0004] Since CENU has strong fat solubility and can ...

Claims

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Application Information

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IPC IPC(8): C07D473/18A61K31/52A61P35/00A61P35/02
CPCC07D473/18
Inventor 赵丽娇孙国辉钟儒刚
Owner BEIJING UNIV OF TECH
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