CN104592203A - 2-amino-4-tetrahydroindazole substituted benzamide compounds and application of compound in preparing anti-tumor drugs - Google Patents

2-amino-4-tetrahydroindazole substituted benzamide compounds and application of compound in preparing anti-tumor drugs Download PDF

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CN104592203A
CN104592203A CN201510051927.2A CN201510051927A CN104592203A CN 104592203 A CN104592203 A CN 104592203A CN 201510051927 A CN201510051927 A CN 201510051927A CN 104592203 A CN104592203 A CN 104592203A
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amino
tetrahydrochysene indazole
benzamide compounds
tetrahydroisoquinoline
replaces
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王一飞
黄云生
刘忠
吴宗文
宋树勇
汪圣
利奕成
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Guangzhou Jinan Biomedicine Research and Development Base Co Ltd
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Guangzhou Jinan Biomedicine Research and Development Base Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings

Abstract

The invention belongs to the field of medicine and particularly relates to 2-amino-4-tetrahydroindazole substituted benzamide compounds and application of compound in preparing anti-tumor drugs. The 2-amino-4-tetrahydroindazole substituted benzamide compounds have the structures represented by the formula I as shown in the description, wherein R1 is alkyl; and n is a natural number. The compounds are prepared by substituting 2-position of 4-tetrahydroindazole substituted benzamide with 6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-alkylamino. The compounds can be used for inhibiting the growth of various tumor cells and inducing the cells to apoptosis channel. Therefore, the compounds have potential application values in the fields of treatment and adjuvant treatment of tumors and the like.

Description

The benzamide compounds that a kind of 2-amino-4-tetrahydrochysene indazole replaces and preparing the application in antitumor drug
Technical field
The invention belongs to field of medicaments, be specifically related to the benzamide compounds of a kind of 2-amino-4-tetrahydrochysene indazole replacement and preparing the application in antitumor drug.
Background technology
Through long unremitting effort, the mankind achieve significant progress in Therapeutic cancer.Wherein multi-medicament is improving the quality of life of cancer patient, extending life, and even treating tumour aspect has obvious effect.However, cancer is still considered to " incurable disease ", and the patient that can thoroughly be cured or eradicate is few, and most of cancer patient still experiences the painful serious illness and tramples on, and dies in youth.Along with the further deterioration of living environment, cancer morbidity constantly increases, and researchs and develops anticancer class medicine that is novel, effective, low toxic side effect and has huge economic and social benefit.
Summary of the invention
In order to overcome the deficiencies in the prior art and shortcoming, primary and foremost purpose of the present invention is the benzamide compounds providing a kind of 2-amino-4-tetrahydrochysene indazole to replace.
Another object of the present invention is to the preparation method of the benzamide compounds providing above-mentioned 2-amino-4-tetrahydrochysene indazole to replace.
Another object of the present invention is the application of the benzamide compounds providing above-mentioned 2-amino-4-tetrahydrochysene indazole to replace.
Object of the present invention is realized by following proposal:
The benzamide compounds that 2-amino-4-tetrahydrochysene indazole replaces, has the structure shown in formula I:
Wherein, R 1for alkyl; N is natural number;
Described R 1be preferably methyl, ethyl, propyl or cyclopropane base;
Described n is preferably 1 ~ 6;
Described n more preferably 2,3,4 or 5;
The benzamide compounds that described 2-amino-4-tetrahydrochysene indazole replaces preferably has structure shown in formula II:
Wherein, n is preferably 1 ~ 5;
The synthetic route of the benzamide compounds that described 2-amino-4-tetrahydrochysene indazole replaces is as follows:
The preparation method of the benzamide compounds that described 2-amino-4-tetrahydrochysene indazole replaces, comprises following steps:
(1) synthesis of intermediate 2-(aminoalkyl)-1,2,3,4-tetrahydroisoquinoline:
1. bromo alkyl nitrile and the reaction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are obtained 1,2,3, the 4-tetrahydroisoquinoline that 2-(ω-cyanoalkyl) replaces;
2. 1,2,3, the 4-tetrahydroisoquinoline that the 2-(ω-cyanoalkyl) step 1. obtained replaces and Lithium Aluminium Hydride reduce and obtain 2-(aminoalkyl)-1,2,3,4-tetrahydroisoquinoline;
(2) synthesis of the fluoro-4-of intermediate 2-(3-alkyl-6,6-dimethyl-4-ketone-4,5,6,7-tetrahydrochysene indazole-1-) cyanobenzene (W8):
1. by 5,5-dimethyl-hydroresorcinol and alkyl acyl chloride (R 1-CO-Cl, as Acetyl Chloride 98Min.) obtained 3-alkyloyl-5, the 5-dimethyl-hydroresorcinol of reaction;
2. 3-alkyloyl-5,5-dimethyl-hydroresorcinol step 1. obtained and hydrazine hydrate reaction form 3-alkyl-6,6-dimethyl-4,5,6,7-tetrahydrochysene indazole-4-ketone (W5);
3. 3-alkyl-6, the 6-dimethyl-4,5,6 2. step obtained, 7-tetrahydrochysene indazole-4-ketone and 2,4 difluorobenzene formonitrile HCN are obtained by reacting the fluoro-4-of 2-(3-alkyl-6,6-dimethyl-4-ketone-4,5,6,7-tetrahydrochysene indazole-1-) cyanobenzene (W8);
(3) synthesis of the benzamide compounds of 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replacement:
1. by 2-(aminoalkyl)-1 obtained for step (1), the fluoro-4-of 2-(the 3-alkyl-6 that 2,3,4-tetrahydroisoquinoline and step (2) obtain, 6-dimethyl-4-ketone-4,5,6,7-tetrahydrochysene indazole-1-) the obtained 2-(6 of cyanobenzene reaction, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replace cyanobenzene compound;
2. the 2-(6 1. step obtained, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replace cyanobenzene compound and hydrogen peroxide react, obtain final product 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replace benzamide compounds, be 2-amino-4-tetrahydrochysene indazole replace benzamide compounds;
The structural formula of the bromo alkyl nitrile described in step (1) is: wherein, n is preferably 1 ~ 5;
The benzamide compounds that described 2-amino-4-tetrahydrochysene indazole replaces can be applicable to prepare in antitumor drug;
Described antitumor drug refers at least one in the benzamide compounds that 2-amino-4-tetrahydrochysene indazole of the present invention replaces or its pharmaceutical salts or solvate; Known, the solvation form of compound and salt do not affect the biologic activity of compound self usually;
The pharmaceutical salts of described compound preferably includes the hydrochloride of these compounds, vitriol, phosphoric acid salt, nitrate, hydrobromate, oxalate, maleate, Citrate trianion, acetate, lactic acid salt, sulfonate, tosilate, mesylate, tartrate, succinate etc.;
Described antitumor drug can contain one or more pharmaceutically acceptable carrier, vehicle or thinners.
Anti-tumor biological measures and shows, the growth of compound of the present invention and pharmaceutically acceptable salt pair kinds of tumor cells has very strong restraining effect.Described tumour cell comprises mammary cancer, liver cancer, lung cancer, cancer before prostatitis, the rectum cancer, cervical cancer etc.Therefore, these compounds and pharmaceutically acceptable salt can be used for treatment or adjuvant treatment of breast cancer, liver cancer, lung cancer, prostate cancer, the rectum cancer, cervical cancer etc.
The present invention, relative to prior art, has following advantage and beneficial effect:
(1) the 2-position of benzamide that replaced by 4-tetrahydrochysene indazole of the present invention is with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-alkylamino replaces, and obtains a series of 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replace benzamide.
(2) benzamide compounds that 2-(6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole that the present invention prepares replaces can suppress the growth of kinds of tumor cells and induce it to move towards apoptosis passage.Therefore, these compounds have potential using value in the field such as treatment, assisting therapy of tumour.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
The synthesis of embodiment 1 intermediate 2-(aminoalkyl)-1,2,3,4-tetrahydroisoquinoline
(1) synthesis of 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) ethamine (J2)
2-bromoacetonitrile (4g, 0.033mol), 6,7-dimethoxy-isoquinoline hydrochloride (5g, 0.022mol), is dissolved in 60mL DCM, add 15mL triethylamine, 50 DEG C of backflow 10h, cross and filter triethylamine hydrochloride, then saturated sodium bicarbonate and saturated common salt water washing is used, anhydrous sodium sulfate drying, dry method upper prop, PE:EA=6:4-4:6 crosses pillar, obtain J1 (4.2g, productive rate 82.35%). 1H NMR(CDCl 3,ppm):δ6.62(s,1H),6.55(s,1H),3.86-3.87(d,6H),3.74-3.75(m,4H),2.87-2.91(m,4H).
Get J1 (1.23g, 5.3mmol) and be dissolved in 100mL THF, under condition of ice bath, add LiAlH in batches 4(0.8g, 19.5mmol), 65 DEG C of backflows are spent the night.Be cooled to room temperature, slowly add 10mL methyl alcohol at night to reaction, cancellation is reacted, and filters and removes solid impurity, and by dichloromethane rinse, decompression is spin-dried for and obtains transparent oily liquid J2 (1.14g, productive rate 87.7%).Product point plate becomes a point, without the need to being further purified directly down single step reaction.
(2) synthesis of 3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) propylamine (G2)
By 3-bromopropionitrile (5.27g, 0.03mol), 6,7-dimethoxy-isoquinoline hydrochloride (6g, 0.026mol), is dissolved in 100mL DCM, add 15mL triethylamine, 50 DEG C of backflow 10h, cross and filter triethylamine hydrochloride, with saturated sodium bicarbonate and saturated common salt water washing, anhydrous sodium sulfate drying, dry method upper prop, PE:EA=6:4-4:6 crosses pillar, obtain G1 (5.46g, productive rate 85%). 1H NMR(CDCl 3,ppm):δ6.59(s,1H),6.51(s,1H),3.83-3.84(d,6H),3.64(s,2H),2.86-2.90(t,2H),2.78-2.84(m,4H),2.59-2.63(t,2H).
Get G1 (0.8g, 3.25mmol) and be dissolved in 30mL THF, under condition of ice bath, add LiAlH in batches 4(0.4g, 9.75mmol), 65 DEG C of backflows are spent the night.Be cooled to room temperature, slowly add 10mL methyl alcohol at night to reaction, cancellation is reacted, and filters and removes solid impurity, and by dichloromethane rinse, decompression is spin-dried for and obtains transparent oily liquid G2 (0.75g, productive rate 92.6%).Product point plate is single, does not cross the direct down single step reaction of pillar.
(3) synthesis of 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) butylamine (D2)
By 4-bromine butyronitrile (2.78g, 0.019mol), 6,7-dimethoxy-isoquinoline hydrochloride (5.2g, 0.022mol), is dissolved in 80mL DCM, add 15mL triethylamine, 50 DEG C of backflow 10h, cross and filter triethylamine hydrochloride, then saturated sodium bicarbonate and saturated common salt water washing is used, anhydrous sodium sulfate drying, dry method upper prop, PE:EA=6:4-4:6 crosses pillar, obtain D1 (4.5g, productive rate 86%). 1H NMR(CDCl 3,ppm):δ6.62(s,1H),6.53(s,1H),3.85-3.86(d,6H),3.57(s,2H),2.82-2.86(t,2H),2.71-2.74(t,2H),2.63-2.66(t,2H),2.48-2.52(t,2H),1.92-1.98(m,2H).
Get D1 (2g, 7.6mmol) and be dissolved in 100mL THF, under condition of ice bath, add LiAlH in batches 4(0.8g, 19.5mmol), 65 DEG C of backflows are spent the night.Be cooled to room temperature, slowly add 10mL methyl alcohol cancellation reaction at night, filter and remove solid impurity to reaction, by dichloromethane rinse, decompression is spin-dried for and obtains transparent oily liquid D2 (1.9g, productive rate 93.6%).Product point plate is very pure, does not cross the direct down single step reaction of pillar.
(4) synthesis of 5-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) amylamine (E2)
By 5-bromine valeronitrile (5g, 3.13mmol), 6,7-dimethoxy-isoquinoline hydrochloride (8g, 3.49mmol), is dissolved in 150mL DCM, add 30mL triethylamine, 50 DEG C of backflow 10h, cross and filter triethylamine hydrochloride, with saturated sodium bicarbonate and saturated common salt water washing, anhydrous sodium sulfate drying, dry method upper prop, PE:EA=7:3-4:6 crosses pillar, obtain E1 (7.6g, productive rate 87%). 1H NMR(CDCl 3,ppm):δ6.62(s,1H),6.54(s,1H),3.85-3.86(d,6H),3.57(s,2H),2.83-2.86(t,2H),2.71-2.74(t,2H),2.55-2.58(t,2H),2.43-2.45(t,2H),1.76-1.80(m,2H),1.62-1.67(m,2H).
Get E1 (0.7g, 2.55mmol) and be dissolved in 60mL THF, under condition of ice bath, add LiAlH in batches 4(0.8g, 19.5mmol), 65 DEG C of backflows are spent the night.Be cooled to room temperature, slowly add 10mL methyl alcohol cancellation reaction at night, filter and remove solid impurity to reaction, by dichloromethane rinse, decompression is spin-dried for and obtains transparent oily liquid E2 (0.65g, productive rate 94.6%).Product point plate is very pure, does not cross the direct down single step reaction of pillar.
(5) synthesis of 5-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) hexylamine (H2)
By own for 6-bromine nitrile (5.43g, 3.08mmol), 6,7-dimethoxy-isoquinoline hydrochloride (9g, 3.92mmol), is dissolved in 150mL DCM, add 30mL triethylamine, 50 DEG C of backflow 10h, cross and filter triethylamine hydrochloride, with saturated sodium bicarbonate and saturated common salt water washing, anhydrous sodium sulfate drying, dry method upper prop, PE:EA=3:7 crosses pillar, obtain H1 (7.5g, productive rate 84.6%). 1H NMR(CDCl 3,ppm):δ6.61(s,1H),6.54(s,1H),3.84-3.86(d,6H),3.56(s,2H),2.83-2.86(t,2H),2.71-2.74(t,2H),2.51-2.55(t,2H),2.36-2.40(t,2H),1.72-1.76(m,2H),1.65-1.68(m,2H),1.55-1.58(m,2H).
Get H1 (1.6g, 5.56mmol) and be dissolved in 100mL THF, under condition of ice bath, add LiAlH in batches 4(0.8g, 19.5mmol), proceeds to room temperature reaction after 30min, and 65 DEG C of backflows are spent the night.Be cooled to room temperature, slowly add 10mL methyl alcohol cancellation reaction at night, filter and remove solid impurity to reaction, by dichloromethane rinse, decompression is spin-dried for and obtains transparent oily liquid H2 (1.58g, productive rate 97.5%).Product is not without the need to crossing the direct down single step reaction of pillar.
The synthesis of embodiment 2 intermediate W8
By compd A (5,5-dimethyl-hydroresorcinol) (6g, 42.8mmol) be dissolved in 150mL acetonitrile solvent and 18mL triethylamine, agitation and dropping Acetyl Chloride 98Min. (3.2mL under condition of ice bath, 42.8mmol) drip off rear 50 DEG C of reaction 3h room temperature reactions to spend the night, cross and filter triethylamine hydrochloride precipitation, removal of solvent under reduced pressure, resistates 150mL diluted ethyl acetate, be adjusted to acidity with the hydrochloric acid of 2N, saturated common salt is washed, organic over anhydrous Na 2sO 4drying, removal of solvent under reduced pressure, resistates column chromatography (PE:EA=9.5:0.5).Obtain B (7.4g, productive rate 95%).
Get B (2-ethanoyl-5,5-dimethyl-hydroresorcinol) (4g; 0.022mol) be dissolved in 40mL ethanol; then 2.6g mono-hydrazine hydrate is added, stirring at room temperature 24h, the ethanol in decompression removing reaction solution; obtain yellow solid; dissolve with methylene dichloride, direct dry method upper prop, DCM:MeOH=8:2 crosses pillar; obtain W5 (3.6g, productive rate 92%). 1H NMR(CDCl 3,ppm):δ2.71(s,2H),2.57(s,3H),2.38(s,2H),1.13(s,6H).
Get W5 (3,6,6-trimethylammonium-4,5,6,7-indazole-4-ketone) (0.5g, 2.81mmol) 2,4 difluorobenzene formonitrile HCN (0.54g, 3.9mmol) and add 20mL DMSO (Non-aqueous processing), K 2cO 3(5g, 3.6mmol) stirring at room temperature 14h, column chromatographic isolation and purification obtains white solid product W8 (0.839g, productive rate 50%). 1H NMR(CDCl 3,ppm):δ7.75-7.79(m,1H),7.48-7.55(m,2H),2.90(s,2H),2.57(s,3H),2.45(s,2H),1.16(s,6H).
The synthesis of the benzamide that embodiment 32-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replaces
(1) benzamide (J4) of 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) ethylamino-4-tetrahydrochysene indazole replacement
J2 (1.1g, 4.66mmol) and W8 (1.05g, 3.5mmol) is dissolved in 40mL DMSO, adds K 2cO 3(3g, 21.7mmol), 120 DEG C of reactions are spent the night.Cooling room temperature, poured into by reaction solution in 50mL water, filter out filter residue water layer and remove, filter residue acetic acid ethyl dissolution, uses anhydrous sodium sulfate drying.Cross pillar PE:EA=3:7, obtain white solid J3 (1.54g, productive rate 85.6%). 1H NMR(CDCl 3,ppm):δ7.49-7.51(d,1H),6.96(s,1H),6.73-6.75(s,1H),6.63(s,1H),6.53(s,1H),5.63(s,1H),3.87(s,3H),3.85(s,3H),3.66(br,2H),3.53(br,2H),2.92(br,6H),2.87(s,2H),2.56(s,3H),2.42(s,2H),1.13(s,6H).
Get J3 (1g, 1.95mmol) and be dissolved in 10mL DMSO, add the H that KOH (0.4g, 7.1mmol) adds 30% (v/v) again 2o 22h is reacted under solution (1.2mL) room temperature condition, be extracted with ethyl acetate product, with saturated sodium-chloride and saturated sodium carbonate washing organic layer, anhydrous sodium sulfate drying, decompression is spin-dried for, with chloroform: methyl alcohol=99:1-95:5 crosses pillar, obtains yellow look solid product J4 (0.95g, productive rate 91.3%). 1H NMR(CDCl 3,ppm):δ8.23(br,1H),7.43-7.45(d,1H),6.88(s,1H),6.63-6.65(d,1H),6.61(s,1H),6.53(s,1H),5.93(br,2H),3.83-3.84(d,6H),3.69(br,2H),3.44(br,2H),2.85-2.95(br,8H),2.56(s,3H),2.40(s,2H),1.11(s,6H).
(2) benzamide (G4) of 3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) third amino-4-tetrahydrochysene indazole replacement
G2 (2g, 8mmol) and W8 (1.05g, 3.5mmol) is dissolved in 40mL DMSO, adds K 2cO 3(3g, 21.7mmol), 120 DEG C of reactions are spent the night.Cooling room temperature, poured into by reaction solution in 50mL water, filter out filter residue water layer and remove, filter residue acetic acid ethyl dissolution, uses anhydrous sodium sulfate drying.Cross pillar, obtain white solid G3 (1.7g, productive rate 89.5%). 1H NMR(CDCl 3,ppm):δ7.46-7.48(d,1H),6.95(s,1H),6.72-6.74(s,1H),6.59(s,1H),6.51(s,1H),5.68(s,1H),3.86(s,3H),3.84(s,3H),3.71(br,2H),3.45(br,2H),2.87(br,4H),2.80(s,2H),2.75(b,2H),2.55(s,3H),2.35(s,2H),1.09(s,6H).
Get G3 (0.3g, 0.57mmol) and be dissolved in 5mL DMSO, add the H that KOH (0.4g, 7.1mmol) adds 30% (v/v) again 2o 22h is reacted under solution (1.2mL) room temperature condition, be extracted with ethyl acetate product, with saturated sodium-chloride and saturated sodium carbonate washing organic layer, anhydrous sodium sulfate drying, decompression is spin-dried for, with chloroform: methyl alcohol=99:1-95:5 crosses pillar, obtains white solid product G4 (0.28g, productive rate 93%). 1H NMR(CDCl 3,ppm):δ8.14(s,1H),7.48-7.50(d,1H),6.92(s,1H),6.66-6.69(dd,1H),6.58(s,1H),6.51(s,1H),5.75-5.85(br,2H),3.84-3.86(d,6H),3.60(s,2H),3.36-3.37(d,2H),2.75-2.80(m,6H),2.65-2.68(t,2H),2.56(s,3H),2.32(s,2H),1.98-2.01(m,2H),1.08(s,6H).
(3) benzamide (D4) of 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) fourth amino-4-tetrahydrochysene indazole replacement
D2 (1.2g, 4.55mmol) and W8 (1.05g, 3.5mmol) is dissolved in 40mL DMSO, adds K 2cO 3(3g, 21.7mmol), 120 DEG C of reactions are spent the night.Cooling room temperature, poured into by reaction solution in 50mL water, filter out filter residue water layer and remove, filter residue acetic acid ethyl dissolution, uses anhydrous sodium sulfate drying.Cross pillar, obtain white solid D3 (1.65g, productive rate 87.3%).
Get D3 (1.4g, 2.59mmol) and be dissolved in 20mL DMSO, add the H that KOH (0.4g, 7.1mmol) adds 30% (v/v) again 2o 22h is reacted under solution (4mL) room temperature condition, be extracted with ethyl acetate product, saturated sodium-chloride and saturated sodium carbonate washing organic layer, anhydrous sodium sulfate drying, decompression is spin-dried for, with chloroform: methyl alcohol=99:1-95:5 crosses pillar, obtains white solid product D4 (1.38g, productive rate 95%). 1H NMR(CDCl 3,ppm):δ8.10(br,1H),7.48-7.50(d,1H),6.81-6.82(s,1H),6.63-6.65(m,1H),6.60(s,1H),6.54(s,1H),5.75-5.85(br,2H),3.85-3.86(d,6H),3.59(br,2H),3.26-3.28(t,2H),2.82-2.85(m,4H),2.74-2.76(m,2H),2.56-2.60(m,5H),2.42(s,2H),1.80(br,4H),1.12(s,6H).
(4) benzamide (E4) of 5-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) penta amino-4-tetrahydrochysene indazole replacement
E2 (1.4g, 5.04mmol) and W8 (1.05g, 3.5mmol) is dissolved in 20mL DMSO, adds K 2cO 3(2g, 14.5mmol), 120 DEG C of reactions are spent the night.Cooling room temperature, poured into by reaction solution in 50mL water, filter out filter residue water layer and remove, filter residue acetic acid ethyl dissolution, uses anhydrous sodium sulfate drying.Cross pillar PE:EA=6:4-2:8, obtain transparent crystalline solid E3 (1.68g, productive rate v=86.6%).
Get E3 (1.4g, 2.59mmol) and be dissolved in 40mL DMSO, add the H that KOH (0.4g, 7.1mmol) adds 30% (v/v) again 2o 22h is reacted under solution (6mL) room temperature condition, be extracted with ethyl acetate product, saturated sodium-chloride and saturated sodium carbonate washing organic layer, anhydrous sodium sulfate drying, decompression is spin-dried for, with chloroform: methyl alcohol=99:1-95:5 crosses pillar, obtains yellow solid product E4 (1.4g, productive rate 94.6%). 1HNMR(CDCl 3,ppm):δ8.08(br,1H),7.48-7.50(d,1H),6.80(s,1H),6.62-6.65(m,1H),6.60(s,1H),6.54(s,1H),5.75-5.85(br,2H),3.85-3.86(d,6H),3.57(s,2H),3.21-3.25(m,2H),2.83(m,4H),2.72-2.74(m,2H),2.54-2.57(m,5H),2.42(s,2H),1.75-1.78(m,4H),1.53-1.55(m,2H),1.13(s,6H).
(5) benzamide (H4) of 6-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) fourth amino-4-tetrahydrochysene indazole replacement
H2 (1.5g, 5.14mmol) and W8 (0.8g, 2.70mmol) is dissolved in 20mL DMSO, adds K 2cO 3(2g, 14.5mmol) or 6mL DIEA, 120 DEG C of reactions are spent the night.Cooling room temperature, poured into by reaction solution in 50mL water, filter out filter residue water layer and remove, filter residue acetic acid ethyl dissolution, uses anhydrous sodium sulfate drying.Cross pillar PE:EA=6:4-2:8, obtain transparent crystalline solid H3 (1.4g, productive rate 90.9%).
Get H3 (0.6g, 1.05mmol) and be dissolved in 10mL DMSO, add the H that KOH (0.4g, 7.1mmol) adds 30% (v/v) again 2o 22h is reacted under solution (3mL) room temperature condition, be extracted with ethyl acetate product, saturated sodium-chloride and saturated sodium carbonate washing organic layer, anhydrous sodium sulfate drying, decompression is spin-dried for, with chloroform: methyl alcohol=99:1-95:5 crosses pillar, obtains white solid product H4 (0.59g, productive rate 95.7%). 1HNMR(CDCl 3,ppm):δ8.07(br,1H),7.49-7.51(d,1H),6.75-6.79(s,1H),6.60-6.64(m,2H),6.54(s,1H),5.75-5.85(br,2H),3.85-3.86(d,6H),3.64(br,2H),3.19-3.23(m,2H),2.83-2.87(m,6H),2.60-2.65(br,2H),2.56(s,3H),2.42(s,2H),1.70-1.75(m,4H),1.44-1.59(m,4H),1.12(s,6H).
Embodiment 4 compound 2-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline))-4-(1-(3,6,6-trimethylammonium-4,5,6,7-tetrahydrochysene indazole-4-ketone)) benzamide (M4)
6,7-dimethoxy-isoquinoline (1.0g, 5.18mmol) and W8 (1.05g, 3.5mmol) are dissolved in 40mL DMSO, add K 2cO 3(3g, 21.7mmol), 120 DEG C of reactions are spent the night.Cooling room temperature, pours into reaction solution in 50mL water, filters out filter residue water layer and remove, filter residue acetic acid ethyl dissolution, anhydrous sodium sulfate drying.Cross pillar PE:EA=6:4, obtain white solid M3 (1.35g, productive rate 81.8%). 1HNMR(CDCl 3,ppm):δ7.65-7.67(d,1H),7.26(s,1H),6.98-7.00(dd,1H),6.67(s,1H),6.64(s,1H),5.45(s,2H),3.86-3.87(d,6H),3.75-3.78(t,2H),3.00-3.03(t,2H),2.76(s,2H),2.55(s,3H),2.40(s,2H),1.10(s,6H).
Get M3 (1g, 2.13mmol) and be dissolved in 10mlDMSO, add the H that KOH (0.4g, 7.1mmol) adds 30% (v/v) again 2o 22h is reacted under solution (1.2mL) room temperature condition, be extracted with ethyl acetate product, saturated sodium-chloride and saturated sodium carbonate washing organic layer, anhydrous sodium sulfate drying, decompression is spin-dried for, with chloroform: methyl alcohol=99:1-95:5 crosses pillar, obtains white solid product M4 (0.98g, productive rate 94.2%). 1H NMR(CDCl 3,ppm):δ9.16(br,1H),8.30-8.32(d,1H),7.52-7.53(d,1H),7.30-7.31(d,1H),6.70(s,1H),6.60(s,1H),5.71(br,1H),4.19(s,2H),3.88-3.90(d,6H),3.43-3.47(t,2H),3.01-3.04(t,2H),2.80(s,2H),2.57(s,3H),2.43(s,2H),1.13(s,6H).
Embodiment 5 antitumor cytolytic activity
For attached cell (HeLa, SiHa, MDA-MB-231, BT474, A549 and EC9706, all purchased from ATCC company), mtt assay is adopted to detect the anti-tumor activity of tetrahydrochysene indazole compound (D4, H4, E4, J4, G4 and M4).The cell of taking the logarithm vegetative period is inoculated in 96 orifice plates, cell density is 4000/hole, dosing after cultivation 12h, drug level is respectively 0.625 μM, 1.25 μMs, 2.5 μMs, 5 μMs, 10 μMs, 20 μMs and 40 μMs, solvent control group adds isopyknic DMSO makes final concentration be 0.5 ‰, often group establishes 4 parallel holes, is placed in 37 DEG C, 5%CO 224h is cultivated in cell culture incubator.Before experiment stops, 4h adds the MTT solution of the 5mg/mL of 20 μ L, cultivate 4h again, before test, discard nutrient solution, add 150 μ L DMSO, slight oscillatory makes the staining agent in solution dissolve completely for 15 minutes, surveys the OD value in every hole by the universal microplate reader of Bio-Rad in 570nm wavelength.Medicine cell growth inhibiting rate is obtained: inhibitory rate of cell growth (%)=(1-medication group mean OD value/control group mean OD value) × 100% by following formula.IC 50value is the concentration of medicine when inhibitory rate of cell growth reaches 50%.
For suspension cell (K562 and KG-1a, all purchased from ATCC company), CCK-8 method is adopted to detect the anti-tumor activity of tetrahydrochysene indazole compound (D4, H4, E4, J4, G4 and M4).The cell of taking the logarithm vegetative period is inoculated in 96 orifice plates, cell density is 10000/hole, dosing after cultivation 12h, drug level is respectively 0.625 μM, 1.25 μMs, 2.5 μMs, 5 μMs, 10 μMs, 20 μMs and 40 μMs, solvent control group adds isopyknic DMSO makes final concentration be 0.5 ‰, often group establishes 4 parallel holes, is placed in 37 DEG C, 5%CO 224h is cultivated in cell culture incubator.Every hole adds 10 μ L CCK-8 solution, continues to cultivate 3h.Survey the OD value in every hole in 450nm wavelength by the universal microplate reader of Bio-Rad.Medicine cell growth inhibiting rate is obtained: inhibitory rate of cell growth (%)=(1-medication group mean OD value/control group mean OD value) × 100% by following formula.
The restraining effect of table 1 compound on tumor Growth of Cells *
* " ++++" represent IC 50<1 μM; " +++ " represents 1 μM of <IC 50<5 μM; " ++ " represents 5 μMs of <IC 50<20 μM; "+" represents 20 μMs of <IC 50<30 μM; "-" represents IC 50>30 μM or be defined as non-activity.
Result as shown in Table 1, 2-(6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replace benzamide compounds (D4, H4, E4, J4, G4) than 2-(2-(6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline))-4-(1-(3, 6, 6-trimethylammonium-4, 5, 6, 7-tetrahydrochysene indazole-4-ketone)) benzamide (M4) has better anti-tumor activity, show 6, 7-dimethoxy-1, 2, 3, the anti-tumor activity of flexibility on the benzamide compounds that amino-4-tetrahydrochysene indazole replaces of 4-tetrahydroisoquinolisubstituted substituted base has important impact.In general, 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-alkyl) amino-4-tetrahydrochysene indazole replace benzamide compounds to human chronic myeloblastic leukemia K562 and Intrauterine device bleeding growth there is good inhibit activities, to cervical cancer BT474 Growth of Cells, there is medium inhibit activities.In addition, part 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-alkyl) amino-4-tetrahydrochysene indazole replace benzamide compounds dialogue blood patient acute myeloid leukaemia KG-1a Growth of Cells also demonstrate good inhibit activities, part of compounds to Cervical Cancer HeLa Cells, mammary cancer MDA-MB-231 cell and esophageal carcinoma 9706 cells growth demonstrate medium inhibit activities.The restraining effect then more weak or non-activity that this compounds grows lung cancer A549 cell.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.

Claims (10)

1. a benzamide compounds for 2-amino-4-tetrahydrochysene indazole replacement, is characterized in that having the structure shown in formula I:
Wherein, R 1for alkyl; N is natural number.
2. the benzamide compounds of 2-amino-4-tetrahydrochysene indazole replacement according to claim 1, is characterized in that:
Described R 1for methyl, ethyl, propyl or cyclopropane base.
3. the benzamide compounds of 2-amino-4-tetrahydrochysene indazole replacement according to claim 1, is characterized in that:
Described n is 1 ~ 6.
4. the benzamide compounds of 2-amino-4-tetrahydrochysene indazole replacement according to claim 1, is characterized in that:
Described n is 2,3,4 or 5.
5. the benzamide compounds of 2-amino-4-tetrahydrochysene indazole replacement according to claim 1, is characterized in that:
The benzamide compounds that described 2-amino-4-tetrahydrochysene indazole replaces is for having structure shown in formula II:
Wherein, n is 1 ~ 5.
6. the preparation method of the benzamide compounds that the 2-amino-4-tetrahydrochysene indazole described in any one of Claims 1 to 5 replaces, is characterized in that comprising following steps:
(1) synthesis of intermediate 2-(aminoalkyl)-1,2,3,4-tetrahydroisoquinoline:
1. bromo alkyl nitrile and the reaction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are obtained 1,2,3, the 4-tetrahydroisoquinoline that 2-(ω-cyanoalkyl) replaces;
2. 1,2,3, the 4-tetrahydroisoquinoline that the 2-(ω-cyanoalkyl) step 1. obtained replaces and Lithium Aluminium Hydride reduce and obtain 2-(aminoalkyl)-1,2,3,4-tetrahydroisoquinoline;
(2) synthesis of the fluoro-4-of intermediate 2-(3-alkyl-6,6-dimethyl-4-ketone-4,5,6,7-tetrahydrochysene indazole-1-) cyanobenzene:
1. by 5,5-dimethyl-hydroresorcinol and obtained 3-alkyloyl-5, the 5-dimethyl-hydroresorcinol of alkyl acyl chloride reaction;
2. 3-alkyloyl-5,5-dimethyl-hydroresorcinol step 1. obtained and hydrazine hydrate reaction form 3-alkyl-6,6-dimethyl-4,5,6,7-tetrahydrochysene indazole-4-ketone;
3. 3-alkyl-6,6-dimethyl-4,5,6,7-tetrahydrochysene indazole-4-ketone step 2. obtained and 2,4 difluorobenzene formonitrile HCN are obtained by reacting the fluoro-4-of 2-(3-alkyl-6,6-dimethyl-4-ketone-4,5,6,7-tetrahydrochysene indazole-1-) cyanobenzene;
(3) synthesis of the benzamide compounds of 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replacement:
1. by 2-(aminoalkyl)-1 obtained for step (1), the fluoro-4-of 2-(the 3-alkyl-6 that 2,3,4-tetrahydroisoquinoline and step (2) obtain, 6-dimethyl-4-ketone-4,5,6,7-tetrahydrochysene indazole-1-) the obtained 2-(6 of cyanobenzene reaction, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replace cyanobenzene compound;
2. the 2-(6 1. step obtained, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replace cyanobenzene compound and hydrogen peroxide react, obtain final product 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-) alkylamino-4-tetrahydrochysene indazole replace benzamide compounds, be 2-amino-4-tetrahydrochysene indazole replace benzamide compounds.
7. the benzamide compounds that the 2-amino-4-tetrahydrochysene indazole described in any one of Claims 1 to 5 replaces is preparing the application in antitumor drug.
8. the benzamide compounds that 2-amino-4-tetrahydrochysene indazole according to claim 7 replaces is preparing the application in antitumor drug, it is characterized in that:
Described antitumor drug refers at least one in the benzamide compounds that 2-amino-4-tetrahydrochysene indazole described in any one of Claims 1 to 5 replaces or its pharmaceutical salts or solvate.
9. the benzamide compounds that 2-amino-4-tetrahydrochysene indazole according to claim 8 replaces is preparing the application in antitumor drug, it is characterized in that:
The pharmaceutical salts of the benzamide compounds that described 2-amino-4-tetrahydrochysene indazole replaces comprises the hydrochloride of the benzamide compounds that the 2-amino-4-tetrahydrochysene indazole described in any one of Claims 1 to 5 replaces, vitriol, phosphoric acid salt, nitrate, hydrobromate, oxalate, maleate, Citrate trianion, acetate, lactic acid salt, sulfonate, tosilate, mesylate, tartrate or succinate.
10. the benzamide compounds that 2-amino-4-tetrahydrochysene indazole according to claim 7 replaces is preparing the application in antitumor drug, it is characterized in that:
Described antitumor drug contains one or more pharmaceutically acceptable carrier, vehicle or thinners.
CN201510051927.2A 2015-01-30 2015-01-30 2-amino-4-tetrahydroindazole substituted benzamide compounds and application of compound in preparing anti-tumor drugs Pending CN104592203A (en)

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