CN102532082A - 2,2-dimethyl benzopyran compound and preparation method and application thereof - Google Patents

2,2-dimethyl benzopyran compound and preparation method and application thereof Download PDF

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CN102532082A
CN102532082A CN2010105782897A CN201010578289A CN102532082A CN 102532082 A CN102532082 A CN 102532082A CN 2010105782897 A CN2010105782897 A CN 2010105782897A CN 201010578289 A CN201010578289 A CN 201010578289A CN 102532082 A CN102532082 A CN 102532082A
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ring
dimethylbiphenyl
methyl
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陈国良
陆秀宏
杨静玉
包雪飞
王立辉
苏专专
张相海
戴文
吴春福
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Shenyang Pharmaceutical University
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Abstract

The invention discloses a 2,2-dimethyl benzopyran compound and a preparation method and application thereof, belonging to the technical field of medicines. The structure of the 2,2-dimethyl benzopyran compound is shown in a figure described in the specification. The preparation method of the 2,2-dimethyl benzopyran compound comprises the following steps of: with 2-methyl-butyl-3-alkyne-2 alcohol as a starting raw material, carrying out four-step reactions comprising chlorination, Williamson etherification, cyclization and Aldol condensation to obtain the 2,2-dimethyl benzopyran compound. The preparation method of the 2,2-dimethyl benzopyran compound, disclosed by the invention, has the advantages of simple operation, convenience for post-treatment and higher yield. The 2,2-dimethyl benzopyran compound has an excellent inhibition function on various cancer cells so as to be applied to treatment of tumors. A formula is described in the specification, wherein R' represents H and C1-6 alkyl and R represents substituted or unsubstituted aromatic ring or heteroaromatic ring.

Description

2,2-dimethylbiphenyl pyran compounds
Technical field
The invention belongs to medical technical field, relate to 2,2-dimethylbiphenyl pyran compounds.
Background technology
2,2-dimethylbiphenyl pyran compounds begin most be the B.S.Bajwa by India Univ Delhi, Pyare Lal Khaanna and T.R.Seshadri in 1973 from the seed of Psoralea corylifolia, extract ( Indian Journal of chemistry, 1973,12:15-19. with Curr. Sci,1971,40:505.), obtained a series of benzopyrans compounds through adopting sherwood oil and ethanol to extract successively, like compound (1-3), but they did not carry out bioactivity research to the compound that their extraction obtains at that time, just they had been done complete synthesis research.
Figure DEST_PATH_IMAGE001
Figure 762310DEST_PATH_IMAGE002
(1) (2)
Figure DEST_PATH_IMAGE003
Figure 554817DEST_PATH_IMAGE004
(3) (4)
Afterwards one by one relevant for the synthetic of this compounds and activity report; As discovering that compound 4 is the responsive potassium-channel opener of ATP the eighties in 20th century; Be one type of novel antihypertensive and myocardial ischemia drug; When its advantage is step-down cardiac muscle there is direct protective action, can reduces the damage of myocardial anoxia pair cell, the K of compound 4 +-ATP passage open EC50 reach 7.9 μ M ( CN101296731A. with CN101296925A); Famous scientist K C Nicolaou etc. have synthesized a large amount of 2 through the method for combinatorial chemistry; 2-dimethylbiphenyl pyran compounds; Adopt the core electron transmission grain of ox that these compounds are carried out high flux screening to the vitro inhibition activity of NADH and Coenzyme Q10 99.0 redox combined enzyme agent; Most target compounds demonstrate good inhibition activity to NADH and Coenzyme Q10 99.0 redox combined enzyme agent; The Van Meir Erwin of U.S. Emory university further tests the anti-tumor activity of these compounds, find the generation of this compounds through suppressing new vessel to kinds of tumor cells such as white blood disease clone, lung cancer cell line, colon carcinoma cell line, breast cancer cell line and black substance knurl have the obvious suppression effect ( Chemistry & Biology, 2000,7 (12): 979-992. and WO006184).
On this basis, we design and have synthesized a series of 2 of bibliographical informations of not seeing, 2-dimethylbiphenyl pyran compounds; Most compounds have good biological activity such as anti-oxidant, anticancer; Can be used to prepare anticarcinogen, anti-oxidant, the medicine of elimination radical and inhibition microglial activation.
Summary of the invention:
The invention provides that some are efficient, low toxicity have anticancer, anti-oxidant, eliminate radical and suppress 2 of microglial activation, 2-dimethylbiphenyl pyran compounds,, the structural formula of The compounds of this invention is like (I):
Figure DEST_PATH_IMAGE005
Wherein R ' is H, C 1-6Alkyl; R is for replacing or unsubstituted aromatic ring or fragrant heterocycle.
Its building-up reactions flow process is following:
With ( E)-1- ( 5-Hydroxyl -2,2-Dimethyl- -2 H- Chromogen alkene -6-Base) -3-(naphthalene -2-Base) third -2-Alkene -1-Ketone (LXH-SYP-1) is example, and concrete steps are:
(1) preparation 3-chloro-3-methyl isophthalic acid-butine (I)
2-methyl-Ding-3-alkynes-2 alcohol and concentrated hydrochloric acid are under the effect of catalyzer calcium chloride, and chloro obtains 3-chloro-3-methyl isophthalic acid-butine
(2) preparation 2-hydroxyl-4-(2-methyl fourth-3-alkynes-2-oxygen base) methyl phenyl ketone (II)
2,4-resacetophenone and 3-chloro-3-methyl isophthalic acid-butine are in suitable solvent, and under the effect of catalyzer KI and solid alkali such as sodium hydroxide (potassium), yellow soda ash (potassium) etc., condensation obtains 2-hydroxyl-4-(2-methyl fourth-3-alkynes-2-oxygen base) methyl phenyl ketone (II)
(3) preparation 1-( 5-Hydroxyl -2,2-Two -2 H- Chromogen alkene -6-Base) methyl phenyl ketone (III)
2-hydroxyl-4-(2-methyl fourth-3-alkynes-2-oxygen base) methyl phenyl ketone backflow cyclization in high boiling solvents such as phenyl ether obtains 1-( 5-Hydroxyl -2,2-Two -2 H- Chromogen alkene -6-Base) methyl phenyl ketone (III)
(4) preparation target compound 2,2-dimethylbiphenyl pyran compounds LXH-SYP-1 (IV)
(5-hydroxyl-2,2-two-2 for 1- H-chromogen alkene-6-yl) condensation under sulphuric acid catalysis of ethyl ketone and β-naphthaldehyde obtains target compound.
Embodiment:
Embodiment 1 Synthesizing of 3-chloro-3-methyl isophthalic acid-butine (I)
Add 20 ml concentrated hydrochloric acids in the 100 ml three-necked bottles, add CaCl 210 g stir down and splash into 2-methyl-Ding-3-alkynes-2-alcohol 20 ml with constant pressure funnel, drip and finish, and 40 ℃ of reaction 12 h are transferred to separating funnel and tell organic layer, and organic layer is with saturated aqueous common salt 20 ml * 1 washing, anhydrous CaCl 2Dry.Filter, get colourless liquid 18 g.
Synthesizing of embodiment 2 2-hydroxyl-4-(2-methyl fourth-3-alkynes-2-oxygen base) methyl phenyl ketone (II)
With 2,4-resacetophenone 9 g join in the 500 ml three-necked bottles under the normal temperature, add ETHYLE ACETATE 100 ml dissolving, add K in three batches 2CO 37.5 g, stir 15 min after, add KI 0.5 g, splash into 3-chloro-3-methyl isophthalic acid-butine 6.4 g with constant pressure funnel, back flow reaction 48 h, cooling, suction filtration boils off solvent, the solid that obtains dissolves with 200 ml methylene dichloride, saturated NaHCO 3The aqueous solution 100 ml * 3 washings, saturated aqueous common salt 100 ml * 1 washing, anhydrous MgSO 4Drying, suction filtration, steaming vibrating dichloromethane get weak yellow liquid 6.2 g.
Embodiment 3 1-( 5-Hydroxyl -2,2-Two -2 H- Chromogen alkene -6-Base) methyl phenyl ketone (III) is synthetic
2-hydroxyl-4-(2-methyl fourth-3-alkynes-2-oxygen base) methyl phenyl ketone 3.6 g are joined in the 50 ml eggplant-shape bottles, add phenyl ether 10 ml, back flow reaction 20 h, cooling adds entry 20 ml, stirs 15 min, CH 2Cl 230 ml * 3 extractions merge organic layer, and organic layer is with 5% HCl, 20 ml * 7 washings, anhydrous MgSO 4Drying, suction filtration boils off solvent, gets faint yellow solid 3.4 g, m.p.65-67 ℃. 1H-NMR?(300MHz，CDCl 3):?δ(ppm)?12.98?(s,?1H),?7.19?(d,? J?=?9.0?Hz,?1H),?7.71?(d,? J?=?10.2?Hz,?1H),?6.34?(d, ?J?=?8.4?Hz,?1H),?5.58?(d,? J?=?10.2?Hz,?1H),?2.54?(s,?3H),?1.48?(s,?6H).
Embodiment 4 target compounds 2,2-dimethylbiphenyl pyran compounds ( E)-1- ( 5-Hydroxyl -2,2-Dimethyl- -2 H- Chromogen alkene -6-Base) -3-(naphthalene -2-Base) third -2-Alkene -1-Ketone ( LXH-SYP-1) preparation of (IV)
(5-hydroxyl-2,2-two-2 with 1- H-chromogen alkene-6-yl) methyl phenyl ketone 2.0 g, β-naphthaldehyde 1.7 g, the vitriol oil a little join in the 100 ml three-necked bottles that water trap is housed, add 40 ml toluene, feed argon gas; Reflux is divided water, and 4 h that reflux boil off solvent; Get crude product 4.5 g; Ethyl alcohol recrystallization gets 4.0 gram yellow solid LXH-SYP-1 elaboration, m.p. 129-131 ℃ 1H NMR (600 MHz, CDCl 3): δ (ppm) 13.71 (s, 1H), 8.73 (d, J=15.2 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.96 – 7.87 (m, 3H), 7.77 (d, J=8.9 Hz, 1H), 7.66 (d, J=15.2 Hz, 1H), 7.61 (ddd, J=8.4,6.8,1.3 Hz, 1H), 7.58 – 7.49 (m, 2H), 6.78 (d, J=10.0 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 5.61 (d, J=10.0 Hz, 1H), 1.48 (s, 6H).
Can make with similar approach:
With pyridine-3-formaldehyde is raw material, can obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(pyridin-3-yl) third-2-alkene-1-ketone ( LXH-SYP-2), yellow solid, m.p. 128-130 ℃. 1H?NMR?(600?MHz,?CDCl 3):?δ(ppm)?13.51?(s,?1H),?8.88?(s,?1H),?8.64?(d,? J?=?4.1?Hz,?1H),?7.98?(d,? J?=?7.9?Hz,?1H),?7.85?(d,? J?=?15.6?Hz,?1H),?7.71?(d,? J?=?8.9?Hz,?1H),?7.64?(d,? J?=?15.6?Hz,?1H),?7.40?(dd,? J?=?7.9,?4.8?Hz,?1H),?6.76?(d,? J?=?10.1?Hz,?1H),?6.41?(d,? J?=?8.8?Hz,?1H),?5.61?(d,? J?=?10.0?Hz,?1H),?1.48?(s,?6H).
With 3-hydroxyl-4-methoxybenzaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(3-hydroxyl-4-p-methoxy-phenyl) third-2-alkene-1-ketone ( LXH-SYP-3), yellow solid, m.p. 164-165 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.78?(s,?1H),?7.76?(dd,? J?=?25.1,?12.1?Hz,?2H),?7.43?(d,? J?=?15.4?Hz,?1H),?7.29?(d,? J?=?2.1?Hz,?1H),?7.15?(dd,? J?=?8.3,?2.0?Hz,?1H),?6.89?(d,? J?=?8.3?Hz,?1H),?6.76?(d,? J?=?10.0?Hz,?1H),?6.39?(d,? J?=?8.9?Hz,?1H),?5.67?(s,?1H),?5.60?(d,? J?=?10.0?Hz,?1H),?3.96?(s,?3H),?1.48?(s,?6H).
With 4-hydroxyl-3,5-di-t-butyl phenyl aldehyde is a raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(4-hydroxyl-3,5-di-tert-butyl-phenyl) third-2-alkene-1-ketone ( LXH-SYP-4), yellow solid, m.p. 148-150 ℃. 1H-NMR?(300MHz，CDCl 3):?δ(ppm)?13.87?(s,?1H),?7.87?(d,? J?=?15.0?Hz,?1H),?7.72?(d,? J?=?8.4?Hz,?1H),?7.49?(m,?2H),?7.39?(d,? J?=?15.6?Hz,?1H),?6.76?(d,? J?=?10.2?Hz,?1H),?6.39?(d,? J?=?9.0?Hz,?1H),?5.59?(m,?2H),?1.54?(s,?18H),?1.45?(s,?6H).
With thiophene-2 formaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(thiophene-2-yl) third-2-alkene-1-ketone ( LXH-SYP-5), yellow solid, m.p. 105-107 ℃. 1H?NMR?(600?MHz,?CDCl 3):?δ(ppm)?13.70?(s,?1H),?8.00?(d,? J?=?15.1?Hz,?1H),?7.68?(d,? J?=?8.9?Hz,?1H),?7.44?(d,? J?=?5.0?Hz,?1H),?7.35?(dd,? J?=?16.6,?9.3?Hz,?2H),?7.10?(dd,? J?=?5.0,?3.7?Hz,?1H),?6.75?(d,? J?=?10.0?Hz,?1H),?6.39?(d,? J?=?8.8?Hz,?1H),?5.59?(d,? J?=?10.0?Hz,?1H),?1.47?(s,?6H).
With benzo [ d] [1,2,3] thiadiazoles-5-formaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(benzo [ d] [1,2,3] thiadiazoles-5-yl) third-2-alkene-1-ketone ( LXH-SYP-6), yellow solid, m.p. 193-195 ℃. 1H?NMR?(600?MHz,?CDCl 3):?δ(ppm)?13.59?(s,?1H),?8.90?(s,?1H),?8.18?(d,? J?=?8.4?Hz,?1H),?8.10?(d,? J?=?15.5?Hz,?1H),?8.01?(dd,? J?=?8.5,?1.4?Hz,?1H),?7.80?(dd,? J?=?12.2,?6.5?Hz,?2H),?6.81?(d,? J?=?10.0?Hz,?1H),?6.47?(d,? J?=?8.8?Hz,?1H),?5.65?(t,? J?=?10.8?Hz,?1H),?1.52?(s,?6H).
With the 4-trifluoromethylated benzaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(4-trifluoromethyl) third-2-alkene-1-ketone ( LXH-SYP-7), yellow solid, m.p. 116-8 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.52?(s,?1H),?7.86?(d,? J?=?15.6?Hz,?1H),?7.74?(m,?2H),?7.71?(d,? J?=?9.0?Hz,?1H),?7.68?(m,?2H),?7.62?(d,? J?=?15.6?Hz,?1H),?6.75?(d,? J?=?10.2?Hz,?1H),?6.40?(d,? J?=?8.4?Hz,?1H),?5.61?(d,? J?=?10.2?Hz,?1H),?1.45?(s,?6H).
With 2, the 3-dimethoxy benzaldehyde is a raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(2, the 3-Dimethoxyphenyl) third-2-alkene-1-ketone ( LXH-SYP-8), yellow solid, m.p. 122-4 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.71?(s,?1H),?8.16?(d,? J?=?15.7?Hz,?1H),?7.69?(dd,? J?=?18.8,?12.3?Hz,?2H),?7.29?(d,? J?=?1.4?Hz,?1H),?7.11?(t,? J?=?8.0?Hz,?1H),?6.98?(dd,? J?=?8.1,?1.4?Hz,?1H),?6.77?(d,? J?=?10.1?Hz,?1H),?6.39?(d,? J?=?8.9?Hz,?1H),?5.60?(d,? J?=?10.0?Hz,?1H),?3.91?(s,?6H),?1.48?(s,?6H).
With the 2-methoxybenzaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(2-p-methoxy-phenyl) third-2-alkene-1-ketone ( LXH-SYP-9), yellow solid, m.p. 149-51 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.81?(s,?1H),?8.19?(d,? J?=?15.6?Hz,?1H),?7.81?–?7.56?(m,?3H),?7.48?–?7.31?(m,?1H),?7.10?–?6.89?(m,?2H),?6.77?(d,? J?=?10.0?Hz,?1H),?6.39?(d,? J?=?8.8?Hz,?1H),?5.60?(d,? J?=?10.0?Hz,?1H),?3.94?(s,?3H),?1.48?(s,?6H).
With 2-hydroxy 3-methoxybenzene formaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(2-hydroxy 3-methoxybenzene base) third-2-alkene-1-ketone ( LXH-SYP-10), yellow solid, m.p. 46-7 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.80?(s,?1H),?8.08?(d,? J?=?15.7?Hz,?1H),?7.83?(d,? J?=?15.6?Hz,?1H),?7.75?(d,? J?=?8.9?Hz,?1H),?7.19?(dd,? J?=?6.3,?3.1?Hz,?1H),?6.96?–?6.87?(m,?2H),?6.77?(d,? J?=?10.0?Hz,?1H),?6.47?–?6.25?(m,?2H),?5.60?(d,? J?=?10.1?Hz,?1H),?3.95?(s,?3H),?1.48?(s,?6H).
With 3-methoxyl group benzaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(3-methoxyl group base phenyl) third-2-alkene-1-ketone ( LXH-SYP-11), yellow solid, m.p. 69-71 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.71?(s,?1H),?8.16?(d,? J?=?15.7?Hz,?1H),?7.69?(dd,? J?=?18.8,?12.3?Hz,?2H),?7.30?–?7.27?(m,?1H),?7.11?(t,? J?=?8.0?Hz,?1H),?6.98?(dd,? J?=?8.1,?1.4?Hz,?1H),?6.77?(d,? J?=?10.1?Hz,?1H),?6.39?(d,? J?=?8.9?Hz,?1H),?5.60?(d,? J?=?10.0?Hz,?1H),?3.91?(s,?6H),?1.48?(s,?6H).
With the 3-trifluoromethylated benzaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(3-trifluoromethyl) third-2-alkene-1-ketone ( LXH-SYP-12), yellow solid, m.p. 112-114 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.55?(s,?1H),?7.95?–?7.84?(m,?2H),?7.80?(d,? J?=?7.7?Hz,?1H),?7.74?(d,? J?=?8.9?Hz,?1H),?7.61?(dq,? J?=?15.6,?7.9?Hz,?3H),?6.76?(d,? J?=?10.1?Hz,?1H),?6.41?(d,? J?=?8.9?Hz,?1H),?5.61?(d,? J?=?10.1?Hz,?1H),?1.48?(s,?6H).
With the 2-fluorobenzaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(2-fluorophenyl) third-2-alkene-1-ketone ( LXH-SYP-13), yellow solid, m.p. 102-104 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.63?(s,?1H),?7.96?(d,? J?=?15.7?Hz,?1H),?7.67?(ddd,? J?=?9.2,?8.3,?2.6?Hz,?3H),?7.47?–?7.33?(m,?1H),?7.25?–?7.08?(m,?2H),?6.77?(d,? J?=?10.0?Hz,?1H),?6.40?(d,? J?=?8.9?Hz,?1H),?5.61?(d,? J?=?10.1?Hz,?1H),?1.48?(s,?6H).
With the 3-fluorobenzaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(3-fluorophenyl) third-2-alkene-1-ketone ( LXH-SYP-14), yellow solid, m.p. 131-133 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.58?(s,?1H),?7.82?(d,? J?=?15.5?Hz,?1H),?7.72?(d,? J?=?8.9?Hz,?1H),?7.55?(d,? J?=?15.5?Hz,?1H),?7.45?–?7.32?(m,?3H),?7.24?–?6.96?(m,?1H),?6.76?(d,? J?=?10.0?Hz,?1H),?6.40?(dd,? J?=?8.9,?0.6?Hz,?1H),?5.61?(d,? J?=?10.1?Hz,?1H),?1.48?(s,?6H).
With the 4-fluorobenzaldehyde is raw material, obtain ( E)-1-(5-hydroxyl-2,2-dimethyl--2 H-chromogen alkene-6-yl)-3-(4-fluorophenyl) third-2-alkene-1-ketone ( LXH-SYP-15), yellow solid, m.p. 133-135 ℃. 1H?NMR?(300?MHz,?CDCl 3):?δ(ppm)?13.65?(s,?1H),?7.85?(d,? J?=?15.5?Hz,?1H),?7.72?(d,? J?=?8.9?Hz,?1H),?7.69?–?7.59?(m,?2H),?7.49?(d,? J?=?15.5?Hz,?1H),?7.21?–?7.01?(m,?2H),?6.76?(d,? J?=?10.0?Hz,?1H),?6.40?(d,? J?=?8.9?Hz,?1H),?5.61?(d,? J?=?10.0?Hz,?1H),?1.48?(s,?6H).
The biological activity test experimental section
2.1Target compound is right U87The experiment of cell strain proliferation inhibition activity
2.1.1 experiment purpose
To 15 compound L XH-SYP-1-LXH-SYP-15 that provided, the glioma cell line U87 that should choose adopts classical mtt assay to carry out antitumor activity screening.
Experiment material
A receives test product
Compound L XH-SYP-1-LXH-SYP-15.
Experimental cell strain and source
People's glioma cell line U87 (available from ATCC)
The C experiment reagent
The DMEM high glucose medium Gibco
Foetal calf serum Tianjin Hao ocean biological products ltd
Tetramethyl-azo azoles salt (MTT) U.S. Sigma
DMSO 99.8MIN. (DMSO) Shenyang chemical reagent factory
NaCl Shenyang chemical reagent factory
KCl Shenyang chemical reagent factory
KH 2PO 3 Shenyang chemical reagent factory
Na 2HPO 3 Shenyang chemical reagent factory
NaHCO 3 Shenyang chemical reagent factory
ELIASA Austria TECAN
96 porocyte culture plates Costar company
2.1.3 experimental technique
The A drug-treated
The dissolving of a medicine
Compound L XH-SYP-1-LXH-SYP-15 is Powdered, uses the DMSO dissolving.Be made into the mother liquor that concentration is 100mmol/L, be stored in-20 ℃.Facing the time spent, to use corresponding nutrient solution be 100 μ mol/L with its dilution, 10 μ mol/L, and 1 μ mol/L and 0.1 μ mol/L experimentize.When the sample of DMSO configuration experimentized, the final concentration of DMSO was 1 ‰.
Administration is handled
The cell of taking the logarithm vegetative period is adjusted suitable cell density, is inoculated in 96 orifice plates, and 100 μ l/well are incubated at 37 ℃, 5% CO 2Incubator in.After cultivating 24h, be 100 μ mol/L with drug dilution, 10 μ mol/L, 1 μ mol/L and four concentration of 0.1 μ mol/L are changed the liquid dosing, effect 48h.Set up blank control group and administration group separately, establish 5 multiple holes for every group.
Check
The ultimate principle of a mtt assay
Cell survival rate is measured and is adopted the MTT analytical method, and ((4,5-dimethyl-2thiahiazoy1)-3,5-di-phenyl-tetrazolium bromide MTT) is the basis to 3-with viable cell metabolism reduction tetramethyl-azo azoles salt.MTT is a yellow compound; It is the hydrionic dyestuff of a kind of acceptance; Can act on the respiratory chain in the viable cell plastosome; Tetrazole ring opening under the effect of succinodehydrogenase and Lrax generates blue Formazan crystallization, and Formazan crystalline growing amount only is directly proportional with the viable cell number.This enzyme disappears in the dead cell, can not MTT be reduced.The Formazan crystallization that is reduced into generation can contain 50%; N; Dissolve in the MTT lysate of N-dimethylformamide and 20% sodium laurylsulfonate (pH4.7); Utilize ELIASA to measure the optical density(OD) OD value that 490 nm go out, the size of OD value is directly proportional with the Formazan crystalline amount that is generated, thereby reflects the influence of medicine pair cell surviving rate.
The measuring method of method
Behind the drug effect 48h, cell and 0.25mg/ml MTT are hatched 4h jointly under 37 ℃, every hole adds 100 μ l DMSO 99.8MIN.s (DMSO) behind the absorption nutrient solution, and the dissolving back uses ELIASA to measure its optical density(OD) OD value in 490nm fully.Be 100% with blank control group OD value at last, calculate and respectively organize cell inhibitory rate.
Figure DEST_PATH_IMAGE007
The C statistical method
All data adopt the analysis of testing of SPSS (13.0) statistical packages.Each organize data with the mean standard error (expression of Mean ± S.E.) adopts One-Way ANOVA to estimate globality difference, and carry out Dunnett or Dunnett ' s T3 check organize between relatively.
50 Method of calculation
Parameters such as each dosage and inhibiting rate are calculated with nonlinear regression and fitting IC 50
Experimental result
The result as Tab 2.1.1Shown in, in the concentration range that sets after the drug effect 48h, compound L XH-SYP-7, LXH-SYP-12, LXH-SYP-13 all has certain lethal effect to the U87 cell strain.Wherein the effect of compound L XH-SYP-7 is the most obvious, secondly is LXH-SYP-12 and LXH-SYP-13.Compound L XH-SYP-2, LXH-SYP-3, LXH-SYP-8, LXH-SYP-9, LXH-SYP-10, LXH-SYP-11, LXH-SYP-14 is though LXH-SYP-15 has certain lethal effect, DeGrain, IC to the U87 cell strain in set concentration range 50All greater than 100 μ mol/L.All the other compounds do not have lethal effect to the U87 cell strain basically in set concentration range.
The survival inhibiting rate to U87 of individual compound under different concns (% ) (Mean ± SE)
Numbering Control 0.1μmol/L 1μmol/L 10μmol/L 100μmol/L IC 50 (μmol/L)
LXH-SYP-1 0.00±1.22 2.41±0.58 -1.85±3.60 -2.95±5.31 -2.21±2.85 >;100
LXH-SYP-2 0.00±1.22 4.82±1.47 5.59±0.70 8.68±2.49 41.77±1.51*** >;100
LXH-SYP-3 0.00±1.22 2.43±1.49 4.29±0.53 4.25±1.00 17.43±1.61*** >;100
LXH-SYP- 4 0.00±0.76 -2.02±3.90 -2.17±2.67 0.12±1.57 -1.63±1.23 >;100
LXH-SYP-5 0.00±0.76 6.42±1.80 0.44±3.17 5.57±3.37 1.05±2.14 >;100
LXH-SYP-6 0.00±0.76 2±2.31 -1.54±1.97 -3.18±0.89 -0.74±0.81 >;100
LXH-SYP-7 0.00±0.68 7.69±1.39** 8.60±1.54*** 34.14±2.03*** 75.62±2.10*** 21.76±2.56
LXH-SYP-8 0.00±0.68 5.78±1.41 8.54±1.57* 7.95±1.58* 41.31±0.93*** >;100
LXH-SYP-9 0.00±0.82 6.05±1.08* 6.89±0.48*** 8.04±0.54*** 7.87±0.67*** >;100
LXH-SYP-10 0.00±0.82 2.29±0.43 3.40±1.21* 6.62±1.16*** 14.82±1.35*** >;100
LXH-SYP-11 0.00±0.96 -1.76±2.30 0.95±2.12 3.34±2.36 47.46±1.37*** >;100
LXH-SYP-12 0.00±0.96 0.69±1.65 1.47±2.25 2.43±1.45 82.96±1.06*** 41.17±0.86
LXH-SYP-13 0.00±1.37 1.25±1.23 3.74±1.91 11.16±2.12*** 83.06±0.60*** 32.07±3.38
LXH-SYP-14 0.00±1.37 1.71±0.82 3.03±1.97 15.51±1.24 13.34±1.04*** >;100
LXH-SYP-15 0.00±3.58 -1.93±1.13 3.89±1.34 3.89±1.08* 10.33±0.74** >;100
Cell?viabilities?were?determined?by?MTT?assay.?The?values?were?expressed?as?means?±?S.E.?The?data?were?obtained?from?three?separate?experiments.?Significance:?* P<0.05,?** P<0.01,?*** ?P<0.001?compared?with?control
2.2Target compound is right U251The experiment of cell strain proliferation inhibition activity
2.2.1 experiment purpose
To 15 compound L XH-SYP-1-LXH-SYP-15 that provided, the glioma cell line U87 that should choose adopts classical mtt assay to carry out antitumor activity screening.
Experiment material
A receives test product:
Compound L XH-SYP-1-LXH-SYP-15.
Experimental cell strain and source
Human glioma cell line U251 (available from ATCC)
The C experiment reagent
With experiment 2.1.2
2.2.3 experimental technique
With experiment 2.1.3
2.2.4 experimental result
The result as Tab 2.2.1Shown in, in the concentration range that sets after the drug effect 48h, compound L XH-SYP-2, LXH-SYP-7, LXH-SYP-11 all has certain lethal effect to the U87 cell strain.Wherein the effect of compound L XH-SYP-2 is the most obvious, secondly is LXH-SYP-11 and LXH-SYP-7.Though compound L XH-SYP-3, LXH-SYP-8, LXH-SYP-10, LXH-SYP-12 have certain lethal effect, DeGrain, IC to the U87 cell strain in set concentration range 50All greater than 100 μ mol/L.All the other compounds do not have lethal effect to the U87 cell strain basically in set concentration range.
The survival inhibiting rate to U251 under different concns of kind of compound (% ) (Mean ± SE)
Numbering Control 0.1μmol/L 1μmol/L 10μmol/L 100μmol/L IC 50 (μmol/L)
LXH-SYP-1 0.00±1.06 0.57±1.82 1.77±0.79 5.04±1.97 6.98±1.37 >;100
LXH-SYP-2 0.00±1.06 2.76±0.99 4.29±3.12 7.77±1.09** 77.58±1.32*** 47.45
LXH-SYP-3 0.00±1.06 0.84±1.38 1.90±0.64 2.67±1.34 8.40±1.08*** >;100
LXH-SYP- 4 0.00±1.86 0.14±1.48 1.46±1.39 1.89±1.40 2.79±2.47 >;100
LXH-SYP-5 0.00±1.86 0.22±1.19 0.47±0.59 0.33±0.60 1.32±0.63 >;100
LXH-SYP-6 0.00±1.86 -2.17±1.92 1.65±2.03 1.05±1.34 2.99±1.28 >;100
LXH-SYP-7 0.00±2.42 -3.50±2.13 1.57±4.04 16.65±2.75*** 59.24±3.09*** 63.80
LXH-SYP-8 0.00±2.42 -3.97±1.58 -4.91±0.99 -3.08±2.27 27.14±2.67*** >;100
LXH-SYP-9 0.00±2.42 -8.87±2.61 -5.73±0.39 -6.96±1.15 0.93±1.20 >;100
LXH-SYP-10 0.00±1.25 -6.07±1.97 -5.01±0.49 -3.33±1.31 7.42±2.72*** >;100
LXH-SYP-11 0.00±1.25 -5.59±1.83 -3.56±1.67 -3.81±1.63 72.29±0.70*** 70.09
LXH-SYP-12 0.00±1.25 -9.06±0.69 -6.70±0.78 -8.63±0.54 28.87±1.13*** >;100
LXH-SYP-13 0.00±1.80 -6.91±1.22 -4.32±3.92 -7.95±2.05 -7.12±0.84 >;100
LXH-SYP-14 0.00±1.80 -11.61±2.70 -13.65±0.89 -8.75±1.81 -4.79±1.77 >;100
LXH-SYP-15 0.00±1.80 -11.61±2.70 -13.65±0.63 -8.75±1.81 -4.80±1.22 >;100
Cell?viabilities?were?determined?by?MTT?assay.?The?values?were?expressed?as?means?±?S.E.?The?data?were?obtained?from?three?separate?experiments.?Significance:?* P<0.05,?** P<0.01,?*** ?P<0.001?compared?with?control.
2.3Compound LXH-SYP-7To nine kinds of cell strain proliferation inhibition activity experiments
2.3.1 experiment purpose
To the compound L XH-SYP-7 that is provided, adopt classical mtt assay to carry out antitumor activity screening.At first select for use people's glioma cell line U87, people's glioma cell line U251 and human leukemia cell HL-60 as research object; After obtaining the result that LXH-SYP-7 significantly suppresses U87, U251 and HL-60 propagation, further enlarge the anti-tumor activity of the tumor cell line kind test compounds LXH-SYP-7 of screening.
Experiment material
A receives test product:
Compound L XH-SYP-7.
Experimental cell strain and source
People's glioma cell line U87 (available from ATCC)
Human liver cancer cell Hep 3B (available from ATCC)
The human lung cancer cell A549 (available from ATCC)
Human colon cancer cell Colon (available from ATCC)
Human Prostate Cancer Cells Du145 (available from ATCC)
Gastric carcinoma cells HGC (available from ATCC)
Human leukemia cell HL-60 (available from ATCC)
People's glioma cell line U251 (available from ATCC)
Rat glioma cell line C6 (available from ATCC)
The C experiment reagent
With experiment 2.1.2
2.3.3 experimental technique
With experiment 3.2.1.3
3.2.3.4 experimental result
The result as Tab 2.3.1Shown in, after the drug effect 48h, compound L XH-SYP-7 all has certain lethal effect to HL-60, U87, U251, HGC, C6 cell strain in the concentration range that sets.Wherein compound L XH-SYP-7 is the most obvious to the effect of HL-60 cell strain, secondly is U87, U251, C6 and HGC cell strain.Though compound L XH-SYP-7 has certain lethal effect, DeGrain, IC to Hep 3B, colon-205, Du145, A549 cell strain in set concentration range 50Greater than 100 μ mol/L.Positive control compound L XH-RS-A all has certain lethal effect, IC to HL-60, U87, C6 and HGC cell strain 50Value is respectively 13.94 μ mol/L, 41.98 μ mol/L, 71.27 μ mol/L, 32.61 μ mol/L.
The survival inhibiting rate to nine kinds of cell strains under the compound L XH-SYP-7 different concns (% ) (Mean ± SE)
Numbering Control 0.1μmol/L 1μmol/L 10μmol/L 100μmol/L IC 50 (μmol/L)
HL-60 0.00±1.08 1.80±0.99 41.72±1.53*** 78.49±0.30*** 88.75±0.51*** 2.41
U-87 0.00±0.68 7.69±1.39** 8.60±1.54*** 34.14±2.03*** 75.62±2.10*** 21.76
C6 0.00±2.32 -4.78±1.67 0.59±2.42 27.37±4.24* 39.41±1.92*** 61.77
U-251 0.00±2.42 -3.50±2.13 1.57±4.04 16.65±2.75*** 59.24±3.09*** 63.8
HGC 0.00±1.50 -1.50±2.72 1.19±0.98 7.73±3.42 39.11±1.93*** 92.29
3B 0.00±1.16 3.38±2.76* -1.99±1.99 4.04±0.89* 36.18±0.57*** >;100
colon 0.00±1.24 -4.83±0.40** -2.42±0.58* -3.20±1.70* 16.13±1.30*** >;100
DU-145 0.00±0.00 2.40±0.27** 2.92±0.85* 4.79±0.46** 36.85±1.02*** >;100
A549 0.00±0.29 4.95±0.28*** 7.26±1.18*** 5.59±1.18*** 8.70±0.97*** >;100
***P<0.001?Vs?Control; **P<0.01?Vs?Control; *P<0.05?Vs?Control
Tab. the survival inhibiting rate under the 2.3.2 positive drug 5-Fu different concns to nine kinds of cell strains (% ) (Mean ± SE)
? control 0.1μmol/L 1μmol/L 10μmol/L 100μmol/L IC 50 (μmol/L)
HL-60 0.00±2.71 9.60±0.97 11.64±1.07 11.02±0.91 19.01±1.06* <100
U-87 0.00±1.44 -1.92±1.01 0.60±1.44 14.87±1.09*** 42.11±1.35*** 144.81
C6 0.00±2.32 12.83±2.73 26.31±1.01** 40.89±0.92*** 49.56±0.67*** 64.63
U-251 0.00±2.71 9.60±0.97 11.64±1.07 11.02±0.91 19.01±1.06* >;100
HGC 0.00±1.50 3.26±1.24 17.26±1.86* 24.76±1.28** 52.60±0.94*** 72.98
3B 0.00±3.37 7.83±3.78 29.61±1.13** 48.12±0.27** 52.24±0.09** 39.27
colon 0.00±7.19 25.95±1.07* 39.59±0.14* 55.91±2.54** 66.08±0.28** 5.55
DU-145 0.00±1.05 3.75±1.42** 4.46±0.96** 16.03±0.23*** 29.32±0.55*** >;100
A549 0.00±0.16 5.02±0.08*** 1.20±1.00 6.06±0.60** 12.99±1.86** >;100
*** P<0.001?Vs?Control; ** P<0.01?Vs?Control; * P<0.05?Vs?Control

Claims (9)

  1. As logical formula I described 2,2-dimethylbiphenyl pyran compounds:
    Figure 664161DEST_PATH_IMAGE001
    Wherein R ' is H, C 1-6Alkyl; R is for replacing or unsubstituted aromatic ring or fragrant heterocycle.
  2. 2. according to claim 12,2-dimethylbiphenyl pyran compounds is characterized in that: the alkyl among the R ' refers to have the straight or branched alkyl of 1-6 carbon atom; The R aromatic ring refers to phenyl or naphthyl, and substituent phenyl or naphthyl is arranged, the position of substitution can be positioned at phenyl ring the neighbour,, any position of contraposition or naphthalene nucleus, single replace or polysubstituted,, substituting group is halogen, alkyl and alkoxyl group; The virtue heterocycle refers to pyridine ring, thiphene ring, pyrimidine ring, indole ring, quinoline ring, isoquinoline 99.9 ring, pyrrole ring, pyrazoles ring, benzoglyoxaline, benzopyrrole ring, benzopyrazoles ring etc.; Substituting group is in any position of fragrant heterocyclic; Single replacement or polysubstituted, substituting group is halogen, alkyl and alkoxyl group.
  3. 3. according to claim 22,2-dimethylbiphenyl pyran compounds is characterized in that: the alkyl on aromatic ring and the fragrant heterocycle in the substituting group alkyl refers to have the straight or branched alkyl of 1-6 carbon atom.
  4. 4. according to claim 22,2-dimethylbiphenyl pyran compounds is characterized in that: the alkyl of the alkoxyl group on aromatic ring and the fragrant heterocycle in the substituting group alkoxyl group refers to have the straight or branched alkyl of 1-6 carbon atom.
  5. 5. each is described 2 according to claim 1-4, and 2-dimethylbiphenyl pyran compounds is characterized in that, described compound comprises its pharmaceutically acceptable salt, comprises its hydrochloride, hydrobromate, vitriol, various organic acid salts etc.
  6. 6. according to each is described 2 among the claim 1-5,2-dimethylbiphenyl pyran compounds is characterized in that, 2, and the preferred following compounds of 2-dimethylbiphenyl pyran compounds:
    Figure 381582DEST_PATH_IMAGE002
    。
  7. 7.2 2-dimethylbiphenyl pyran compounds and salt are at the preparation anticarcinogen, and is anti-oxidant, eliminates radical and suppress the application in the microglial activation medicine.
  8. One kind as claimed in claim 12, the preparation method of 2-dimethylbiphenyl pyran compounds is characterized in that:
    The building-up reactions flow process of The compounds of this invention is following:
    Figure 776791DEST_PATH_IMAGE003
    。
  9. 9. preparation method as claimed in claim 8 is characterized in that, concrete steps are:
    (1) preparation 3-chloro-3-methyl isophthalic acid-butine (I)
    2-methyl-Ding-3-alkynes-2 alcohol and concentrated hydrochloric acid are under the effect of catalyzer calcium chloride, and chloro obtains 3-chloro-3-methyl isophthalic acid-butine;
    (2) preparation 2-hydroxyl-4-(2-methyl fourth-3-alkynes-2-oxygen base) methyl phenyl ketone (II)
    2,4-resacetophenone and 3-chloro-3-methyl isophthalic acid-butine are in suitable solvent, and under the effect of catalyzer KI and solid alkali such as sodium hydroxide (potassium), yellow soda ash (potassium) etc., condensation obtains 2-hydroxyl-4-(2-methyl fourth-3-alkynes-2-oxygen base) methyl phenyl ketone (II);
    (3) preparation 1-( 5-Hydroxyl -2,2-Two -2 H- Chromogen alkene -6-Base) methyl phenyl ketone (III)
    2-hydroxyl-4-(2-methyl fourth-3-alkynes-2-oxygen base) methyl phenyl ketone backflow cyclization in high boiling solvents such as phenyl ether obtains 1-( 5-Hydroxyl -2,2-Two -2 H- Chromogen alkene -6-Base) methyl phenyl ketone (III);
    (4) preparation target compound 2,2-dimethylbiphenyl pyran compounds (IV);
    (5-hydroxyl-2,2-two-2 for 1- H-chromogen alkene-6-yl) condensation under sulphuric acid catalysis of ethyl ketone and various aldehyde obtains target compound.
CN2010105782897A 2010-12-08 2010-12-08 2,2-dimethyl benzopyran compound and preparation method and application thereof Pending CN102532082A (en)

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CN116283936A (en) * 2023-02-20 2023-06-23 沈阳药科大学 Substituted amino ether-containing 2, 2-dimethyl benzopyran derivative and salt or solvate thereof, preparation and application thereof, and composition
CN117603175A (en) * 2023-11-27 2024-02-27 南开大学 Chalcone derivative with benzopyran structure, and preparation method and application thereof

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Publication number Priority date Publication date Assignee Title
CN107540566A (en) * 2017-08-28 2018-01-05 江苏绿叶农化有限公司 A kind of preparation method of propyzamide
CN109096235A (en) * 2018-11-01 2018-12-28 沈阳药科大学 2,2- dimethylebenzopyran analog derivative and its preparation method and application
CN109096235B (en) * 2018-11-01 2022-06-21 沈阳药科大学 2, 2-dimethyl benzopyran derivative and preparation method and application thereof
CN116283936A (en) * 2023-02-20 2023-06-23 沈阳药科大学 Substituted amino ether-containing 2, 2-dimethyl benzopyran derivative and salt or solvate thereof, preparation and application thereof, and composition
CN117603175A (en) * 2023-11-27 2024-02-27 南开大学 Chalcone derivative with benzopyran structure, and preparation method and application thereof
CN117603175B (en) * 2023-11-27 2024-08-06 南开大学 Chalcone derivative with benzopyran structure, and preparation method and application thereof

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