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Dihydropyrazolohexahydropyridine derivatives, preparation method and application thereof

A technology of dihydropyrazole and hexahydropyridine, which is applied in the field of pyridine derivatives, and achieves the effects of simple process, remarkable practicability and easy production

Inactive Publication Date: 2011-12-14
SHANGHAI NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0003] Existing research results have shown that dihydropyrazolohexahydropyridine compounds have many important biological and pharmacological activities, but in the treatment of leukemia, there are no reports on dihydropyrazolohexahydropyridine compounds

Method used

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  • Dihydropyrazolohexahydropyridine derivatives, preparation method and application thereof
  • Dihydropyrazolohexahydropyridine derivatives, preparation method and application thereof
  • Dihydropyrazolohexahydropyridine derivatives, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Preparation of 2-phenyl-3-(4-methylphenyl)-5-(4-methylbenzyl)-7-(4-methylbenzylidene)-4,5-dihydro Pyrazolo[4,3-c]hexahydropyridine (Ia);

[0047] At room temperature, add 0.16mol methyl acrylate and 7mL methanol to a 100mL three-necked flask, and slowly add a mixture of 0.04mol p-methylbenzylamine and 4mL methanol into the three-necked flask while stirring, so that the temperature of the reaction system does not exceed 50 ℃. After the dropwise addition, heat to reflux for 8 hours. After the reaction is over, reclaim methanol and unreacted methyl acrylate, and distill under reduced pressure to obtain light yellow oily liquid N, N-bis(β-methyl propionate) p-methyl Benzylamine (2a).

[0048]Add 15mL of anhydrous toluene and 0.122mol of sodium metal to a 250mL dry three-necked flask, stir and heat to reflux, add 0.2mL of anhydrous methanol, and then slowly add 0.04mol of N,N-bis(β-propionate methyl ester)) A mixture of p-methylbenzylamine (2a) and 20mL of anhy...

Embodiment 2

[0052] Example 2: Preparation of 2-phenyl-3-(4-methylphenyl)-5-(4-fluorobenzyl)-7-(4-methylbenzylidene)-4,5-dihydropyridine Azolo[4,3-c]hexahydropyridine (Ib);

[0053] Replace p-methylbenzylamine with p-fluorobenzylamine, other raw materials are the same, according to the method of Example 1, obtain (Ib).

[0054] Yield, 77%; mp 190-191°C; 1 HNMR (400MHz,) δ2.35(s, 6H), 2.46(t, J=10.5Hz, 1H), 3.17(m, 2H), 3.33-3.24(m, 1H), 3.58(dd, J=28.3, 13.2Hz, 2H), 4.01(d, J=13.9Hz, 1H), 4.55(d, J=12.5Hz, 1H), 6.81(t, J=7.3Hz, 1H), 6.92(dd, J=12.1, 5.3Hz, 2H), 7.04(dd, J=8.7, 1.0Hz, 2H), 7.11-7.21(m, 10H), 7.25(s, 1H), 7.26-7.30(m, 2H); IR(KBr, cm -1 )3020, 2920, 1710, 1604, 1269, 1201, 1129; Anal.Calcd for C 34 h 32 FN 3 : C, 81.47; H, 6.49; N, 8.34; Found: C, 81.41; H, 6.48; N, 8.38.

Embodiment 3

[0055] Example 3: Preparation of 2-phenyl-3-(4-methoxyphenyl)-5-(4-fluorobenzyl)-7-(4-methoxybenzylidene)-4,5-di Hydropyrazolo[4,3-c]hexahydropyridine (Ic);

[0056] Replace p-methylbenzylamine with p-fluorobenzylamine, replace p-tolualdehyde with p-methoxybenzaldehyde, and other raw materials are the same, according to the experimental method in Example 1, obtain (Ic).

[0057] Yield, 72%; mp 168-169°C; 1 H NMR (400 MHz, CDCl 3 )δ2.43(t, J=10.3Hz, 1H), 3.12-3.25(m, 2H), 3.22-3.34(m, 1H), 3.61(dd, J=38.3, 13.1Hz, 2H), 3.81(d , J=8.3Hz, 6H), 4.03(d, J=13.9Hz, 1H), 4.52(d, J=12.3Hz, 1H), 6.81(t, J=7.2Hz, 1H), 6.83-6.92(m , 4H), 7.05(t, J=8.1Hz, 4H), 7.08-7.23(m, 7H), 7.29(d, J=8.7Hz, 2H); IR(KBr, cm -1 )3066, 2910, 1733, 1612, 1269, 1200, 1121; Anal.Calcd for C 34 h 32 FN 3 o 2 : C, 76.50; H, 6.09; N, 7.84. Found: C, 76.52; H, 6.04; N, 7.87.

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Abstract

The invention provides a dihydro-pyrazolo hexahydropyridine derivative and a preparation method thereof. The method comprises the following steps of: performing Michael addition reaction of substituted amine (a) and methyl acrylate to prepare N,N-bis(beta-methyl propionate) substituted amine (b); performing Dieckmann condensation of (b) under the action of sodium alcoholate and hydrolyzing and decarboxylating under the action of acid to obtain yellow oily matter N-substituted piperidine-4-ketone (d); reacting (d) and aromatic aldehyde to remove bimolecular water to obtain N-substitution-3,5-dibenzal piperidine-4-ketone (e); and performing reaction of (e) to form the dihydro-pyrazolo hexahydropyridine derivative. The preparation method is simple, and the dihydro-pyrazolo hexahydropyridine derivative is convenient to produce in large scale; and a lead compound of the prepared dihydro-pyrazolo hexahydropyridine new medicine has the obvious inhibitory activity on leukemia K562 cancer cellproliferation, and has the obvious practicality in the production of modern medicines.

Description

technical field [0001] The invention relates to a pyridine derivative, specifically a dihydropyrazolohexahydropyridine derivative and its preparation, as well as its application in inhibiting the proliferation of leukemia K562 cells. Background technique [0002] Leukemia is one of the diseases with the highest mortality rate in the world today, and it has caused serious harm to human health. According to statistics, the incidence of leukemia in various regions of our country occupies the sixth place among all kinds of tumors. Chronic leukemia is divided into chronic myelogenous leukemia and chronic lymphocytic leukemia. Chronic myelogenous leukemia, referred to as chronic myelogenous leukemia (CML), is a clinical leukemia with relatively slow onset and development. The cell line K562 in chronic myeloid leukemia is more resistant to self-apoptosis than other cell lines, which is one of the main factors leading to chronic myeloid leukocytes. Therefore, in the treatment of ...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P35/02
Inventor 孙传文王静薛思佳
Owner SHANGHAI NORMAL UNIVERSITY
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