CN106632050A - Benzoindazole derivative, preparation method and applications thereof - Google Patents
Benzoindazole derivative, preparation method and applications thereof Download PDFInfo
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Abstract
The present invention relates to a benzoindazole derivative, a preparation method and applications thereof, wherein the structural general formula of the benzoIndazole derivative is defined in the specification, R1 is selected from hydrogen, alkoxy, halogen, nitro, amino, and an oxygen substituent, R2 is selected from hydrogen and alkoxy, and R3 is selected from hydrogen, straight chain alkyl, substituted alkyl, aryl, carboxylic acid, and carboxylic acid ester. According to the present invention, the benzoindazole derivative can inhibit tubulin polymerization, has antitumor activity in leukemia, non-small cell lung cancers, colon cancers, central nervous system neoplasms, melanoma, ovarian cancers, kidney cancers, prostate cancers, breast cancers and the like, and has low cytotoxicity.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, is benzo indazole analog derivative and its preparation specifically
Method, application.
Background technology
Tumour, particularly malignant tumour, seriously threaten the health of the mankind.The World Health Organization (WHO)
Issue《Global cancer report 2014》Show, developing country's cancer of Africa, Asia and Central and South America
Disease morbidity situation is the severeest.The whole world increases altogether 14,000,000 cases of cancers newly and has 8,200,000 people dead within 2012
Die.Wherein, China increases 3,070,000 cancer patients newly and causes about 2,200,000 people dead, and global total amount is accounted for respectively
21.9% and 26.8%.The global cases of cancer of this report prediction will be presented swift and violent growing trend, by 2012
14,000,000 people in year, 19,000,000 people of cumulative year after year to 2025 were up to 24,000,000 by 2035
People.Although antineoplastic is to extend the life span of patient and improve its quality of life to be made that very big tribute
Offer, but most drug is cell toxicity medicament, and it lacks selectively can injure substantial amounts of normal cell, and
And easily there is drug resistance, so, vascular targeting agents become study hotspot.
Micro-pipe is made up of tubulin and microtubule bindin, is the main component for constituting cytoskeleton.Micro-pipe
There is the dynamics of polymerization and depolymerization, in the group for keeping cellular morphology, the division growth of cell, organelle
Play a significant role into the conduction aspect with transport and semiochemicals.Antineoplastic with micro-pipe as target spot is just
It is to utilize its dynamics, or promotes its depolymerization or suppress it to be polymerized, so as to reach cell is directly affected
Mitosis, affects many normal physiological functions of cell, makes cell division stop at the M phases.Research table
There are 3 different drug binding sites in bright micro-pipe：Taxol site, vincristine site and colchicin
Site.Because colchicin site cavity volume is less and the structure of corresponding inhibitor is relatively simple, thus closely
Also receive much concern with regard to the research of its inhibitor over year.
The inhibitor Effects of Colchicine In Treating window that the site is originally found is narrower, limits its clinical practice.And two
The discovery of phenylethylene natural products inhibitor combretastatins causes the very big concern of researcher, generation
Table compound Combretastatin A-4 (CA-4), shows very high microtubule polymerization inhibitory action and resists swollen
Tumor activity, also shows tumor vessel blocking effect.Researcher has carried out substantial amounts of structure of modification to CA-4,
There are multiple analogs to enter clinical research at present, show good development prospect.Wherein CA-4P is 2013
July in year, Europe drug administration authorized the Orphan drug status of its treatment oophoroma, and current CA-4P is not dividing
Change and carried out clinical research in thyroid cancer, NET and oophoroma.
Chinese patent literature CN201510064131.0 discloses a kind of replacement benzylidene tetralone class and spreads out
Biology, chemical structural formula is：
Wherein, X represents that CHOH or C=O, R represent H, OH, F, Cl, CN, CONH2、NO2、
CH3、OCH3、NH2In any one.But the benzo indazole analog derivative and its preparation with regard to the present invention
Method, application yet there are no report.
The content of the invention
The purpose of the present invention is for deficiency of the prior art, there is provided a kind of benzo indazole analog derivative.
Another purpose of the present invention is to provide a kind of application of benzo indazole analog derivative.
Another purpose of the present invention is to provide a kind of preparation method of benzo indazole analog derivative.
For achieving the above object, the present invention is adopted the technical scheme that：Benzo indazole class shown in formula (I)
Derivative and its pharmaceutically acceptable salt,
Wherein, R1Selected from hydrogen, alkoxyl, halogen, nitro, amino, oxygen substituent, substituent is identical or different,
For monosubstituted or polysubstituted；
R2It is monosubstituted or polysubstituted selected from hydrogen, alkoxyl；
R3Selected from hydrogen, straight chained alkyl, replace alkyl, aromatic radical, carboxylic acid, carboxylate.
Preferably, R1Selected from hydrogen, methoxyl group, halogen, nitro, amino, hydroxyl.
Preferably, R2For methoxyl group.
Preferably, R3Selected from hydrogen, straight chained alkyl, replace alkyl, aromatic radical, carboxylic acid, carboxylate.
Preferably, R1、R2、R3The group of expression is as follows：
| Sequence number | R1 | R2 | R3 |
| SC-1 | 3,4,5- trimethoxies | 7- methoxyl groups | -H |
| SC-2 | 3,4,5- trimethoxies | 7- methoxyl groups | -CH3 |
| SC-3 | 3,4,5- trimethoxies | 7- methoxyl groups | -CH2CH2OH |
| SC-4 | 3,4,5- trimethoxies | 7- methoxyl groups | -Ph |
| SC-5 | 3,4,5- trimethoxies | 7- methoxyl groups | -CH2COOC2H5 |
| TCa-1 | 4- methoxyl groups | 6,7,8- trimethoxies | -H |
| TCa-2 | 4- methoxyl groups | 6,7,8- trimethoxies | -CH3 |
| TCb-1 | The fluoro- 4- methoxyl groups of 3- | 6,7,8- trimethoxies | -H |
| TCb-3 | The fluoro- 4- methoxyl groups of 3- | 6,7,8- trimethoxies | -CH2CH2OH |
| TCb-4 | The fluoro- 4- methoxyl groups of 3- | 6,7,8- trimethoxies | -Ph |
| TCc-1 | 3- nitro -4- methoxyl groups | 6,7,8- trimethoxies | -Ph |
| TCd-1 | 3- amino-4-methoxyls | 6,7,8- trimethoxies | -Ph |
Preferably, described benzo indazole analog derivative is 7- methoxyl group -1- (3,4,5- trimethoxyphenyl) -4,5-
Dihydro -2H- benzos [e] indazole.
To realize above-mentioned second purpose, the present invention is adopted the technical scheme that：Described benzo indazole class is spread out
Application of the biological and its pharmaceutically acceptable salt in tubulin polymerization inhibitor is prepared.
Described benzo indazole analog derivative and its pharmaceutically acceptable salt is preparing treatment tumor disease medicine
Application in thing.
Described tumor disease be leukaemia, non-small cell lung cancer, colon cancer, central nerve neuroma,
Melanoma, oophoroma, kidney, prostate cancer or breast cancer.
To realize above-mentioned 3rd purpose, the present invention is adopted the technical scheme that：Described benzo indazole class is spread out
The synthetic route of biological preparation method is：
Wherein, R1Selected from hydrogen, straight chained alkyl, replace alkyl, aromatic radical, carboxylic acid, carboxylate.
The invention has the advantages that：
1st, there is compound double bond to tie in patent before the benzo indazole class formation in the present invention is thoroughly solved
, there is cis-trans isomerization in structure and caused compound is unstable.
2nd, the compound in the present invention has wider array of antitumor spectra, and wherein SC1 is studied in National Cancer
There are very high activity, average IC in the 60 cell lines screening tested50Value reaches 10nM ranks.
3rd, compound TCd-1 shows the activity higher than SC1 in preliminary screening in the present invention, reaches
To pM ranks.Its substituent R2For amino when, hydrochloride etc. can be made, with more preferable water solubility
And oral administration biaavailability.And prodrug forms can be further made, possess more preferable druggability.Possess into
The value of one step exploitation.
Description of the drawings
Accompanying drawing 1 is 60 cell line the selection results that compound SC1 is tested in National Cancer Institute.
Specific embodiment
The specific embodiment that the present invention is provided is elaborated with reference to embodiment.
The synthesis formula of the compound of the present invention is as follows：
The concrete synthetic route of the compound of the present invention is as follows：
Reagent and condition：(a) LDA, the anisoyl chloride of 3 replacements, anhydrous tetrahydro furan, -15 DEG C；(b)
R1-NH-NH2, ethanol, room temperature；(c) NaOH, methyl alcohol, room temperature；(d) iron powder, acetic acid, 70% ethanol, backflow.
The synthetic method of related compound is as follows：
The synthesis of (1H) -one (1) of raw material 6- methoxyl group -3,4- dihydronaphthalene -2 referring to document J Med Chem 2012,
55,5720-5733.。
The synthesis of raw material 5,6,7- trimethoxies -3,4- dihydronaphthalene -2- ketone (2) is referring to patent《Replace benzylidene
Tetralone analog derivative and preparation method, application》(application number：201510064131.0).
Embodiment 1：6- methoxyl group -1- (3,4,5- trimethoxyphenyls) -3,4- dihydronaphthalene -2 (1H) -one (S-dk)
Raw material 6- methoxyl group -3,4- dihydronaphthalene -2 (1H) -one (1) (5.68mmol, 1.0equiv) are dissolved in
In the anhydrous THF of 20mL, nitrogen protection, plus ice salt bath, LDA (6.24mmol, 1.1equiv) is slowly added dropwise,
Stirring adds the THF solution (6.24mmol, 1.1equiv) of 3,4,5- trimethoxy-benzoyl chlorides after 4 hours,
It is slowly increased to be stirred at room temperature, TLC monitorings.Saturated aqueous ammonium chloride is added to be quenched under ice bath after completion of the reaction.
Reactant liquor is extracted with ethyl acetate (2 × 100mL), merges organic phase, uses saturated common salt water washing, anhydrous
Sodium sulphate be dried, after reduced pressure concentration with silica gel column chromatography purify (ethyl acetate/petroleum ether is eluted) obtain product
For yellow solid, yield 61%.1H NMR(600MHz,CDCl3) δ 6.77 (s, 2H), 6.72 (d, J=
2.3Hz, 1H), 6.66 (d, J=8.6Hz, 1H), 6.47 (dd, J=8.6,2.5Hz, 1H), 3.92 (d, J=
6.2Hz, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.69 (s, 6H), 2.93 (t, J=6.8Hz, 2H), 2.68-
2.52(m,2H).HRMS(ES+)m/z found 371.1486(M+H+)；C21H23O6(M+H+)
requires 371.1489.
Embodiment 2：7- methoxyl group -1- (3,4,5- trimethoxyphenyls) -4,5- dihydro -2H- benzos [e] indazoles
(SC1)
The hydrazine hydrate of ethanol, intermediate S-dk and equivalent is sequentially added in 100mL flasks, it is stirred
Night, isolate and purify after concentration SC1 be white solid.172-173 DEG C of fusing point,1H NMR(600MHz,
CDCl3) δ 7.35 (d, J=8.5Hz, 1H), 6.84 (s, 2H), 6.82 (d, J=2.5Hz, 1H), 6.64 (dd,
J=8.5,2.7Hz, 1H), 3.92 (s, 3H), 3.83 (s, 6H), 3.79 (s, 3H), 2.99 (t, J=7.2Hz,
2H), 2.83 (t, J=7.2Hz, 2H),13C NMR(150MHz,CDCl3)δ157.92,153.57,
148.74,140.29,138.47,136.92,126.69,124.28,123.15,114.38,113.61,111.66,
105.49,61.01,56.28,55.28,30.46,21.81.HRMS(ES+)m/z found 367.1653
(M+H+)；C21H23N2O4(M+H+)requires 367.1652.
Embodiment 3：7- methoxyl group -2- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -4,5- dihydros -2H- benzos [e]
Indazole (SC2)
With reference to embodiment 2, intermediate S-dk and methyl hydrazine reaction are obtained into SC2 for white solid.Fusing point 157
- 158 DEG C,1H NMR(600MHz,CDCl3) δ 7.33 (d, J=8.5Hz, 1H), 6.89 (s, 2H),
6.81 (d, J=2.4Hz, 1H), 6.55 (dd, J=8.5,2.6Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H),
3.84 (s, 6H), 3.78 (s, 3H), 3.03 (t, J=7.5Hz, 2H), 2.89 (t, J=7.3Hz, 2H).13C
NMR(151MHz,CDCl3)δ157.84,153.78,138.74,136.76,125.73,123.66,114.42,
111.74,106.95,61.05,56.37,55.26,36.66,30.34,21.92.HRMS(ES+)m/z found
381.1821(M+H+)；C22H25N2O4(M+H+)requires 381.1809.
Embodiment 4：7- methoxyl group -2- hydroxyethyl -1- (3,4,5- trimethoxyphenyls) -4,5- dihydro -2H- benzos
[e] indazole (SC3)
With reference to embodiment 2, intermediate S-dk and hydroxyethyl hydrazine reaction are obtained into SC3 for white solid.It is molten
143-144 DEG C of point,1H NMR(600MHz,CDCl3) δ 6.86 (d, J=8.5Hz, 1H), 6.78 (d, J
=2.6Hz, 1H), 6.63 (s, 2H), 6.55 (dd, J=8.5,2.7Hz, 1H), 4.07-4.04 (m, 2H),
3.97 (d, J=5.1Hz, 2H), 3.95 (s, 3H), 3.84 (s, 6H), 3.77 (s, 3H), 3.01 (t, J=7.2Hz,
2H), 2.89 (t, J=7.2Hz, 2H).13C NMR(150MHz,CDCl3)δ157.72,153.73,
149.38,138.61,138.08,136.80,125.94,123.71,123.16,114.81,114.39,111.69,
107.20,62.17,61.03,56.34,55.24,50.31,30.46,22.19.HRMS(ES+)m/z found
411.1910(M+H+)；C23H27N2O5(M+H+)requires 411.1914.
Embodiment 5：7- methoxyl group -2- phenyl -1- (3,4,5- trimethoxyphenyls) -4,5- dihydros -2H- benzos [e]
Indazole (SC4)
With reference to embodiment 2, intermediate S-dk and phenyl hydrazine reaction are obtained into SC4 for gray solid.Fusing point 142
- 143 DEG C,1H NMR(600MHz,CDCl3) δ 7.30-7.20 (m, 5H), 7.08 (d, J=8.5Hz,
1H), 6.83 (d, J=2.6Hz, 1H), 6.60 (dd, J=8.6,2.7Hz, 1H), 6.52 (s, 2H), 3.92 (s,
3H), (m, the 2H) .HRMS of 3.79 (s, 3H), 3.66 (s, 6H), 3.06 (t, J=7.1Hz, 2H), 3.00-2.94
(ES+)m/z found 443.1969(M+H+)；C27H27N2O4(M+H+)requires 443.1965.
Embodiment 6：2- (7- methoxyl group -1- (3,4,5- trimethoxyphenyls) -4,5- dihydro -2H- benzos [e] indazole -2-)
Ethyl acetate (SC5)
With reference to embodiment 2, by intermediate S-dk and 2- diazanyl ethyl acetate react SC4 is gray solid.
118-119 DEG C of fusing point,1H NMR(600MHz,CDCl3) δ 6.90 (d, J=8.5Hz, 1H), 6.79 (d,
J=2.6Hz, 1H), 6.66 (s, 2H), 6.56 (dd, J=8.5,2.7Hz, 1H), 4.70 (s, 2H), 4.20 (q, J
=7.1Hz, 2H), 3.95 (s, 3H), 3.81 (s, 6H), 3.77 (s, 3H), 3.02 (t, J=7.2Hz, 2H), 2.91
(t, J=7.2Hz, 2H), 1.26 (t, J=7.1Hz, 3H).13C NMR(151MHz,CDCl3)δ168.71,
157.77,153.67,150.06,138.62,138.38,136.94,125.80,123.78,123.19,115.21,
114.33,111.72,106.98,102.71,61.68,61.01,56.25,55.24,50.62,42.65,30.44,
25.62,23.07,22.21,14.16,14.02.HRMS(ES+)m/z found 453.2023(M+H+)；
C25H29N2O6(M+H+)requires 453.2020.
Embodiment 7：2- (7- methoxyl group -1- (3,4,5- trimethoxyphenyls) -4,5- dihydro -2H- benzos [e] indazole -2-)
Acetic acid (SC6)
By 2- (7- methoxyl group -1- (3,4,5- trimethoxyphenyls) -4,5- dihydro -2H- benzos [e] indazole -2-) acetic acid second
During ester (SC5) is dissolved in ethanol, the NaOH aqueous solution of 5 times of equivalents is added, be stirred overnight, in watery hydrochloric acid
With to pH<Extracted with dichloromethane after 7, thin-layer chromatography is prepared into SC6 for white solid after organic layer concentration.1H NMR(600MHz,CDCl3) δ 6.90 (d, J=8.5Hz, 1H), 6.78 (d, J=2.6Hz, 1H),
6.63 (s, 2H), 6.57 (dd, J=8.5,2.7Hz, 1H), 4.74 (s, 2H), 3.95 (s, 3H), 3.82 (s, 6H),
3.77(s,3H),3.12(m,2H),2.96(m,2H).HRMS(ES+)m/z found 425.1699
(M+H+)；C23H25N2O6(M+H+)requires 425.1707.
Embodiment 8：5,6,7- trimethoxy -1- (4- methoxyphenyls) -3,4- dihydronaphthalene -2 (1H) -one (T-dk-a)
With reference to embodiment 1, with trimethoxy -3 of raw material 5,6,7-, 4- dihydronaphthalene -2- ketone (2) and 4- methoxybenzenes
Formyl chloride reaction is prepared into T-dk-a for yellow solid.86-87 DEG C of fusing point,1H NMR(600MHz,
CDCl3) δ 7.51 (d, J=8.8Hz, 2H), 6.85 (d, J=8.8Hz, 2H), 6.06 (s, 1H), 3.88 (s,
3H), 3.88 (s, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.29 (s, 3H), 2.92 (t, J=6.9Hz, 2H),
2.61–2.53(m,2H).HRMS(ES+)m/z found 371.1481(M+H+)；C21H23O6(M+H+)
requires 371.1489.
Embodiment 9：5,6,7- trimethoxy -1- (the fluoro- 4- methoxyphenyls of 3-) -3,4- dihydronaphthalene -2 (1H) -one
(T-dk-b)
With reference to embodiment 1, with trimethoxy -3 of raw material 5,6,7-, the fluoro- 4- methoxies of 4- dihydronaphthalene -2- ketone (2) and 3-
The reaction of base chlorobenzoyl chloride is prepared into T-dk-b for yellow solid.1H NMR(600MHz,CDCl3)δ7.32
(dd, J=11.7,1.9Hz, 1H), 7.30 (d, J=9.2Hz, 1H), 6.89 (t, J=8.4Hz, 1H), 6.05 (s,
1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.33 (s, 3H), 2.93 (t, J=6.9Hz, 2H),
2.61–2.52(m,2H).13C NMR(150MHz,CDCl3)δ197.21,180.59,152.02,150.51,
150.38,149.72,149.65,139.64,128.69,128.66,127.86,125.91,120.28,116.75,
116.62,111.92,108.89,107.78,60.72,60.52,55.86,55.09,33.81,19.47.
Embodiment 10：5,6,7- trimethoxy -1- (3- nitro -4- methoxyphenyls) -3,4- dihydronaphthalene -2 (1H) -one
(T-dk-c)
With reference to embodiment 1, with trimethoxy -3 of raw material 5,6,7-, 4- dihydronaphthalene -2- ketone (2) and 3- nitro -4-
Methoxy benzoyl chloride reaction is prepared into T-dk-c for yellow solid.1H NMR(600MHz,CDCl3)δ
8.10 (d, J=2.2Hz, 1H), 7.71 (dd, J=8.8,2.2Hz, 1H), 7.02 (d, J=8.8Hz, 1H),
6.04(s,1H),3.99(s,3H),3.90(s,3H),3.86(s,3H),3.36(s,3H),3.00–2.89(m,
2H),2.64–2.54(m,2H).
Embodiment 11：6,7,8- trimethoxy -1- (4- methoxyphenyls) -4,5- dihydro -2H- benzos [e] indazoles
(TCa-1)
With reference to embodiment 2, intermediate T-dk-a and hydration hydrazine reaction are obtained into TCa-1 for brown solid.It is molten
105-106 DEG C of point,1H NMR(600MHz,CDCl3) δ 7.55 (d, J=8.5Hz, 2H), 6.99 (d, J=
8.5Hz, 2H), 6.70 (s, 1H), 3.88 (s, 3H), 3.86 (s, 6H), 3.54 (s, 3H), 3.00 (t, J=7.2Hz,
2H), 2.82 (t, J=7.2Hz, 2H)；13C NMR(150MHz,CDCl3)δ160.13,151.63,
151.43,140.45,129.88,126.55,123.49,121.13,114.20,113.39,103.08,60.98,
60.95,55.75,55.41,22.10,21.73.HRMS(ES+)m/z found 367.1652(M+H+)；
C21H23O6(M+H+)requires 367.1662.
Embodiment 12：6,7,8- trimethoxy -1- (4- methoxyphenyls) -2- methyl -4,5- dihydros -2H- benzos [e]
Indazole (TCa-2)
With reference to embodiment 2, intermediate T-dk-a and methyl hydrazine reaction are obtained into TCa-2 for brown solid.It is molten
126-127 DEG C of point,1H NMR(600MHz,CDCl3) δ 7.37 (d, J=8.5Hz, 2H), 7.05 (d, J
=8.5Hz, 2H), 6.30 (s, 1H), 3.88 (s, 3H), 3.86 (s, 4H), 3.83 (s, 3H), 3.70 (s, 3H),
3.42 (s, 3H), 3.00 (t, J=7.4Hz, 2H), 2.85 (t, J=7.4Hz, 2H).13C NMR(151MHz,
CDCl3)δ160.18,151.51,151.39,149.28,140.16,138.11,131.43,130.14,126.65,
123.03,120.90,114.81,114.37,113.71,102.43,60.94,60.88,55.43,36.47,29.70,
22.14,21.74.HRMS(ES+)m/z found 381.1805(M+H+)；C21H23O6(M+H+)requires
381.1809.
Embodiment 13：6,7,8- trimethoxy -1- (the fluoro- 4- methoxyphenyls of 3-) -4,5- dihydro -2H- benzos [e] Yin
Azoles (TCb-1)
With reference to embodiment 2, intermediate T-dk-b and hydration hydrazine reaction are obtained into TCb-1 for violet solid.It is molten
147-148 DEG C of point,1H NMR(600MHz,CDCl3) δ 7.38 (dd, J=11.8,2.0Hz, 1H), 7.35
- 7.30 (m, 1H), 6.97 (t, J=8.5Hz, 1H), 6.70 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H),
3.87(s,3H),3.57(s,3H),3.01–2.92(m,2H),2.79–2.70(m,2H)；13C NMR(150
MHz,CDCl3)δ152.93,151.67,151.44,151.30,147.98,147.91,140.48,126.34,
124.70,120.92,116.47,116.34,113.56,113.28,103.11,61.00,60.98,56.28,55.77,
21.98,21.28.HRMS(ES+)m/z found 385.1564(M+H+)；C21H23O6(M+H+)requires
385.1558.
Embodiment 14：6,7,8- trimethoxy -1- (the fluoro- 4- methoxyphenyls of 3-) -2- hydroxyethyl -4,5- dihydros
- 2H- benzos [e] indazole (TCb-3)
With reference to embodiment 2, intermediate T-dk-b and hydroxyethyl hydrazine reaction are obtained into TCb-3 for brown solid.
150-151 DEG C of fusing point,1H NMR(600MHz,CDCl3) δ 7.22 (dd, J=11.4,2.0Hz, 1H),
7.20-7.16 (m, 1H), 7.11 (t, J=8.4Hz, 1H), 6.25 (s, 1H), 4.06-4.01 (m, 2H), 3.97
(s, 3H), 3.95 (dd, J=9.1,4.5Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.45 (s, 3H), 2.99
(t, J=7.4Hz, 2H), 2.84 (t, J=7.4Hz, 2H).13C NMR(151MHz,CDCl3)δ153.17,
151.69,151.49,149.42,148.73,148.66,140.75,137.58,126.76,125.39,122.39,
122.34,121.07,118.20,118.08,115.35,113.79,102.68,61.77,60.95,60.90,56.42,
55.50,50.35,21.77,21.45.HRMS(ES+)m/z found 429.1830(M+H+)；C21H23O6
(M+H+)requires 429.1820.
Embodiment 15：6,7,8- trimethoxy -1- (the fluoro- 4- methoxyphenyls of 3-) -2- phenyl -4,5- dihydro -2H- benzene
And [e] indazole (TCb-4)
With reference to embodiment 2, by intermediate T-dk-b and phenylhydrazine react TCb-4 is brown solid.Fusing point
159-160 DEG C,1H NMR(600MHz,CDCl3)δ7.32–7.28(m,2H),7.26–7.22(m,
3H), 7.13 (dd, J=11.6,2.0Hz, 1H), 7.09-7.05 (m, 1H), 6.98 (t, J=8.5Hz, 1H),
6.40 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.48 (s, 3H), 3.05 (t, J=7.3Hz,
2H), 2.93 (t, J=7.2Hz, 2H).13C NMR(151MHz,CDCl3)δ153.04,151.72,151.51,
151.39,151.05,148.34,148.27,140.96,138.93,136.30,128.97,127.48,126.88,
125.36,125.10,122.98,121.68,120.65,118.21,118.09,116.67,115.32,113.48,
103.06,60.98,56.29,55.57,21.84,21.63.HRMS(ES+)m/z found 461.1870
(M+H+)；C21H23O6(M+H+)requires 461.1871.
Embodiment 16：6,7,8- trimethoxy -1- (3- nitro -4- methoxyphenyls) -2- phenyl -4,5- dihydro -2H-
Benzo [e] indazole (TCc-1)
With reference to embodiment 2, intermediate T-dk-c and hydration hydrazine reaction are obtained into TCc-1 for brown solid.Fusing point
108-109 DEG C,1H NMR(600MHz,CDCl3) δ 8.16 (d, J=2.2Hz, 1H), 7.84 (dd, J=
8.6,2.2Hz, 1H), 7.16 (d, J=8.7Hz, 1H), 6.65 (s, 1H), 4.02 (s, 3H), 3.89 (s, 3H),
3.88 (s, 3H), 3.60 (s, 3H), 3.01 (t, J=7.4Hz, 2H), 2.87-2.80 (m, 2H).13C NMR
(151MHz,CDCl3)δ152.68,151.90,151.59,140.81,139.68,134.04,125.87,
125.43,124.97,120.86,114.05,113.62,102.98,61.00,56.70,55.89,21.89,21.04.
Embodiment 17：6,7,8- trimethoxy -1- (3- amino-4-methoxyl phenyl) -2- phenyl -4,5- dihydro -2H-
Benzo [e] indazole (TCd-1)
Add acetic acid in the ethanol of 10mL 75%, be adjusted to PH=3～4, stirring is lower add iron powder (90mg,
1.6mmol), it is heated to 90 DEG C to stir one hour.Compound TCc-1 (66mg, 0.16mmol) is added,
Continue to stir 30 minutes, reaction is finished.Reactant liquor Anhydrous potassium carbonate is neutralized to PH ≈ 8, and diatomite is filtered,
Washed with ethyl acetate.Filtrate is extracted with ethyl acetate, brine It, and organic phase is dry with anhydrous sodium sulfate
Dry, simultaneously silica gel column chromatography obtains yellow powder TCd-1 (41mg, 67%yield) for concentration.1H NMR(600
MHz,CDCl3) δ 6.95 (t, J=5.4Hz, 2H), 6.84 (s, 1H), 6.83 (d, J=8.1Hz, 1H), 4.19
(s,2H),3.89(s,3H),3.87(s,3H),3.86(s,3H),3.58(s,3H),3.48(s,1H),3.02–
2.92(m,2H),2.83–2.73(m,2H).13C NMR(150MHz,CDCl3)δ151.56,151.33,
150.26,147.71,140.29,140.10,136.49,126.72,123.68,121.09,118.61,114.63,
113.04,110.30,103.27,60.99,60.95,55.79,55.61,22.10,21.72.
Embodiment 18：CDCCs of the object SC1-SC6 to K562, HCT116 cell line.
First, experiment material and method：
1st, experiment material
(1) experimental cell strain
This experiment employs the cell line of human leukemia cell, human colon cancer cell as screening object, the cancer
Cell line is provided by Shanghai Institute of Pharmaceutical Industry's Pharmacology Lab.
1) K562 (human leukemia cell)
2) HT116 (people's colon-cancer cell)
(2) nutrient solution is that DMEM+10%FBS+ is dual anti-, full-automatic ELIASA model used：
Varioskan Flash, production firm：Thermo scientific.Well culture plate of import 96 etc..
2nd, test method
Anti tumor activity in vitro adopts mtt assay.
Sample preparation：After being dissolved into 10mM with DMSO (Merck), PBS (-) is added to be made into 1000 μM
Solution or uniform suspension, then with containing DMSO PBS (-) dilution.
Experimental procedure is as follows：
It is 4-5 × 10 that 96 orifice plates add concentration per hole4The μ l of cell suspension 100 of individual/ml, put 37 DEG C, 5%CO2
In incubator.
2nd, experimental result：
The tumor cell proliferation experiment of the compound SC1 of table 1-SC6
Note：The compound is the compound 1 in patent CN103130632A
Embodiment 19：CDCC of the object to Colo205 cell lines.
First, experiment material and method：
1st, experiment material
(1) experimental cell strain
This experiment employs human colon cancer cell Colo205 as screening object, and the JEG-3 is by Shanghai
Medical industry research institute Pharmacology Lab is provided.
(2) nutrient solution is that DMEM+10%FBS+ is dual anti-, full-automatic ELIASA model used：
Varioskan Flash, production firm：Thermo scientific.Well culture plate of import 96 etc..
2nd, test method
Anti tumor activity in vitro adopts mtt assay.
Mtt assay.It is 5 × 10 that 96 orifice plates add concentration per hole4The μ l of cell suspension 100 of individual/ml, put 37 DEG C,
5%CO2In incubator.After 24h, addition sample liquid, 10 μ l/ holes, if three wells, 37 DEG C, 5%CO2
Effect 72h.The μ l of MTT solution 20 of 5mg/ml are added per hole, after effect 4h lysate, 100 μ l/ are added
Hole, puts in incubator, and 570nm OD values are surveyed with all-wave length multi-function microplate reader after dissolving.
2nd, experimental result：
In-vitro multiplication inhibitory action of the target compound of table 2 to human colon cancer cell Colo205
Note：The compound is the compound 1 in patent CN103130632A
Experimental example 20：Compound SC1 is screened in 60 cell lines that National Cancer Institute is tested
Test result shows compound SC1 to leukaemia, non-small cell lung cancer, colon cancer, nervous centralis
System tumor, melanoma, oophoroma, kidney, prostate cancer and breast cancer have extraordinary effect,
To the average IC of 60 cell lines for being surveyed50Value reaches 12.88nM.
Experimental example 21：Suppress tubulin polymerization experiment
First, experiment material and method：
1st, experiment material
(1) tubulin
This experiment employs ox tubulin as screening object, manufacturer：Cytoskeleton.
(2) buffer solution
General Tubulin Buffer:80mM PIPES pH=6.9,2mM MgCl2,0.5mM EGTA,
Manufacturer:Cytoskeleton.
Tubulin Glycerol Buffer:60%glycerol, manufacturer:Cytoskeleton.
GTP：100mM, manufacturer:Cytoskeleton
Full-automatic ELIASA model used：Synergy 4, production firm：BioTek.The hole of import 96 half
Area culture plate etc..
2nd, test method
Using literature method (Cell Biochemistry and Biophysics, 2003,38:1-21), and micro-pipe
Protein reagent cassette method (CytoDYNAMIX Screen 03).
Sample preparation：After with DMSO (Merck) dissolvings, buffer solution is added to be made into the solution of respective concentration
Or uniform suspension, then diluted with buffer solution.
Experimental procedure is as follows：
Respective concentration is added to be the μ l of testing compound 10 per hole in 96 well culture plates, in putting 37 DEG C of ELIASAs,
After 2min, the tubulin liquid of 3mg/ml, 100 μ l/ holes is added if duplicate hole, 37 DEG C, to act on 1h,
Survey 340nmOD values per minute.
2nd, experimental result
The part of compounds of table 3 suppresses the effect of tubulin polymerization
Test result indicate that, above-claimed cpd is respectively provided with the effect of excellent suppression tubulin polymerization, wherein
The activity of compound SC1, SC2, Tca-1, Tcb-1 and Tcd-1 is suitable with positive control drug CA-4,
The tubulin of SC1, Tcd-1 suppresses polymerization activity to be even better than CA-4, is worth entering as antineoplastic
Row further investigation.
The above is only the preferred embodiment of the present invention, it is noted that common for the art
Technical staff, on the premise of without departing from the inventive method, can also make some improvement and supplement, these
Improve and supplement also should be regarded as protection scope of the present invention.
Claims (10)
1. the benzo indazole analog derivative and its pharmaceutically acceptable salt shown in formula (I),
Wherein, R1Selected from hydrogen, alkoxyl, halogen, nitro, amino, oxygen substituent, substituent is identical or different,
For monosubstituted or polysubstituted；
R2It is monosubstituted or polysubstituted selected from hydrogen, alkoxyl；
R3Selected from hydrogen, straight chained alkyl, replace alkyl, aromatic radical, carboxylic acid, carboxylate.
2. benzo indazole analog derivative as claimed in claim 1 and its pharmaceutically acceptable salt, its feature exists
In R1Selected from hydrogen, methoxyl group, halogen, nitro, amino, hydroxyl.
3. benzo indazole analog derivative as claimed in claim 1 and its pharmaceutically acceptable salt, its feature exists
In R2For methoxyl group.
4. benzo indazole analog derivative as claimed in claim 1 and its pharmaceutically acceptable salt, its feature exists
In R3Selected from hydrogen, straight chained alkyl, replace alkyl, aromatic radical, carboxylic acid, carboxylate.
5. benzo indazole analog derivative as claimed in claim 1 and its pharmaceutically acceptable salt, its feature exists
In R1、R2、R3The group of expression is as follows：
。
6. benzo indazole analog derivative as claimed in claim 1 and its pharmaceutically acceptable salt, its feature exists
In described benzo indazole analog derivative is 7- methoxyl group -1- (3,4,5- trimethoxyphenyl) -4,5- dihydro -2H-
Benzo [e] indazole.
7. the benzo indazole analog derivative and its pharmaceutically acceptable salt as described in claim 1-6 is arbitrary is in system
Application in standby tubulin polymerization inhibitor.
8. the benzo indazole analog derivative and its pharmaceutically acceptable salt as described in claim 1-6 is arbitrary is in system
Application in standby treatment tumor disease medicine.
9. application as claimed in claim 8, it is characterised in that described tumor disease is leukaemia, non-little thin
Born of the same parents' lung cancer, colon cancer, central nerve neuroma, melanoma, oophoroma, kidney, prostate cancer or
Breast cancer.
10. the preparation method of benzo indazole analog derivative as claimed in claim 1, it is characterised in that described
The synthetic route of preparation method is：
Wherein, R1Selected from hydrogen, straight chained alkyl, replace alkyl, aromatic radical, carboxylic acid, carboxylate.
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| CN110872299A (en) * | 2019-11-19 | 2020-03-10 | 广州中医药大学(广州中医药研究院) | P-benzoquinone-bis-triazole core skeleton derivative and preparation method and application thereof |
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| CN107011266A (en) * | 2017-05-02 | 2017-08-04 | 中国人民解放军第二军医大学 | Prodrug of benzo indazole analog derivative and preparation method thereof, application |
| WO2018201939A1 (en) * | 2017-05-02 | 2018-11-08 | 中国人民解放军第二军医大学 | Prodrug of benzoindazole derivative, preparation method therefor, and application thereof |
| CN107011266B (en) * | 2017-05-02 | 2023-04-14 | 中国人民解放军第二军医大学 | Prodrug of benzimidazole derivative, preparation method and application thereof |
| CN110872299A (en) * | 2019-11-19 | 2020-03-10 | 广州中医药大学(广州中医药研究院) | P-benzoquinone-bis-triazole core skeleton derivative and preparation method and application thereof |
| CN110872299B (en) * | 2019-11-19 | 2022-09-30 | 广州中医药大学(广州中医药研究院) | P-benzoquinone-bis-triazole core skeleton derivative and preparation method and application thereof |
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