CN106316942A - A kind of Combretastatin A-4 analogs with a condensed ring structure as well as a preparation method, pharmaceutical compositions and applications thereof - Google Patents
A kind of Combretastatin A-4 analogs with a condensed ring structure as well as a preparation method, pharmaceutical compositions and applications thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides Combretastatin A-4 (CA-4) analogs with a condensed ring structure or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal form or diastereoisomers thereof as shown in the following formula I and II, and applications of the compounds or compositions to treatment/prevention of cancer related diseases. Test results for resisting proliferation and inhibiting activity show that the CA-4 analogs can effectively inhibit proliferation of a plurality of tumor cells; tubulin aggregation inhibition tests show that the compounds can inhibit aggregation of tubulin in vitro, so that cell cycle is influenced, apoptosis of tumor cells is induced, and effects for prevention or treatment of cancers are shown. The Combretastatin A-4 (CA-4) analogs with a condensed ring structure are shown in the formula I and II, wherein R1, R2, R3, R4, R5, R6, R7, R8, and R9 in the formula I and II are shown in the specification.
Description
Technical field
The invention belongs to pharmaceutical chemistry and pharmacotherapeutics field, be specifically related to a class and there is the Combretastatin of condensed cyclic structure
A-4 (CA-4) analog and preparation method thereof, pharmaceutical composition and its application in preparation cancer treatment drugs.
Background technology
Malignant tumor is the common disease of a kind of serious threat human health.Find effective antitumour medicine and method, thoroughly capture
Cancer, is a global difficult problem.Although the chemical constitution of antitumor drug and mechanism of action are diversified, but mesh
Before antitumor drug conventional clinically generally there is, toxic and side effects poor to solid tumor curative effect and produce greatly and easily multidrug resistance
Many defects such as property.Consequently found that the new type antineoplastic medicine of high-efficiency low-toxicity, it is still an extremely important research topic.
Antitubulin is the very important antitumor drug of class applied clinically at present.They act on micro-pipe of cell
Albumen, thus stop the normal mitosis of cell.This kind of medicine major part all derives from natural product, specifically includes that autumn waters--limid eyes
Celestial alkali, camptothecine, vinblastine, paclitaxel and podophyllotoxin etc..
Micro-pipe is to be widely present in the kytoplasm of eukaryotic cell, by the tubular polymer of two kinds of tubulin polymerizations of α β.As
Constituting one of main component of cytoskeleton, micro-pipe is maintaining cellular morphology, the transport of material in the contraction of participation cell and kytoplasm
Etc. aspect play an important role.Especially it forms spindle in prophase of cell division depolymerization restructuring and participates in cell mitogenic and divide
This special biological function in splitting makes the important target spot of antitumor drug.Tumor cell has the energy of fast breeding
Power, if suppressing the formation of its spindle, will affect being normally carried out of cell mitogen so that growth of tumour cell stagnate in
The G2/M phase.The earlier 1900s taxanes medicine with micro-pipe as target spot successful Application clinically has evoked people and has found and change
Make the great interest of novel micro-tubing target drug.Although constantly paclitaxel is carried out people structure of modification and modification but it is water-soluble
Property poor, be easily generated the problems such as multidrug resistance and toxic and side effects are strong and still limit its extensive utilization clinically.Find novel
One of micro-pipe target drug focus being always antitumor drug area research, until National Cancer Institute in 1987
Pettit etc. are found that natural active product CA-4 from the short raw willow in South Africa (Combretum caffrum).CA-4 is a class knot
Structure simple cis-stilbene compounds, it is one of compound that in the Antitubulin being currently known, activity is the strongest.
But CA-4 poorly water-soluble, bioavailability are low, and after being administered CA-4 to be easy to be changed into the structure of parmacodynamics-less activity relative
Stable transconfiguration.Therefore, in order to overcome this shortcoming, the structure around CA-4 is transformed the most in recent years, makees
Substantial amounts of work, has synthesized hundreds of CA-4 derivants.(Anti-Cancer Drug Design, 1995,10,299-309;
Journal of Medicinal Chemistry, 2013,56,685-699;Current Medicinal Chemistry 2011,18,
523-538;Current Medicinal Chemistry 2003,10,1697-1722;Journal of Medicinal Chemistry
2015,58,692-704)
Summary of the invention
It is an object of the invention to the shortcoming overcoming CA-4 to be easily changed into parmacodynamics-less activity transconfiguration, it is provided that series of stable
Property CA-4 analog representated by I or II formula good, following, its architectural feature is: in the compound representated by I and II two formula,
All having amide structure on B ring: I series represents B ring and C condenses, ii represents A ring and B ring condenses.
It is a further object of the present invention to provide the preparation method of a kind of above-claimed cpd.
A further object of the present invention is to provide a kind of antitumor medicine composition.
It is a further object to provide above-claimed cpd purposes in terms of preparing anti-tumor drug.
The purpose of the present invention is achieved through the following technical solutions:
In first aspect the present invention provide such as the acceptable prodrug of compound or its pharmaceutical college of following formula I, salt, hydrate,
Solvate, crystalline forms or diastereomer:
Wherein:
X is CH2、CHF、CF2;
N is 0,1,2;
R1For H, OCH3、OCF3、OH;
R2, R3, R4, R5, R6 the most independent for H, halogen, C1-4Alkyl, CH2F、CHF2、CF3、CN、
NO2、OH、C1-4Alkyl OH, OC1-4Alkyl, OCF3、CO2R8、NR8R9、CONR8R9;Wherein R8、R9Respectively
From independently be H, C1-4Alkyl, maybe can be connected to form 3-6 ring;
R7For H, C1-6Alkyl, maybe can be connected to form 3-6 ring.
In second aspect, the present invention provides the compositions of the compound comprising carrier and at least one first aspect present invention.
The method that the present invention provides a kind for the treatment of/prophylaxis of cancer relevant disease in a third aspect, the method includes that drug treatment is effective
The compound of at least one first aspect of amount or the compositions of second aspect.
At the 4th aspect, the present invention provide such as the acceptable prodrug of compound or its pharmaceutical college of Formula Il, salt, hydrate,
Solvate, crystalline forms or diastereomer:
Wherein:
X is CH2、CHF、CF2;
N is 0,1,2;
R1For H, OCH3、OCF3、OH;
R2, R3, R4, R5, R6 the most independent for H, halogen, C1-4Alkyl, CH2F、CHF2、CF3、CN、
NO2、OH、C1-4Alkyl OH, OC1-4Alkyl, OCF3、CO2R8、NR8R9、CONR8R9;Wherein R8、R9Respectively
From independently be H, C1-4Alkyl, maybe can be connected to form 3-6 ring;
R7For H, C1-6Alkyl, maybe can be connected to form 3-6 ring.
In the 5th aspect, the present invention provides the compositions of the compound comprising carrier and at least one fourth aspect present invention.
The method that the present invention provides a kind for the treatment of/prophylaxis of cancer relevant disease in the 6th aspect, the method includes that drug treatment is effective
The compound of at least one fourth aspect of amount or the compositions of the 5th aspect.
Formula I shown in the present invention and II representation compound are as shown in table 1, but the scope of the present invention is not by table 1 compound example
The restriction of son.
Detailed description of the invention
The preparation of embodiment 1. compound 7-methoxyl group-4-(3,4,5-trimethoxyphenyl) quinoline-2 (1H) ketone (I-1)
The preparation of the first step (3,4,5-trimethoxyphenyl-4'-methoxyl groups-2 '-acetylamino) ketone.
By 3-p-methoxyacetanilide (1.0equi), 3,4,5-Trimethoxybenzaldehyde (2.0equi), Pd (OAc)2(0.05
Equiv), Polyethylene glycol-2000 (0.2equiv) and water add in reactor, after stirring 2 minutes, add under room temperature
Tert-butyl hydroperoxide (4.0equiv), trifluoroacetic acid (0.26equiv) continues to react 12 hours at 40 DEG C.Will
Reaction system is as cold as room temperature, adds unsaturated carbonate potassium solution, was both extracted with ethyl acetate.Separate and merge organic facies,
Saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and removal of solvent under reduced pressure obtains crude product, column chromatography for separation (ethyl acetate:
Petroleum ether, 1: 1) pure (3,4,5-trimethoxyphenyl-4'-methoxyl groups-2 '-acetylamino) ketone product.Productivity:
91%;Fusing point .156.7-157.9 DEG C;1H NMR (400MHz, CDCl3) δ 11.30 (s, 1H), 8.35 (d, J=2.4Hz,
1H), 7.56 (d, J=8.9Hz, 1H), 6.89 (s, 2H), 6.59 (d, J=8.9Hz, 1H), 3.93 (s, 3H), 3.91 (s,
3H), 3.87 (s, 6H), 2.24 (s, 3H).13C NMR (101MHz, CDCl3) δ 197.82,169.41,164.45,
152.83,143.47,141.55,135.65,134.40,115.82,108.81,107.22,105.12,60.90,56.28,55.60,
25.37.
The preparation of second step 7-methoxyl group-4-(3,4,5-trimethoxyphenyl) quinoline-2 (1H) ketone (I-1).
3 that the first step is obtained, 4,5-trimethoxyphenyls-4 '-methoxyl group-2 '-acetylamino) ketone is dissolved in DMF
(DMF), in solution, add the Feldalat NM of 10 times of equivalents, reflux 12 hours.Removal of solvent under reduced pressure, dichloromethane extraction.
Saturated aqueous common salt is washed by extracting solution, and anhydrous sodium sulfate is dried, and filters, and removes the crude product of solvent, then obtains through silica gel column chromatography
Product.Productivity: 52.2%;Fusing point: 261.9-262.6 DEG C;1H NMR (400MHz, CDCl3) δ 11.99 (s, 1H), 7.54 (d, J
=9.0Hz, 1H), 6.89 (d, J=2.4Hz, 1H), 6.79 (dd, J=9.0,2.4Hz, 1H), 6.67 (s, 2H), 6.54 (s, 1H),
3.94 (s, 3H), 3.93 (s, 3H), 3.89 (s, 6H).13C NMR (101MHz, CDCl3) δ 164.61,161.93,153.40,
153.31,140.87,138.44,132.93,128.08,117.38,113.73,112.35,106.13,98.69,60.97,56.28,55.73.
HRMS(ESI)(m/z)[M+H]+calcd for C19H19NO5, 342.1336;Found, 342.1340.Purity:98.3% (by
HPLC).
The preparation of embodiment 2.8-methoxyl group-5-(3,4,5-trimethoxyphenyl)-1H-benzo [b] azatropylidene-2 (3H) ketone (I-13)
The preparation of first step nitrogen-(5-methoxyl group-2-(3,4,5--trimethoxy) phenyl)-2-carbonyl propionic acid amide.
By nitrogen-(3-methoxyphenyl)-2-carbonyl propionic acid amide. (1.0equi), 3,4,5-Trimethoxybenzaldehyde (2.0equi), Pd (TFA)
In 2 (0.05equi), and toluene addition reactor, after stirring two minutes, add tert-butyl hydroperoxide (4equi) under room temperature, continue
React 12 hours at 80 DEG C.Reaction system is cooled to room temperature, adds unsaturated carbonate potassium solution, be extracted with ethyl acetate.
Separating organic facies, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and removal of solvent under reduced pressure obtains crude product.Column chromatography for separation (second
Acetoacetic ester: petroleum ether=1: 3) obtain purity nitrogen-(5-methoxyl group-2-(3,4,5--trimethoxy) phenyl)-2-carbonyl propionic acid amide., produce
Rate 64%, fusing point: 172.4-173.3 DEG C;1H NMR (400MHz, CDCl3) δ 7.82 (s, 1H), 7.38 (s, 1H), 6.92 (t, J
=1.0Hz, 3H), 3.89 (s, 6H), 3.83 (s, 3H), 3.81 (s, 3H), 2.26 (s, 3H).13C NMR (101MHz, CDCl3)δ
199.24,191.89,162.46,160.70,153.89,143.61,141.13,131.97,129.84,123.49,109.04,106.03,
104.1,60.65,56.79,56.04,25.06.
Second step 8-methoxyl group-5-(3,4,5-trimethoxyphenyl)-1H-benzo [b] azatropylidene-2, the preparation of 3-diketone
The nitrogen first step obtained-(5-methoxyl group-2-(3,4,5--trimethoxy) phenyl)-2-carbonyl propionic acid amide. is dissolved in N, N-dimethyl
In Methanamide (DMF), add the Feldalat NM of 10 times of equivalents, react 12 hours at 90 DEG C.Removal of solvent under reduced pressure, dichloromethane
Alkane extracts.Separating organic facies, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and removal of solvent under reduced pressure obtains crude product.Column chromatography
Separate to obtain 8-methoxyl group-5-(3,4,5-trimethoxyphenyl)-1H-benzo [b] azatropylidene-2,3-diketone.Productivity: 53.4%;Fusing point:
201.3-202.1℃.1H NMR (4MHz, CDCl3) δ 8.36 (s, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 6.91 (s, 1H),
6.83 (s, 1H), 6.82-6.79 (m, 2H), 3.88 (s, 6H), 3.82 (s, 3H), 3.81 (s, 3H).13C NMR (101MHz,
CDCl3) δ 179.98,160.36,158.52,152.63,151.11,141.75,139.33,134.70,131.72,128.98,125.64,
110.06,108.22,104.15,60.65,56.79,56.04.
The preparation of the 3rd step 8-methoxyl group-5-(3,4,5-trimethoxyphenyl)-1H-benzo [b] azatropylidene-2 (3H) ketone
8-methoxyl group-5-(3,4,5-trimethoxyphenyl)-1H-benzo [b] azatropylidene-2 obtained by second step, 3-diketone is dissolved in ethylene glycol
In, add 10 times of equivalent hydrazine hydrates, 100 DEG C are stirred 1 hour, add the potassium hydroxide of 3 times of equivalents, and 180 DEG C are stirred overnight.
Reaction system being cooled to room temperature, adds water, dilute hydrochloric acid adjusts PH to neutral.Dichloromethane extracts, and separates organic facies, saturated
Brine It, anhydrous sodium sulfate is dried, and removal of solvent under reduced pressure obtains crude product.Column chromatography for separation obtains product.Productivity: 61.4%;
Fusing point: 211.6-212.1 DEG C.1H NMR (400MHz, CDCl3) δ 7.73 (s, 1H), 7.36 (s, 1H), 7.03 (s, lH), 6.77 (s,
1H), 6.66-6.50 (m, 2H), 6.39 (s, 1H), 3.88 (s, 6H), 3.83 (s, 3H), 3.80 (s, 3H), 2.90 (s, 2H).13C
NMR (101MHz, CDCl3) δ 173.17,157.08,153.11,140.20,139.88,138.64,136.23,128.91,127.89,
124.21,107.61,105.00,104.26,60.65,56.78,56.03,37.23.HRMS found (ESI) (M+H)+356.3848
C20H21NO5.requires 356.3844.Purity:97.4% (by HPLC).
The preparation of embodiment 3. compound 6,7,8-trimethoxy-4-(4-methoxyphenyl) quinoline-2 (1H) ketone (II-1).
The preparation of first step nitrogen-(6-(3-hydroxyl-4-methoxyphenyl)-2,3,4-trimethoxyphenyls) acetamide
By 2,3,4-trimethoxy acetanilide (1.0equi), 4-methoxyl group-3-(methoxymethoxy) benzaldehyde (2.0equi), Pd
(TFA)2(0.05equi), and toluene adds in reactor, after stirring two minutes, adds tert-butyl hydroperoxide (4equi) under room temperature,
Continue to react 12 hours at 80 DEG C.Reaction system is cooled to room temperature, adds unsaturated carbonate potassium solution, extract by ethyl acetate
Take.Separating organic facies, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and removal of solvent under reduced pressure obtains crude product.Column chromatography for separation
(ethyl acetate: petroleum ether=1: 3) obtains purity nitrogen-(6-(3-hydroxyl-4-methoxyphenyl)-2,3,4-trimethoxyphenyls) acetyl
Amine, productivity 63%;Fusing point 178.3-178.9 DEG C;1H NMR (400MHz, DMSO) δ 7.47 (s, 1H), 7.45 (d, J=1.4
Hz, 1H), 7.13 (s, 1H), 7.10 (d, J=7.2Hz, 1H), 4.87 (s, 2H), 3.87 (d, J=8.2Hz, 6H), 3.81 (d, J=
5.1Hz, 6H), 3.39 (s, 3H), 2.07 (s, 3H) .13C NMR (100MHz, Common NMR Solvents) δ 198.09,
185.64,170.79,153.90,150.68,146.18,142.90,140.28,136.54,131.05,125.68,124.60,113.25,
113.05,107.35,105.00,97.97,60.65,56.78,55.45,23.79 ,-17.48.
Second step 6,7, the preparation of 8-trimethoxy-4-(4-methoxyl group-3-(methoxymethoxy) phenyl) quinazoline-2 (1H) ketone
6 that the first step is obtained, 7,8-trimethoxy-4-(4-methoxyl group-3-(methoxymethoxy) phenyl) quinazoline-2 (1H) ketone
Being dissolved in DMF (DMF) solution, the Feldalat NM adding ten times of equivalents refluxes 12 hours.Pressurization removes
Methylene chloride is extracted, and saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, and removes solvent, obtains through column chromatography purification
Product.Productivity 65.1%, fusing point 198..1-198.5 DEG C.1H NMR (400MHz, DMSO) δ 7.95 (s, 1H), 7.17 (s, 1H),
7.05 (dd, J=7.5,1.5Hz, 1H), 6.94 (dd, J=20.3,4.4Hz, 2H), 6.76 (s, 1H), 4.87 (s, 2H), 3.94-
3.84 (m, 9H), 3.80 (s, 3H), 3.40 (s, 3H).13C NMR (100MHz, Common NMR Solvents) δ 185.64,
181.80,180.45,162.00,151.70,148.75,146.22,143.41,143.17,135.41,132.18,131.78,125.69,
124.78,119.58,118.27,113.59,106.80,105.00,97.97,60.65,56.78,55.45 ,-1.86 ,-18.20.
The preparation of the 3rd step 4-(3-hydroxyl-4-methoxyphenyl)-6,7,8-trimethoxy quinoline-2 (1H) ketone (II-1).
4-(3-hydroxyl-4-methoxyphenyl)-6,7, the 8-trimethoxy quinazolines-2 (1H)-be dissolved among ethanol obtained by second step, add
Concentrated hydrochloric acid, is stirred at room temperature reaction 4 hours, and after reaction terminates, the dichloromethane that adds water extracts, and organic facies anhydrous sodium sulfate is dried
Afterwards, removal of solvent under reduced pressure, crude product obtains target product after recrystallization.Productivity 51%;M.p:235.3.0-236.1 DEG C;1H
NMR (400MHz, CDCl3) δ 9.16 (s, 1H), 7.42 (t, J=7.9Hz, 1H), 7.04-7.01 (m, 2H), 6.98-6.96
(m, 1H), 6.76 (s, 1H), 6.56 (s, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 3.86 (s, 3H), 3.74 (s, 3H).13C NMR
(101MHz, CDCl3) δ 161.72,152.14,149.04,147.22,145.79,143.86,139.06,130.37,127.62,
120.55,120.51,115.09,115.04,110.81,103.44,61.39,61.20,56.25,56.04.HRMS (ESI) (m/z)
[M+H]+calcd for C19H19NO6, 359.1218;Found, 359.1329.Purity:98.9% (by HPLC).
Embodiment 47,8, the preparation of 9-trimethoxy-5-(4-methoxyphenyl)-1H-benzo [b] azatropylidene-2 (3H) ketone (II-8)
The preparation of first step 2-carbonyl-nitrogen-(2,3,4-trimethoxy-6-(4-anisoyl) phenyl) propionic acid amide.
By 2-carbonyl-nitrogen-(2,3,4-trimethoxyphenyl) propionic acid amide. (1.0equi), 4-methoxybenzaldehyde (2.0equi), Pd (TFA)
In 2 (0.05equi), and toluene addition reactor, after stirring two minutes, add tert-butyl hydroperoxide (4equi) under room temperature, continue
React 12 hours at 80 DEG C.Reaction system is cooled to room temperature, adds unsaturated carbonate potassium solution, be extracted with ethyl acetate.
Separating organic facies, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and removal of solvent under reduced pressure obtains crude product.Column chromatography for separation (second
Acetoacetic ester: petroleum ether=1: 3) obtain pure 2-carbonyl-nitrogen-(2,3,4-trimethoxy-6-(4-anisoyl) phenyl) propionyl
Amine, productivity 66%, fusing point: 168.7-169.4 DEG C.1H NMR (400MHz, CDCl3) δ 9.55 (s, 1H), 7.77-7.63 (m,
2H), 7.17 (s, 1H), 7.09-6.95 (m, 2H), 3.93 (s, 6H), 3.91 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 2.19 (s,
3H).13C NMR (101MHz, CDCl3) δ 198.10,191.89,163.23,160.48,151.25,143.19,141.34,
139.12,131.80,129.91,125.17,112.63,106.81,60.65,56.78,56.03,25.05.
Second step 7,8,9-trimethoxy-5-(4-methoxyphenyl)-1H-benzo [b] azatropylidene-2, the preparation of 3-diketone
2-carbonyl-the nitrogen first step obtained-(2,3,4-trimethoxy-6-(4-anisoyl) phenyl) propionic acid amide. is dissolved in N, N-
In dimethylformamide (DMF), add the Feldalat NM of 10 times of equivalents, react 12 hours at 90 DEG C.Removal of solvent under reduced pressure,
Dichloromethane extraction.Separating organic facies, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and removal of solvent under reduced pressure obtains crude product.
Column chromatography for separation obtains 7,8,9-trimethoxy-5-(4-methoxyphenyl)-1H-benzo [b] azatropylidene-2,3-diketone.Productivity: 55.4%;
Fusing point: 203.3-204.1 DEG C1H NMR (400MHz, CDCl3) δ 8.62 (s, 1H), 7.61-7.47 (m, 2H), 7.11 (s, 1H),
7.09-7.00 (m, 3H), 6.66 (s, 1H), 3.94 (s, 6H), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H).13C NMR
(125MHz, Common NMR Solvents) δ 179.97,160.84,159.19,150.89,148.94,141.72,141.44,
135.93,133.20,132.24,131.84,129.73,113.43,109.05,60.65,56.78,56.03.
3rd step 7, the preparation of 8,9-trimethoxy-5-(4-methoxyphenyl)-1H-benzo [b] azatropylidene-2 (3H) ketone (II-8)
7 obtained by second step, 8,9-trimethoxy-5-(4-methoxyphenyl)-1H-benzo [b] azatropylidene-2,3-diketone is dissolved in ethylene glycol
In, add 10 times of equivalent hydrazine hydrates, 100 DEG C are stirred 1 hour, add the potassium hydroxide of 3 times of equivalents, and 180 DEG C are stirred overnight.
Reaction system being cooled to room temperature, adds water, dilute hydrochloric acid adjusts PH to neutral.Dichloromethane extracts, and separates organic facies, saturated
Brine It, anhydrous sodium sulfate is dried, and removal of solvent under reduced pressure obtains crude product.Column chromatography for separation obtains product.Productivity: 65.4%;
Fusing point: 217.6-218.3 DEG C.1H NMR (400MHz, CDCl3) δ 7.43-7.29 (m, 2H), 7.27 (s, 1H), 6.98-6.84
(m, 2H), 6.76 (s, 1H), 6.39 (s, 1H), 3.92-3.84 (m, 9H), 3.79 (s, 3H), 2.90 (s, 2H).13C NMR(101
MHz, CDCl3) δ 171.90,157.76,149.08,141.95,139.23,137.87,135.02,132.95,130.85,128.82,
126.95,113.48,108.84,60.65,56.78,56.03,37.23.HRMS found (ESI) (M+H)+356.3848
C20H21NO5.requires 356.3844.Purity:99.7% (by HPLC).
Embodiment 5 antiproliferative inhibitory activity is tested
Cell is cultivated: cell strain used in this patent has: A549 (human lung carcinoma cell line), Bel-7402 (human hepatoma cell strain),
Hela (human cervical carcinoma cell lines), MCF-7 (Breast cancer lines), MGC-803 (human stomach cancer cell line).Five kinds thin
Born of the same parents are all incubated at the hyclone containing 10% heated inactivation, 100U/mL penicillin, the DMEM of 100 μ g/mL streptomycins
In high glucose medium, in 37 DEG C, 5%CO2The incubator of saturated humidity is cultivated.
Antiproliferative inhibitory activity method of testing: use the synthesized compound increasing to five kinds of man-machine systems of MTT method test in this patent
Grow inhibitory activity.Concrete operation step is as follows: after being in the cell trypsinization of exponential phase, with 5 × 104Individual/hole
Density is laid in 96 orifice plates, after continuing to cultivate 24h, inhales the pastille culture medium abandoning old culture medium addition variable concentrations, each
Medicine arranges six concentration, and each concentration arranges three multiple holes.After 48h is cultivated in dosing, add the MTT of 5mg/mL to every hole
Solution, inhales after cultivating 4h and abandons culture medium, and after every hole adds the DMSO of 150 μ L, on horizontal shaker, lucifuge places 15min
The absorbance under 570nM is read by microplate reader after dissolving crystallized purple.Calculate cell growth according to absorbance with formula once to press down
Rate processed: suppression ratio %=(1-(ADosing-ABlank)/(Acontrol-ABlank)) * 100% (note: ADosing, ABlank, AcontrolRespectively
Represent medicine feeding hole, blank well, the absorbance of control wells.
Embodiment 6 tubulin assembles inhibition test
Tubulin assembles the suppression method of testing test kit description with reference to Cytoskeleton (BK110P, Denver, CO) company.Tool
Body operational approach is: configures Tubulin working solution according to the explanation of test kit, preserves on ice, by testing compound DMSO
It is diluted to 10 different × test concentrations, 5ul sample solution is added in 96 orifice plates, then 96 orifice plates are placed on 37 DEG C of enzyme marks
In instrument, preheating 1min, adds 50ul Tubulin working solution to every hole, mixes by moderate speed, and avoids bubble to produce,
Reading immediately after mixing, reading excitation wavelength in microplate reader is 360nm, the fluorescent value under a length of 450rm of transmitted wave, every 1
Min reading once, reads the fluorescent value of 90min altogether.Suppression ratio %=(1-(the A that tubulin is assembled by variable concentrationsDosing-ABlank)/(Acontrol-ABlank)) * 100% (note: ADosing, ABlank, AcontrolRepresent medicine feeding hole respectively, blank well, control wells
Fluorescent value, then utilizes GraphPad Prism 5 software to obtain each compound IC to Antitubulin activity5oValue.
Result
Table 1 shows the activity of a series of compound.The concentration of 10 μMs, there is the suppression change higher than the ability of 50% cell growth
Compound be labeled as "+";The compound label grown at 10 μMs of cells that can not suppress 50% is "-".Undeterminate compound label
For " NT ".Equally, 20 μMs can suppress more than 50% tubulin polymerization compound label for "+",
The compound label of 20 μMs of tubulin polymerizations that can not suppress 50% is "-".Undeterminate compound label is " NT ".
Table 1
Claims (6)
1. the compound shown in following formula I or its pharmaceutically acceptable prodrug, salt, hydrate, solvate, crystalline forms or non-
Enantiomer:
Wherein:
X is CH2、CHF、CF2;
N is 0,1,2;
R1For H, OCH3、OCF3、OH;
R2, R3, R4, R5, R6 the most independent for H, halogen, C1-4Alkyl, CH2F、CHF2、CF3、CN、NO2、
OH、C1-4Alkyl OH, OC1-4Alkyl, OCF3、CO2R8、NR8R9、CONR8R9;Wherein R8、R9The most solely
It is on the spot H, C1-4Alkyl, maybe can be connected to form 3-6 ring;
R7For H, C1-6Alkyl, maybe can be connected to form 3-6 ring.
2. the application in the medicine of preparation treatment/prophylaxis of cancer relevant disease of the compound described in claim 1.
3. for treating/pharmaceutical composition of prophylaxis of cancer relevant disease, it comprises compound described in claim 1, optionally
Also comprise pharmaceutically acceptable adjuvant.
4. the compound shown in formula II below or its pharmaceutically acceptable prodrug, salt, hydrate, solvate, crystalline forms or
Diastereomer:
Wherein:
X is CH2、CHF、CF2;
N is 0,1,2;
R1For H, OCH3、OCF3、OH;
R2, R3, R4, R5, R6 the most independent for H, halogen, C1-4Alkyl, CH2F、CHF2、CF3、CN、NO2、
OH、C1-4Alkyl OH, OC1-4Alkyl, OCF3、CO2R8、NR8R9、CONR8R9;Wherein R8、R9The most solely
It is on the spot H, C1-4Alkyl, maybe can be connected to form 3-6 ring;
R7For H, C1-6Alkyl, maybe can be connected to form 3-6 ring.
5. the application in the medicine of preparation treatment/prophylaxis of cancer relevant disease of the compound described in claim 4.
6. for treating/pharmaceutical composition of prophylaxis of cancer relevant disease, it comprises compound described in claim 4, optionally
Also comprise pharmaceutically acceptable adjuvant.
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Cited By (2)
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CN109320456A (en) * | 2018-11-16 | 2019-02-12 | 天津商业大学 | Antitumoral compounds of novel crystal forms and preparation method thereof and composition containing it |
WO2020071550A1 (en) * | 2018-10-04 | 2020-04-09 | 京都薬品工業株式会社 | Cdk8 inhibitor and use of same |
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2015
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WO2020071550A1 (en) * | 2018-10-04 | 2020-04-09 | 京都薬品工業株式会社 | Cdk8 inhibitor and use of same |
CN109320456A (en) * | 2018-11-16 | 2019-02-12 | 天津商业大学 | Antitumoral compounds of novel crystal forms and preparation method thereof and composition containing it |
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