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2, 3, 5, 7-tetrasubstituted dihydro-pyrazolo piperidine derivative and preparation method and application thereof
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A technology of dihydropyrazole and hexahydropyridine, which is used in drug combination, organic chemistry, antitumor drugs, etc.
Inactive Publication Date: 2013-12-04
SHANGHAI NORMAL UNIVERSITY
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However, the number of new anti-cancer drugs on the market in my country and the number of candidate drugs in preclinical research is very small, especially the number of candidate drugs with my country's independent intellectual property rights is even smaller
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preparation example Construction
[0039] 2. The preparation method of the embodiment of the general formula (I) of the present invention
[0040] (1) At room temperature, add 0.16mol methyl acrylate and 7mL methanol to a 100mL three-neck bottle, and slowly add the mixture of 0.04mol substituted aromatic methylamine represented by formula (A) and 4mL methanol into the three-neck bottle while stirring During the process, the temperature of the reaction system should not exceed 50°C. After the dropwise addition, heat and reflux for 8 hours. After the reaction is over, recover methanol and unreacted methyl acrylate, distill under reduced pressure, and obtain light yellow oily liquid N,N-bis(β-methyl acrylate ) Aromatic methylamine.
[0046] Example 1: 2-(4-nitrophenyl)-3-(4-fluorophenyl)-5-(2-furylmethyl)-7-(4-fluorobenzylidene)-2H-pyrazole And [4,3-c] hexahydropyridine (Ⅰ 1 )
[0047] Yield 86%; melting point 245-246°C; 1 H NMR (CDCl 3 ,400MHz)δ2.43-2.49(m,1H),3.16-3.42(m,3H),3.43-3.63(m,2H),4.06(d,J=14.1Hz,1H),4.47(d,J= 12.7Hz,1H),6.11(s,1H),,6.37(s,1H),6.82(t,J=7.2Hz,1H),7.01-7.74(m,13H).IR(KBr,cm -1 )3445,1640,1597,1495,1436,1082,747;;Anal.Calcd for C 30 h 24 f 2 N 4 o 3 :C,68.43;H,4.59;N,10.64.Found:C,68.45;H,4.63;N,10.61.
Embodiment 2
[0048] Example 2: 2-(3-nitrophenyl)-3-(4-fluorophenyl)-5-(2-furylmethyl)-7-(4-fluorobenzylidene)-2H-pyrazole And [4,3-c] hexahydropyridine (Ⅰ 2 )
[0049] Yield 77%; melting point 259-260°C; 1 HNMR(400MHz,)δ2.44-2.51(m,1H),3.15-3.33(m,3H),3.47-3.63(m,2H),4.11(d,J=14.3Hz,1H),4.42(d, J=12.4Hz,1H),6.13(s,1H),,6.37(s,1H),6.87(t,J=7.2Hz,1H),7.03-7.72(m,13H);IR(KBr,cm -1 )3447,1641,1598,1495,1436,1081,748;Anal.Calcd for C 30 h 24 f 2 N 4 o 3 :C,68.43;H,4.59;N,10.64;Found:C,68.41;H,4.61;N,10.61.
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Abstract
The invention provides 2, 3, 5, 7-tetrasubstituted dihydro-pyrazolo piperidine derivative and a preparation method and application thereof. The derivative is 2, 3-bis(substituted phenyl)-5-subsituted arylmethyl-7-substituted benzylidene dihydro-pyrazolo piperidine derivative, having the following formula (I). The preparation method includes using substituted arylmethyl amine and methyl acrylate as raw materials; subjecting the materials to Michael addition, Dieckmann condensation and hydrolysis-decarboxylation sequentially; allowing for Aldol reaction with substituted benzaldehyde to obtain intermediate N-substituted arylmethyl-3, 5-bis(substituted benzylidene)-4-piperidone; allowing for condensation with substituted phenylhydrazine to obtain a compound according to the formula (I). The derivative is efficient in inhibiting multiplication of various carcinomacell lines such as leukemia, esophaguscancer, ovarian cancer and breast cancer in human, is well stably metabolic in liver microsomes of human and rat, is free of direct and competitive inhibition on five enzymes of liver microsomes, such as CYP3A4, CYP2D6, CYP2C9, CYP1A2 and CYP2C19, is highly bioavailable, is low in toxicity to normal cells, and is available for the preparation of drugs for the cancers.
Description
technical field [0001] The invention belongs to the field of organic synthesis and medicinal chemistry, and relates to a 2,3,5,7-tetrasubstituted dihydropyrazolohexahydropyridine derivative, specifically a 2,3-disubstituted phenyl-5 -Substituted arylmethyl-7-substituted benzylidene dihydropyrazolohexahydropyridine derivatives and their preparation methods, and related to their preparation and inhibition of human leukemia, human esophageal cancer, human livercancer, human ovarian cancer and human Breast cancer, and many other human cancercell lines proliferation drug application. Background technique [0002] According to the estimates of the World Health Organization, there are more than 3 million cancer patients in my country, and 1.6 to 2 million new cancers are diagnosed every year, with an increase of 3% and a younger trend. For example, leukemia, a blood cell cancer, is more likely to occur in adolescents, and its incidence rate ranks first among adolescent tumors, s...
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