CN102863376A - N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof - Google Patents
N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of organic synthesis and medicine, and discloses a preparation method for N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and biological activity for efficiently inhibiting cell line proliferation such as leukemia, ovarian cancer, breast cancer, liver cancer and esophagus cancer. The method includes: starting from various substituted methylamine and methyl acrylate, sequentially going through Michael addition, Dieckmann condensation, acidolysis and decarboxylation to obtain N-substituted methyl-4-piperidone, and subjecting the N-substituted methyl-4-piperidone to aldol reaction with substituted benzaldehyde to obtain a target compound N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone. The target compound can selectively and efficiently inhibit cell line proliferation such as leukemia, ovarian cancer, breast cancer, liver cancer and esophagus cancer, and activity of inhibiting carcinoma cell line proliferation is obviously higher than conventional chemotherapeutic 5-fluorouracil.
Description
Technical field
The invention belongs to the chemicals field, be specifically related to N-substituent methyl-3, the two benzal base-4-piperidone that replace of 5-can be used as the lead compound for the treatment of leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer medicine.
Background technology
Cancer is one of disease that mortality ratio is the highest in the world today, and according to the epidemiology statistics of China's issue, China's each department leukemia, Primary Hepatic cancer morbidity account for respectively the 6th and the 8th in various tumours.Leukemia is a class hematopoietic cell malignant disease, is apt to occur in the teenager, and its sickness rate comes first of teenager's tumour, has at present 4,000,000 leukaemics at least, annual newly-increased about 40,000.
Primary hepatocarcinoma is one of modal malignant tumour in the world, and the liver cancer of the whole world more than 50% occurs in China.Although the onset of liver cancer rate in the whole world is ranked the 8th in various tumours, its mortality ratio comes the 4th.
Ovarian cancer and mammary cancer are the modal tumor diseases of women, have a strong impact on women's physical and mental health even threat to life.According to statistics, ovarian cancer and breast cancer incidence are only second to cervical cancer and carcinoma of uterine body.
At present, still adopt the method for chemotherapy to treat for above-mentioned various cancers, chemotherapy only can make the patient obtain the short-term alleviation by killing and wounding in a large number the cancer cells of highly breeding, but can't effect a radical cure.Because used chemotherapeutics lacks specificity more at present, so toxic side effect is very large.More thorny is that the cancer cells of most of patients with recurrents has usually produced resistance to existing chemotherapeutics.
The common shortcoming of chemotherapeutics commonly used is that selectivity is not strong clinically now, and normal cell and tumour cell are had almost identical lethal effect, marrow, digestive tube cell and sexual cell is also had very strong lethal effect, so toxicity is larger.
Summary of the invention
The object of the invention provides a series of N-substituent methyls-3, the two benzal base-4-piperidone that replace of 5-, and this series compound can be used as the lead compound for the treatment of leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer medicine.
Second purpose of the present invention is to provide N-substituent methyl-3, the two preparation methods that replace benzal base-4-piperidone of 5-.
The 3rd purpose of the present invention is that with N-substituent methyl-3, the two benzal base-4-piperidone that replace of 5-are used for system
The medicine of the kinds cancers such as standby treatment leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer, this N-replaces
Methyl-3, the two benzal base-4-piperidone compounds that replace of 5-have the biological activity that the multiple cancerous cell line such as efficient inhibition leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer is bred, and the IC50 value all is starkly lower than conventional chemotherapy medicine 5 FU 5 fluorouracil (5Fu).
The objective of the invention is to be achieved through the following technical solutions:
Activity with multiple cancer cells such as efficiently killing leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer provided by the invention, the lead compound N-substituent methyl-3 of cancer therapy drug, the structural formula that 5-is two to replace benzal base-4-piperidone be as shown in the formula (I):
R
1Be substituted-phenyl, five-membered ring substituting group or hexa-member heterocycle substituting group; Substituted-phenyl is a kind of in 4-tolyl, 2-tolyl, 4-p-methoxy-phenyl, 2-p-methoxy-phenyl, 4-bromophenyl, 2-bromophenyl, 3-bromophenyl, 2-fluorophenyl, the 3-fluorophenyl, described five-membered ring substituting group is a kind of in 2-tetrahydrofuran base, 2-furyl, 2-thienyl, the 5-chloro-2-thiazolyl, and described hexa-member heterocycle is a kind of in 3-pyridyl, the 6-chloro-3-pyridyl base;
R
2Be 4-cyano group, 2-cyano group, 3,4-dichloro, 2, a kind of in the substituting groups such as 4-dichloro, 3-nitro, 2-nitro, 3-chlorine, 2-bromine, 3-bromine, 4-bromine, 2-fluorine, 3-fluorine, 4-fluorine, 2-trifluoromethyl, 4-dimethylamino, 2-dimethylamino, 4-hydroxy-3-methoxy.
The invention provides the preparation method of formula (I) compound, comprise the steps:
(1) substituted methylamine and the methyl acrylate process Michael addition reaction of formula (a) structure are made formula (II) N, two (β-methyl propionate) substituted methylamines of N-; Substituted methylamine and the methyl acrylate mol ratio of formula (II) structure are 1:2～1:4, take alcohols as solvent, are preferably methyl alcohol or ethanol, back flow reaction 6～10 hours; Be specially, the alcoholic solution that will contain substituted methylamine under the condition of ice bath is added drop-wise to and contains in the methyl acrylate alcoholic solution, and the control temperature is no more than 50 ℃; Dropwise rear stirring 20～60min, back flow reaction 6～10 hours;
(2) the Dieckmann condensation is occured step (1) product under the sodium alkoxide effect, with acid hydrolysis extraction, water intaking phase back flow reaction 6～10 hours is regulated pH=8～9, and decarboxylation obtains the N-substituent methyl of formula (III)-4-piperidone;
R
1-CH
2NH
2 R
1CHN(CH
2CH
2COOCH
3)
2
（a） （II）
(3) the substituted benzaldehyde generation aldol condensation with step (2) product N-substituent methyl-4-piperidone and formula (IV) structure also dewaters,
Getting general formula is the N-substituent methyl-3 of (I), the two benzal base-4-piperidone that replace of 5-; The mol ratio of N-substituent methyl-4-piperidone and substituted benzaldehyde is 1:2;
R
1Be substituted-phenyl, five-membered ring substituting group or hexa-member heterocycle substituting group;
R
2Be 4-cyano group, 2-cyano group, 3,4-dichloro, 2, a kind of in 4-dichloro, 3-nitro, 2-nitro, 3-chlorine, 2-bromine, 3-bromine, 4-bromine, 2-fluorine, 3-fluorine, 4-fluorine, 2-trifluoromethyl, 4-dimethylamino, 2-dimethylamino, the 4-hydroxy-3-methoxy.
The reaction formula of above-mentioned preparation process is:
Compound N-substituent methyl of the present invention-3, the two benzal base-4-piperidone that replace of 5-can be applied to preparation treatment leukemia, the medicine of the kinds cancers such as ovarian cancer, mammary cancer, liver cancer and esophagus cancer.
Cancer therapy drug lead compound N-substituent methyl-3 provided by the invention, the two benzal base-4-piperidone that replace of 5-, have the biological activity of the multiple cancerous cell line propagation of efficient inhibition, specifically comprise following cancerous cell line: 2 kinds of Leukemia Cell Lines such as leukemia K 562 and Jarket clone, ovarian cancer HO-8910 clone, breast cancer mcf-7 cell line, SMMC-7721 liver cancer cells system and esophagus cancer ECA-109 clone.This compound can be applied to prepare the medicine of the system such as the cancer cell that suppresses Leukemia Cell Lines, ovarian cancer cell line, breast cancer cell line, hepatoma cell line and esophageal cancer cell system propagation.
Cancer therapy drug lead compound N-substituent methyl-3, the two benzal base-4-piperidone that replace of 5-suppress 2 kinds of Leukemia Cell Lines such as leukemia K 562, ovary HO-8910 clone, breast cancer mcf-7 cell line, the activity of SMMC-7721 liver cancer cells system and esophagus cancer ECA-109 cell line proliferation are all apparently higher than the anticancer chemotherapeutic agent 5-fluor-uracil (IC of routine
50Value all is starkly lower than 5 FU 5 fluorouracil), might become novel anti-leukemia medicine special efficacy, that toxic side effect is less, have potential practicality.
Embodiment
The N-substituent methyl-3 that antitumour activity is just arranged of the present invention's preparation, the example of the two benzal phenylpiperidines of 5--4-ketone cancer therapy drug lead compound is:
(Ia) N-(4-methoxy-benzyl)-3, two (4-cyano group benzal the base)-4-piperidone of 5-;
(Ib) N-(4-methoxy-benzyl)-3, two (3,4-dichloro benzal the base)-4-piperidone of 5-;
(Ic) N-(4-methoxy-benzyl)-3, two (2,4-dichloro benzal the base)-4-piperidone of 5-;
(Id) N-(2-luorobenzyl)-3, two (3-nitre benzal the base)-4-piperidone of 5-;
(Ie) N-(2-luorobenzyl)-3, two (2-trifluoromethyl benzal the base)-4-piperidone of 5-;
(If) N-(2-luorobenzyl)-3, two (4-trifluoromethyl benzal the base)-4-piperidone of 5-;
(Ig) N-(2-bromobenzyl)-3, two (3-benzyl chloride fork the base)-4-piperidone of 5-;
(Ih) N-(2-bromobenzyl)-3, two (4-dimethylamino benzal the base)-4-piperidone of 5-;
(Ii) N-(2-bromobenzyl)-3, two (4-hydroxyl-2-methoxyl group benzal the base)-4-piperidone of 5-;
(Ij) N-(4-luorobenzyl)-3, two (2,4-dichloro benzal the base)-4-piperidone of 5-.
Embodiment 1 N-(4-methoxy-benzyl)-3, two (4-cyano group benzal the base)-4-piperidone (Ia) of 5-
In 0 ℃ of ice-water bath, methyl acrylate and the 7mL methyl alcohol of 0.4mol are added in the 100mL there-necked flask, after stirring 30min, to the methanol mixed solution that wherein slowly drips 0.1mol 4-methoxybenzylamine and 10mL, the control rate of addition makes system temperature be no more than 50 ℃ (about 1 drops/sec of rate of addition).After dropwising, stir 30min under the room temperature, continue rising temperature to 65 ℃, reflux, thin-layer chromatography (TLC) is followed the tracks of reaction process.After reacting about 8h, stopped reaction, methyl alcohol and unreacted methyl acrylate are reclaimed in underpressure distillation,
Obtain light yellow oily liquid intermediate (2a).
Under the room temperature, 15mL dry toluene and 0.1mol sodium Metal 99.5 (being cut into bulk) are added in the there-necked flask of 250mL drying, the about 40min of stirring heating backflow, present pearl to the sodium piece, slowly drip 0.1mol intermediate (2a) and 20mL dry toluene mixed solution, when reaction has just begun, drip 3 carrying out that anhydrous methanol impels reaction with dropper.Reaction system becomes light yellow thickly gradually in the dropping process, need to strengthen stirring velocity, after dropwising, the 40mL dry toluene is joined in the reaction vessel in batches if needed, and hierarchy of control temperature is 110 ℃, backflow 6h.
Reflux complete after, be cooled to room temperature, adding the 1mL anhydrous methanol and also stir 1h, to remove the complete sodium Metal 99.5 of unreacted, is that 25% hydrochloric acid soln 40mL * 3 extract with the mixture massfraction subsequently, collect extraction liquid (water), with extraction liquid oil bath backflow 8h, after reaction finished, cooling reaction system was to room temperature, stir the lower pH value that is with NaOH solution conditioned reaction to alkalescence (about pH=8.5), with ethyl acetate 40mL * 3 extractions.The combined ethyl acetate layer carries out drying with the 10g anhydrous sodium sulphate to it, and ethyl acetate is reclaimed in underpressure distillation, and the distillation substrate is pale yellow oily liquid body N-4-methoxybenzyl-4-piperidone (3a).
In the round-bottomed flask of 50mL, add intermediate (3a) (0.005mol) and 4-cyanobenzaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (Ia) with ethyl acetate and sherwood oil recrystallization.
Yield: 76.3%; Yellow solid, mp 139-141 ° C; 1H NMR (400MHz, CDCl
3); 1H NMR (400MHz, CDCl
3) δ 3.67 (s, 2H), 3.64 (s, 3H), 3.82 (s, 4H), 7.04 (d, J=8.7Hz, 2H), 7.14 (d, J=8.7Hz, 2H), 7.23 (d, J=8.0Hz, 4H), (7.37 d, J=8.0Hz, 4H), 7.75 (s, 2H) IR (KBr): 3138,2814,1672,1594,1525,1342,1261,1109,1005,854cm
-1; Anal.calcd.for C
29H
23N
3O
2.C%78.18, H%5.20, N%9.43; Found:C%78.16, H%5.19, N%9.45
Embodiment 2 N-(4-methoxy-benzyl)-3, two (3,4-dichloro benzal the base)-4-piperidone (Ib) of 5-
Prepare (2b) and (3b) with preparation (2a) method identical with (3a).
In the round-bottomed flask of 50mL, add intermediate N 4-methoxybenzyl-4-piperidone (3b) (0.005mol) with 3,4-dichlorobenzaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (Ib) with ethyl acetate and sherwood oil recrystallization.
Yield: 80.2%; Yellow solid, mp 131-133 ° C;
1H NMR (400MHz, CDCl
3) δ 3.65 (s, 2H), 3.71 (s, 3H), 3.85 (s, 4H), 7.02 (d, J=8.7Hz, 2H), 7.13 (d, J=8.7Hz, 2H), 7.24 (d, J=8.0Hz, 4H), 7.36 (d, J=8.0Hz, 2H), 7.71 (s, 2H); IR (KBr): 2805,2745,1667,1615,1575,1480,1260,1185,1085,821cm
-1; Anal.calcd.for C
27H
21Cl
4NO
2C%60.81, H%3.97, N%2.63; Found:C%60.72H%3.95, N%2.68
Embodiment 3 N-(4-methoxy-benzyl)-3, two (2,4-dichloro benzal the base)-4-piperidone (Ic) of 5-
Prepare (2c) and (3c) with preparation (2a) method identical with (3a).
In the round-bottomed flask of 50mL, add intermediate N 4-methoxybenzyl-4-piperidone (3c) (0.005mol) with 3,4-dichlorobenzaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (Ic) with ethyl acetate and sherwood oil recrystallization.
Yield: 73.7%; Yellow solid, mp 183-185 ° C;
1H NMR (400MHz, CDCl
3) δ 3.62 (s, 2H), 3.75 (s, 3H), 3.82 (s, 4H), 7.03 (d, J=8.7Hz, 2H), 7.12 (d, J=8.7Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.28 (d, J=8.0Hz, 4H), 7.73 (s, 2H); ; IR (KBr): 2805,2743,1664,1603,1574,1487,1262,1185,1094,821cm
-1; Anal.calcd.for C
27H
21Cl
4NO
2C%60.81, H%3.97, N%2.63; Found:C%60.72H%3.95, N%2.68
Embodiment 4 N-(2-luorobenzyl)-3, two (3-nitre benzal the base)-4-piperidone (Id) of 5-
In 0 ℃ of ice-water bath, in the methyl acrylate and 7mL methyl alcohol adding 100mL there-necked flask with 0.4mol, behind the stirring 30min, to the methanol mixed solution that wherein slowly drips 0.1mol 2-flunamine and 10mL, the control rate of addition,, make system temperature be no more than 50 ℃ (about 1 drops/secs).After dropwising, stir 30min under the room temperature, continue rising temperature to 65 ℃, reflux, thin-layer chromatography (TLC) is followed the tracks of reaction process.After reacting about 8h, stopped reaction, methyl alcohol and unreacted methyl acrylate are reclaimed in underpressure distillation, obtain light yellow oily liquid intermediate (2d).
Under the room temperature, 15mL dry toluene and 0.1mol sodium Metal 99.5 (being cut into bulk) are added in the there-necked flask of 250mL drying, the about 40min of stirring heating backflow, present pearl to the sodium piece, slowly drip 0.1mol intermediate (2d) and 20mL dry toluene mixed solution, when reaction has just begun, drip 3 carrying out that anhydrous methanol impels reaction with dropper.Reaction system becomes light yellow thickly gradually in the dropping process, need to strengthen stirring velocity, after dropwising, the 40mL dry toluene is joined in the reaction vessel in batches if needed, and hierarchy of control temperature is 110 ℃, backflow 6h.
Reflux complete after, be cooled to room temperature, adding the 1mL anhydrous methanol and also stir 1h, to remove the complete sodium Metal 99.5 of unreacted, is that 25% hydrochloric acid soln 40mL * 3 extract with the mixture massfraction subsequently, collect extraction liquid (water), with extraction liquid oil bath backflow 8h, after reaction finished, cooling reaction system was to room temperature, stir the lower pH value that is with NaOH solution conditioned reaction to alkalescence (about pH=8.5), with ethyl acetate 40mL * 3 extractions.The combined ethyl acetate layer carries out drying with the 10g anhydrous sodium sulphate to it, and ethyl acetate is reclaimed in underpressure distillation, and the distillation substrate is pale yellow oily liquid body N-2-luorobenzyl-4-piperidone (3d).
In the round-bottomed flask of 50mL, add intermediate (3d) (0.005mol) and 3-nitrobenzaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (Id) with ethyl acetate and sherwood oil recrystallization.
Yield: 75.2%; Yellow solid, mp 129-131 ° C;
1H NMR (400MHz, CDCl
3) 3.65 (s, 2H), 3.85 (s, 4H), 7.05 (d, J=7.8Hz, 2H), 7.14 (d, J=7.9Hz, 2H), 7.55 (d, J=8.6Hz, 4H), 7.87 (s, 2H), 8.18 (d, J=8.6Hz, 4H); IR (KBr): 2824,1603,1487,1456,1264,11802,1096,1004,819cm
-1; Anal.calcd.forC
26H
20FN
3O
5C%65.96, H%4.26, N%8.88; Found:C%65.82H%4.17, N%8.78.
Embodiment 5 N-(2-luorobenzyl)-3, two (2-trifluoromethyl benzal the base)-4-piperidone (Ie) of 5-
Prepare (2e) and (3e) with preparation (2d) method identical with (3d).
In the round-bottomed flask of 50mL, add intermediate N 2-luorobenzyl-4-piperidone (3e) (0.005mol) and 2-trifluoromethylated benzaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (Ie) with ethyl acetate and sherwood oil recrystallization.
Yield: 87.7%; Yellow solid, mp 121-123 ° C;
1H NMR (400MHz, CDCl
3) δ 3.63 (s, 2H), 3.87 (s, 4H), 7.05 (d, J=7.8Hz, 2H), 7.16 (d, J=7.9Hz, 2H), 7.55 (d, J=8.6Hz, 4H), 7.92 (s, 2H), 8.24 (d, J=8.6Hz, 4H); IR (KBr): 3127,2983,1679,1615,1506,1267,1224,1193,996,763cm
-1; Anal.calcd.for C
28H
20F
7NO C%64.74, H%3.88, N%2.70; Found:C%64.72H%3.97, N%2.78.
Embodiment 6 N-(2-luorobenzyl)-3, two (4-trifluoromethyl benzal the base)-4-piperidone (If) of 5-
Prepare (2f) and (3f) with preparation (2d) method identical with (3d).
In the round-bottomed flask of 50mL, add intermediate N 2-luorobenzyl-4-piperidone (3f) (0.005mol) and 4-trifluoromethylated benzaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (If) with ethyl acetate and sherwood oil recrystallization.
Yield: 76.6%; Yellow solid, mp 143-145 ° C;
1H NMR (400MHz, CDCl
3) δ 3.67 (s, 2H), 3.84 (s, 4H), 7.05 (d, J=7.8Hz, 2H), 7.21 (d, J=7.9Hz, 2H), 7.51 (d, J=8.6Hz, 4H), 7.94 (s, 2H), 8.21 (d, J=8.6Hz, 4H); IR (KBr): 3124,2996,1665,1615,1504,1267,1221,1193,997,763cm
-1; Anal.calcd.for C
28H
20F
7NO C%64.74, H%3.88, N%2.70; Found:C%64.72H%3.97, N%2.78.
Embodiment 7 N-(2-bromobenzyl)-3, two (3-benzyl chloride fork the base)-4-piperidone (Ig) of 5-
In 0 ℃ of ice-water bath, in the methyl acrylate and 7mL methyl alcohol adding 100mL there-necked flask with 0.4mol, behind the stirring 30min, to the methanol mixed solution that wherein slowly drips 0.1mol 2-bretylium and 10mL, the control rate of addition,, make system temperature be no more than 50 ℃ (about 1 drops/secs).After dropwising, stir 30min under the room temperature, continue rising temperature to 65 ℃, reflux, thin-layer chromatography (TLC) is followed the tracks of reaction process.After reacting about 8h, stopped reaction, methyl alcohol and unreacted methyl acrylate are reclaimed in underpressure distillation, obtain light yellow oily liquid intermediate (2g).
Under the room temperature, 15mL dry toluene and 0.1mol sodium Metal 99.5 (being cut into bulk) are added in the there-necked flask of 250mL drying, the about 40min of stirring heating backflow, present pearl to the sodium piece, slowly drip 0.1mol intermediate (2g) and 20mL dry toluene mixed solution, when reaction has just begun, drip 3 carrying out that anhydrous methanol impels reaction with dropper.Reaction system becomes light yellow thickly gradually in the dropping process, need to strengthen stirring velocity, after dropwising, the 40mL dry toluene is joined in the reaction vessel in batches if needed, and hierarchy of control temperature is 110 ℃, backflow 6h.
Reflux complete after, be cooled to room temperature, adding the 1mL anhydrous methanol and also stir 1h, to remove the complete sodium Metal 99.5 of unreacted, is that 25% hydrochloric acid soln 40mL * 3 extract with the mixture massfraction subsequently, collect extraction liquid (water), with extraction liquid oil bath backflow 8h, after reaction finished, cooling reaction system was to room temperature, stir the lower pH value that is with NaOH solution conditioned reaction to alkalescence (about pH=8.5), with ethyl acetate 40mL * 3 extractions.The combined ethyl acetate layer carries out drying with the 10g anhydrous sodium sulphate to it, and ethyl acetate is reclaimed in underpressure distillation, and the distillation substrate is pale yellow oily liquid body N-2-bromobenzyl-4-piperidone (3g).
In the round-bottomed flask of 50mL, add intermediate (3g) (0.005mol) and 3-chlorobenzaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (Ig) with ethyl acetate and sherwood oil recrystallization.
Yield: 85.1%; Yellow solid, mp 172-175 ° C;
1H NMR (400MHz, CDCl
3) δ 3.66 (s, 2H), 3.78 (s, 4H), 7.14 (d, J=8.4Hz, 2H), 7.23-7.24 (m, 2H), 7.26-7.37 (m, 8H), 7.73 (s, 2H); ; IR (KBr): 2825,1606,1486,1455,1263,1181,1096,1001,817cm
-1; Anal.calcd.for C
26H
20BrCl
2NO C%60.84, H%3.93, N%2.73; Found:C%60.78H%3.97, N%2.78.
Embodiment 8 N-(2-bromobenzyl)-3, two (4-dimethylamino benzal the base)-4-piperidone (Ih) of 5-
Prepare (2h) and (3h) with preparation (2g) method identical with (3g).
In the round-bottomed flask of 50mL, add intermediate N/-2-bromobenzyl-4-piperidone (3h) (0.005mol) and 4-dimethylaminobenzaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (Ih) with ethyl acetate and sherwood oil recrystallization.
Yield: 67.4%; Yellow solid, mp 109-111 ° C;
1H NMR (400MHz, CDCl
3) δ δ 2.85(s, 12H), 3.63 (s, 2H), 3.78 (s, 4H), 7.14 (d, J=8.4Hz, 2H), 7.22-7.24 (m, 2H), 7.25-7.37 (m, 8H), 7.75 (s, 2H); ; IR (KBr): 2821,1604,1489,1455,1265,1254,1181,1093,1002,817cm
-1; Anal.calcd.for C
30H
32BrN
3O C%67.92, H%6.08, N%7.92; Found:C%67.82H%5.97, N%7.78.
Embodiment 9 N-(2-bromobenzyl)-3, two (4-hydroxyl-2-methoxyl group benzal the base)-4-piperidone (Ii) of 5-
Prepare (2i) and (3i) with preparation (2g) method identical with (3g).
In the round-bottomed flask of 50mL, add intermediate N 2-bromobenzyl-4-piperidone (3i) (0.005mol) and 4-hydroxyl-2-methoxybenzaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (Ii) with ethyl acetate and sherwood oil recrystallization.
Yield: 66.3%; Yellow solid, mp 167-169 ° C;
1H NMR (400MHz, CDCl
3) δ 3.62 (s, 2H), 3.83 (s, 4H), (3.92 s, 6H), 5.03 (s, 2H), (7.05 d, J=7.8Hz, 2H), 7.14 (d, J=7.9Hz, 2H), 7.26 (d, J=8.3Hz, 2H), 7.44 (d, J=8.4Hz, 4H), 7.81 (s, 2H); ; IR (KBr): 3125,2995,1668,1615,1507,1269,1223,1195,997,764cm
-1; Anal.calcd.for C
28H
26BrNO
5C%62.69, H%4.89, N%2.61; Found:C%62.72H%4.97, N%2.68.
Embodiment 10 N-(4-luorobenzyl)-3, two (2,4-dichloro benzal the base)-4-piperidone (Ii) of 5-
In 0 ℃ of ice-water bath, in the methyl acrylate and 7mL methyl alcohol adding 100mL there-necked flask with 0.4mol, behind the stirring 30min, to the methanol mixed solution that wherein slowly drips 0.1mol 4-flunamine and 10mL, the control rate of addition,, make system temperature be no more than 50 ℃ (about 1 drops/secs).After dropwising, stir 30min under the room temperature, continue rising temperature to 65 ℃, reflux, thin-layer chromatography (TLC) is followed the tracks of reaction process.After reacting about 8h, stopped reaction, methyl alcohol and unreacted methyl acrylate are reclaimed in underpressure distillation, obtain light yellow oily liquid intermediate (2j).
Under the room temperature, 15mL dry toluene and 0.1mol sodium Metal 99.5 (being cut into bulk) are added in the there-necked flask of 250mL drying, the about 40min of stirring heating backflow, present pearl to the sodium piece, slowly drip 0.1mol intermediate (2j) and 20mL dry toluene mixed solution, when reaction has just begun, drip 3 carrying out that anhydrous methanol impels reaction with dropper.Reaction system becomes light yellow thickly gradually in the dropping process, need to strengthen stirring velocity, after dropwising, the 40mL dry toluene is joined in the reaction vessel in batches if needed, and hierarchy of control temperature is 110 ℃, backflow 6h.
Reflux complete after, be cooled to room temperature, adding the 1mL anhydrous methanol and also stir 1h, to remove the complete sodium Metal 99.5 of unreacted, is that 25% hydrochloric acid soln 40mL * 3 extract with the mixture massfraction subsequently, collect extraction liquid (water), with extraction liquid oil bath backflow 8h, after reaction finished, cooling reaction system was to room temperature, stir the lower pH value that is with NaOH solution conditioned reaction to alkalescence (about pH=8.5), with ethyl acetate 40mL * 3 extractions.The combined ethyl acetate layer carries out drying with the 10g anhydrous sodium sulphate to it, and ethyl acetate is reclaimed in underpressure distillation, and the distillation substrate is pale yellow oily liquid body N-4-luorobenzyl-4-piperidone (3j).
In the round-bottomed flask of 50mL, add intermediate (3j) (0.005mol) and 2,4 dichloro benzene formaldehyde (0.01mmol), 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL.Room temperature (15～25 ℃) stirs 1h, has solid to separate out, and suction filtration is used the absolute ethanol washing product again, or namely obtains target compound (Ij) with ethyl acetate and sherwood oil recrystallization.
Yield: 74.7%; Yellow solid, mp 119-121 ° C;
1H NMR (400MHz, CDCl
3) δ 3.63 (s, 2H), 3.79 (s, 4H), 7.13 (d, J=8.4Hz, 2H), 7.21-7.24 (m, 2H), 7.26-7.37 (m, 6H), 7.76 (s, 2H); IR (KBr): 2827,1603,1487,1455,1265,1263,1182,1094,1002,815cm
-1; Anal.calcd.for C
26H
18Cl
4FNO C%59.91, H%3.48, N%2.69; Found:C%60.12H%3.57, N%2.78.
Embodiment 11 compounds (I) suppress leukemia, ovarian cancer, mammary cancer, liver cancer and the propagation IC of esophageal cancer cell system
50Test.
1. test medicament and equipment
Experimental drug and reagent: self-control compound (I), with the DMSO dissolving, adding distil water is assigned to desired concn (DMSO concentration≤1 ‰), the 4 ℃ of preservations of sterilizing.MTT (tetramethyl-azo azoles is blue) reagent is available from Sigma company.Leukemia K562 cell, Jarket, ovarian cancer HO-8910, mammary cancer MCF-7, liver cancer SMMC-7721 and esophagus cancer ECA-109 clone are purchased from Shanghai Chinese Academy of Sciences cell bank.10%SDS reagent (Sino-American Biotechnology product), with RPMI-1640 (the U.S. GiBCo company) nutrient solution that contains 20% calf serum (FBS), other reagent all is commercially available analytical pure.At 37 ℃, 5%CO
2, saturated humidity incubator in the cultivation of going down to posterity, treat to be used for when cell is in logarithmic phase experiment.
Plant and instrument: Bechtop, cleaning＜3.5/L (〉 0.5 μ m grit), the clean treating plant in upper sea company limited; CO
2Cell culture incubator, the Forma Scientific of Thermo company, Inc; Inverted microscope, Japanese Olympus (OLYMPUS) company, model C KX41; Enzyme-linked immunosorbent assay instrument, Bio-RAD Model 680; 96 holes are dull and stereotyped, U.S. Costar company; SK2200H type ultrasonic cleaner, Shanghai High Kudos Science Instrument Co., Ltd..
2. test method
Experiment is carried out in 96 orifice plates, collects the logarithmic phase cell, adjusts concentration of cell suspension, divides in 96 orifice plates 1 * 10
4/ hole, every hole cumulative volume 100 μ L, 8 every group multiple holes arrange medicine color control wells (not containing cell) and contain cell and the culture hole of different concns medicine, after cultivating 44h respectively, in each hole, add MTT (5mg/mL, 10 μ L), continue to cultivate 4h, add again 10%SDS 100 μ L termination reactions, 37 ℃ are spent the night, and in the absorbancy OD of 570nm value, calculate survival rate by following formula with each hole of enzyme linked immunosorbent detection: survival rate (%)=OD administration/OD contrast * 100%; And according to the survival rate of each concentration, adopt the LOGIT method to calculate 50% inhibition concentration (IC
50).
3. result's investigation
Measured N-replacement-3 with mtt assay, the two benzal phenylpiperidines of 5--4-ketone (I) suppresses 2 kinds of IC that leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer cell system breed such as leukemia K 562
50Value, IC
50Value sees Table 1.
Table 1 Compound I a～Ij suppresses the IC of 2 kinds of leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer cell system propagation
50Value
4. conclusion: table 1 is depicted as Compound I a ~ Ij suppresses 2 kinds of leukemia of people, ovarian cancer, mammary cancer, liver cancer and esophageal cancer cell system propagation in the cell in vitro level IC
50By table 1 data as can be known, Compound I a～Ij suppresses the IC of above-mentioned 2 kinds of leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer cell system propagation
50Value all is starkly lower than conventional chemotherapy medicine 5 FU 5 fluorouracil (5Fu).
Claims (9)
1.N-substituent methyl-3, the two benzal base-4-piperidone that replace of 5-is characterized in that, structure as shown in the formula (I):
In the formula: R
1Be substituted-phenyl, five-membered ring substituting group or hexa-member heterocycle substituting group;
R
2Be 4-cyano group, 2-cyano group, 3,4-dichloro, 2, a kind of in 4-dichloro, 3-nitro, 2-nitro, 3-chlorine, 2-bromine, 3-bromine, 4-bromine, 2-fluorine, 3-fluorine, 4-fluorine, 2-trifluoromethyl, 4-dimethylamino, 2-dimethylamino, the 4-hydroxy-3-methoxy.
2. the described N-substituent methyl-3 of claim 1, the two benzal base-4-piperidone that replace of 5-is characterized in that described R
1In, substituted-phenyl is a kind of in 4-tolyl, 2-tolyl, 4-p-methoxy-phenyl, 2-p-methoxy-phenyl, 4-bromophenyl, 2-bromophenyl, 3-bromophenyl, 2-fluorophenyl, the 3-fluorophenyl, described five-membered ring substituting group is a kind of in 2-tetrahydrofuran base, 2-furyl, 2-thienyl, the 5-chloro-2-thiazolyl, and described hexa-member heterocycle is a kind of in 3-pyridyl, the 6-chloro-3-pyridyl base.
3. claim 1 or 2 described N-substituent methyls-3, the two preparation methods that replace benzal base-4-piperidone of 5-is characterized in that, comprise the steps:
(1) substituted methylamine and the methyl acrylate process Michael addition reaction of formula (a) structure are made formula (II) N, two (β-methyl propionate) substituted methylamines of N-;
(2) with step (1) product N, the Dieckmann condensation occurs in two (β-methyl propionate) substituted methylamines of N-under the sodium alkoxide effect, obtains the N-substituent methyl of formula (III)-4-piperidone with the acid hydrolysis decarboxylation;
R
1-CH
2NH
2 R
1CHN(CH
2CH
2COOCH
3)
2
（a） （II）
(3) the substituted benzaldehyde generation aldol condensation with step (2) product N-substituent methyl-4-piperidone and formula (IV) structure also dewaters,
Getting general formula is the N-substituent methyl-3 of (I), the two benzal base-4-piperidone that replace of 5-.
4. the described N-substituent methyl-3 of claim 3, the two preparation methods that replace benzal base-4-piperidone of 5-is characterized in that, in the step (1), substituted methylamine and the methyl acrylate mol ratio of formula (II) structure are 1:2～1:4, take methyl alcohol or ethanol as solvent, and back flow reaction 6～10 hours.
5. the described N-substituent methyl-3 of claim 3, the two preparation methods that replace benzal base-4-piperidone of 5-is characterized in that R
1Be substituted-phenyl, five-membered ring substituting group or hexa-member heterocycle substituting group;
R
2Be 4-cyano group, 2-cyano group, 3,4-dichloro, 2, a kind of in 4-dichloro, 3-nitro, 2-nitro, 3-chlorine, 2-bromine, 3-bromine, 4-bromine, 2-fluorine, 3-fluorine, 4-fluorine, 2-trifluoromethyl, 4-dimethylamino, 2-dimethylamino, the 4-hydroxy-3-methoxy.
6. the described N-substituent methyl-3 of claim 3, the two preparation methods that replace benzal base-4-piperidone of 5-is characterized in that in the step (3), N-substituent methyl-4-piperidone and substituted benzaldehyde mol ratio are 1:2.
7. claim 1 or 2 described N-substituent methyls-3,5-is two to replace the application of benzal base-4-piperidone aspect preparation treatment leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer medicine.
8. claim 1 or 2 described N-substituent methyls-3, the two benzal base-4-piperidone that replace of 5-are for the preparation of the medicine that suppresses Leukemia Cell Lines, ovarian cancer cell line, breast cancer cell line, hepatoma cell line and esophageal cancer cell system propagation.
9. claim 1 or 2 described N-substituent methyls-3, the two benzal base-4-piperidone that replace of 5-are for the preparation of the medicine that suppresses leukemia K 562 clone, leukemia Jarket clone, ovarian cancer HO-8910 clone, breast cancer mcf-7 cell line, SMMC-7721 liver cancer cells system and esophagus cancer ECA-109 cell line proliferation.
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| CN104262240A (en) * | 2014-07-31 | 2015-01-07 | 滨州医学院 | Antitumor 3,5-diphenylmethylene-4-piperidone derivative and preparation method thereof |
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