Amino-substituted tetrahydropyridinopyrimidine compound or usable salt thereof, and preparation method and application thereof

A tetrahydropyridine and compound technology, which is applied in the field of preparation of antitumor drugs, can solve the problems of short action time and half-life in vivo, low bioavailability, weak selectivity and inhibitory activity, etc.

Active Publication Date: 2018-08-10
FUJIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, compound AZD2281 has weak selectivity and inhibitory activity on PARP1, the effective dose of inhibitory activity at the cellular level is 200nM, and the in vivo dose is above 100mg to show obvious anti-tumor activity
Clinically, the daily dose is as high as 400mg (50mg capsules, 8 capsules), the in vivo action time and half-life are short (<1 hour), and the bioavailability is also low (<15%)

Method used

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  • Amino-substituted tetrahydropyridinopyrimidine compound or usable salt thereof, and preparation method and application thereof
  • Amino-substituted tetrahydropyridinopyrimidine compound or usable salt thereof, and preparation method and application thereof
  • Amino-substituted tetrahydropyridinopyrimidine compound or usable salt thereof, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 2-chloro 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl)-(2-fluoro-5-[(4-oxo-3,4-dihydrodi Preparation of azinaphthalen-1-yl)methyl]phenyl)methanone

[0024]

[0025] 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid was purchased from Shanghai Bobang Pharmaceutical Technology Co., Ltd., 2-chloro-5,6,7, References for the synthesis of 8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride European Journal of Medicinal Chemistry.2014,79,399-412.

[0026] Dissolve 0.05g (0.1508mmol) of 2-fluoro-5-[(4-oxo-3,4-dihydronaphthalene-1-yl)methyl]benzoic acid in 5ml of dichloromethane, and add EDCI 0.0516g (0.268mmol) and HOBT 0.0362g (0.268mmol), add a few drops of DMF to help dissolve. After stirring at room temperature for 1 h, DIEA (1.88ml, 13,4mmol) was added, and 0.551g (0.268mmol) of 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride was added ), continue stirring at room temperature for 24h. The reaction solution was washed three time...

Embodiment 2

[0028] (2-(1-Methyl-piperazinyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl)-(2-fluoro-5-[(4-oxo Preparation of -3,4-dihydronaphthalene-1-yl)methyl]phenyl)methanone

[0029]

[0030] 2-Chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl)-(2-fluoro-5-[(4-oxo-3,4-dihydrodiazepine Naphthalene-1-yl)methyl]phenyl)methanone (50mg 0.111mmol 449) was dissolved in 10ml anhydrous THF (plus 2ml DMF co-solvent), N-methylpiperazine (22.29mg 0.22mmol 100.1) and three Ethylamine (0.046ml 0.33mmol 101.19) was reacted overnight at 60°C. The reaction solution was spin-dried and dispersed in 20 ml of ethyl acetate, washed with 20 ml of water and saturated sodium chloride solution successively, and the ethyl acetate layer was dried over anhydrous sodium sulfate. Column chromatography: (petroleum ether: ethyl acetate = 1:2), 12.5 mg of white solid was obtained. Yield 22%. Mp: 154.5-156. 1H NMR (400MHz, Methanol-d 4 )δ8.37(tt,1H),8.20(s,1H),8.02–7.78(m,4H),7.51(dtd,1H),7.42(dd,J=6.4,2.3Hz,1H)...

Embodiment 3

[0032] (2-(1-piperidinyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl)-(2-fluoro-5-[(4-oxo-3, Preparation of 4-dihydronaphthalene-1-yl)methyl]phenyl)methanone

[0033]

[0034] This product consists of 2-chloro 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl)-(2-fluoro-5-[(4-oxo-3,4-dihydrodi Azanaphthalen-1-yl)methyl]phenyl)methanone (50mg 0.111mmol 449) and piperidine (18.9mg 0.22mmol 85.15) were prepared by the same preparation method as in Experimental Example 2 to obtain 28.3mg of white solid. Yield 51%. Mp: 119.9-121.1°C.

[0035] 1H NMR (400MHz, Chloroform-d) δ11.20(d, J=9.2Hz, 1H), 8.49(q, J=4.2, 3.8Hz, 1H), 8.14(s, 1H), 8.05–7.55(m, 3H),7.58–7.17(m,2H),7.07(d,J=3.4Hz,1H),4.74(s,1H),4.31(d,J=7.1Hz,2H),4.27–3.83(m,1H ), 3.77(t, J=5.3Hz, 3H), 3.57(t, J=5.9Hz, 1H), 2.88(s, 2H), 2.00(d, J=46.1Hz, 2H), 1.77–1.50(m ,4H),1.53–0.62(m,2H).MS(ESI),[M+H] + 499.3.

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Abstract

The invention discloses an amino-substituted tetrahydropyridinopyrimidine compound or a usable salt thereof, and a preparation method and an application thereof. The compound or the usable salt thereof has a structure represented by general formula shown in the description; and in the formula, each of R1 and R2 is a C1-5 alkyl group or an amino group, R3 and N form a five to six-membered heterocyclic radical, and the heterocyclic radical is a heterocyclic radical containing hydrogen, substituted nitrogen or oxygen. The compound or the pharmaceutically acceptable salt thereof has strong PARP1 inhibitory activity, and can be used in disease or cancer treatment medicines to prevent and / or treat PARP1-related diseases.

Description

technical field [0001] The invention relates to the field of preparation of antitumor drugs, in particular to an amino-substituted tetrahydropyridopyrimidine compound or an available salt thereof, a preparation method and application thereof. Background technique [0002] Polyadenosine diphosphate-ribose polymerase [poly(ADP-ribose) polymerase, PARP] is a ribozyme closely related to single-strand DNA damage repair, including 18 subtypes, of which PARP-1 is abundant in eukaryotic cells The highest, and its functional research is the most in-depth. The PARP-1 gene is located in the q41-42 region of chromosome 1 and has a length of 47400 base pairs. PARP-1 protein is composed of a single peptide chain composed of 1014 amino acids, which can be divided into three parts according to the function: DNA binding domain (DBD), autonomous modification domain (AMD) and C-terminal catalytic domain (CD). DNA break ends, form PARP-1-ADP ribose oligomers, and participate in DNA damage rep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61K31/5377A61P35/00A61P9/10A61P25/28A61P25/16A61P21/00
CPCA61P9/10A61P21/00A61P25/16A61P25/28A61P35/00C07D471/04
Inventor 吴丽贤刘洋张潇林珊珊黄秀旺许建华
Owner FUJIAN MEDICAL UNIV
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