CN109748785A - Two aromatic hydrocarbon substituted propenone class compounds of one kind and preparation method and application - Google Patents

Two aromatic hydrocarbon substituted propenone class compounds of one kind and preparation method and application Download PDF

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CN109748785A
CN109748785A CN201910032299.1A CN201910032299A CN109748785A CN 109748785 A CN109748785 A CN 109748785A CN 201910032299 A CN201910032299 A CN 201910032299A CN 109748785 A CN109748785 A CN 109748785A
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phenyl
methyl
chloro
acryloyl
bis
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赵桂森
戴长浩
刘洋
郑静
郭凯文
王鲁华
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Shandong University
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Shandong University
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Priority to CN202010022360.7A priority patent/CN111004107B/en
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Abstract

The invention discloses a kind of two aromatic hydrocarbon substituted propenone class compounds and preparation method and applications, shown in structural formula such as formula (I):Wherein A is

Description

Two aromatic hydrocarbon substituted propenone class compounds of one kind and preparation method and application
Technical field
The invention belongs to organic compound synthesis and medical applications technical fields, and in particular to two fragrance of one kind replaces propylene Ketone compounds and preparation method and application.
Background technique
Here statement only provides background information related to the present invention, without necessarily constituting the prior art.
Lymphoma mantle cell (Mantle cell lymphoma, MCL) is that a kind of grade malignancy is high, the B of prognosis mala is thin Born of the same parents' non-Hodgkin lymphoma (Non-Hodgkin lymphoma, NHL) is one of life cycle shortest lymthoma hypotype.According to Shandong It is the oral BTK covalency inhibitor of first listing for Buddhist nun (Ibrutinib, IBN).Clinical research shows: application is controlled according to Shandong for Buddhist nun It treats recurrence and intractable MCL patient (the median age 68 years old) is significant in efficacy, Overall response rate (overall response rate, It ORR) is 68%.Based on this clinical test results, U.S. FDA in November, 2013 is ratified according to Shandong for Buddhist nun for treating recurrence and hardly possible The property controlled MCL patient.
However, most MCL patients occur replacing Buddhist nun's drug resistance phenomenon according to Shandong, and patient replaces Buddhist nun to according to Shandong with the progress for the treatment of It can be dead in 12 months after drug resistance.The hot spot for being developed into research of novel MCL therapeutic agent as a result,.
Summary of the invention
The phenomenon that for MCL patient to Buddhist nun's drug resistance is replaced according to Shandong, the object of the present invention is to provide one kind, and there is MCL cell to inhibit Active two fragrant substituted propenone class compounds and preparation method and application, which has structure novel, to MCL cell With the advantages such as inhibitory activity effect, preparation cost be cheap, the very promising drug of MCL can be used as.
To achieve the goals above, the technical solution of the present invention is as follows:
The first aspect of the present invention provides a kind of formula (I) compound represented or its pharmaceutically acceptable salt,
Wherein A is B is hydrogen, methyl or ethyl；C is to take For phenyl ring, pyridine and furans heterocycle, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 5-1H- indyl, 4- (N, TMSDMA N dimethylamine base) Phenyl, 4- (N- pyrrole radicals) phenyl, 4- [1- (N-methyl piperazine base)] phenyl or 4- (1- morpholinyl) phenyl.
Preferably, A isB is H；C is To dimethylamino phenyl, p-nitrophenyl, p-methoxyphenyl, to cyano-phenyl, p-fluorophenyl, rubigan, p-bromophenyl, 2- pyridyl group, 3- pyridyl group or 4- pyridyl group.
Preferably, the compound has structure shown in formula (II):
Wherein, wherein R1For methyl or ethyl；R2For hydrogen, methyl or ethyl；R3For phenyl ring, substituted benzene ring, pyridine and furans Heterocycle.The substituted benzene ring be benzene radicals one or more hydrogen replaced by other groups, other groups be halogen, cyano, Amido, methoxyl group, nitro etc..
It is further preferred that R1For methyl, R2For hydrogen, R3For phenyl ring, substituted benzene ring, pyridine and furans heterocycle.
Preferably, the compound has structure shown in formula (III):
Wherein, R4For 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 5-1H- indyl, 4- (N, TMSDMA N dimethylamine base) phenyl, 4- (N- pyrrole radicals) phenyl, 4- [1- (N-methyl piperazine base)] phenyl or 4- (1- morpholinyl) phenyl；R5For
Preferably, include following compound:
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (2- ethyl -3- phenyl) acryloyl] } phenyl ether (II a)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (2- methoxyphenyl)] acryloyl } } phenyl ether (II b)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (3- methoxyphenyl)] acryloyl } } phenyl ether (II c)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- methoxyphenyl)] acryloyl } } phenyl ether (II d)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- dimethylamino phenyl)] acryloyl } } phenyl ether (II e)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- cyano-phenyl)] acryloyl } } phenyl ether (II f)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- nitrobenzophenone)] acryloyl } } phenyl ether (II g)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- fluorophenyl)] acryloyl } } phenyl ether (II h)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- chlorphenyl)] acryloyl } } phenyl ether (II i)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- bromophenyl)] acryloyl } } phenyl ether (II j)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (furans -2- base)] acryloyl } } phenyl ether (II k)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (pyridin-4-yl)] acryloyl } } phenyl ether (II l)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (naphthalene -1- base)] acryloyl } } phenyl ether (II m)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (2,3- dioxane simultaneously [b] [1,4] -6- base)] propylene Acyl } } phenyl ether (II n)；
(E)-methyl-[the chloro- 4- of 2,3- bis- (3- phenylacryloyl)] phenyl ether (II o)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (2- methyl -3- phenyl) acryloyl] } phenyl ether (II p)；
(E)-ethyl-{ the chloro- 4- of 2,3- bis- [3- (2- ethyl -3- phenyl) acryloyl] } phenyl ether (II q)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (2- pyridyl group) acryloyl] } phenyl ether (III -1a)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (3- pyridyl group) acryloyl] } phenyl ether (III -1b)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (4- pyridyl group) acryloyl] } phenyl ether (III -1c)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (5-1H- indyl) acryloyl] } phenyl ether (III -1d)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [4- (N, TMSDMA N dimethylamine base) phenyl] acryloyl } } phenyl ether (III -1e)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [4- (N- pyrrole radicals) phenyl] acryloyl } } phenyl ether (III -1f)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- { 4- [1- (N-methyl piperazine base)] phenyl } acryloyl } } phenyl ether (III- 1g)；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [4- (1- morpholinyl) phenyl] acryloyl } } phenyl ether (III -1h)；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethyl alcohol (III -2a)；
(E) the chloro- 4- of -2,3- two [3- (4- dimethylaminophenyl) acryloyl] phenoxyacetonitrile (III -2b)；
(E)-methyl -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethylether (III - 2c)；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethyl piperidine (III -2d)；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethyl morpholine (III -2e)；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group }-N- methylacetamide (III - 3a)；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group }-DMAC N,N' dimethyl acetamide (Ⅲ-3b)；
(E) the chloro- 4- of -2- acetyl pyrrole base -2,3- two [3- (4- dimethylaminophenyl) acryloyl] phenyl ether (III -3c)；
(E) the chloro- 4- of -2- acetyl morphine base -2,3- two [3- (4- dimethylaminophenyl) acryloyl] phenyl ether (III -3d)；
(E) the chloro- 4- of -2,3- two [3- (4- dimethylaminophenyl) acryloyl] aniline (III -4).
The structural formula of above compound is as follows:
It is its corresponding code name in bracket after above-mentioned preferred 35 compound names, it is simple with expression for sake of convenience Clean, the code name in above-mentioned bracket will be directly applied in this specification the following contents.
The second aspect of the present invention provides a kind of preparation method of above compound comprising with intermediate 1 be starting Raw material prepares formula (I) compound by following reaction route:
Wherein, A is B is hydrogen, first Base or ethyl；C is substituted benzene ring, pyridine and furans heterocycle, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 5-1H- indyl, 4- (N, TMSDMA N dimethylamine base) phenyl, 4- (N- pyrrole radicals) phenyl, 4- [1- (N-methyl piperazine base)] phenyl or 4- (1- morpholinyl) benzene Base；R2For hydrogen, methyl or ethyl；R5For
Preferably, the reaction route of formula (II) compound is as follows:
R1For methyl or ethyl；R2For hydrogen, methyl or ethyl；R3For phenyl ring, substituted benzene ring, pyridine and furans heterocycle.
Reagent and condition: (a) dimethyl suflfate/dithyl sulfate, 50%KOH, toluene, 100 DEG C；(b) n-butyryl chloride/the third Acyl chlorides/chloroacetic chloride, alchlor, methylene chloride, 0 DEG C；(c) replace aldehyde, sodium ethoxide, dehydrated alcohol, room temperature.
It is further preferred that formula (II) compound the preparation method comprises the following steps: with 2,3- chlorophenesic acid (1) is starting material, with Dimethyl suflfate or dithyl sulfate reaction obtain midbody compound 2,2 compound represented of formula and substitution acyl chloride reaction, Compound shown in formula M-1, compound shown in formula M-1 and substitution aldehyde reaction are obtained, formula (II) compound represented is obtained；Wherein Replace acyl chlorides beReplace aldehyde be
Preferably, the reaction route of formula (III) compound is as follows:
Wherein, R4For 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 5-1H- indyl, 4- (N, TMSDMA N dimethylamine base) phenyl, 4- (N- pyrrole radicals) phenyl, 4- [1- (N-methyl piperazine base)] phenyl or 4- (1- morpholinyl) phenyl；R6For ethyl alcohol base, acetonitrile Base, methoxy ethyl, ethyl piperidine base, ethyl morpholine base；R7For N- methyl vinyl amido, n,N-dimethylacetamide base, second Acyl pyrrole radicals or acetyl morphine base.
Reagent and condition: (c) replaces aldehyde, sodium ethoxide, dehydrated alcohol, room temperature；(e) alchlor, methylene chloride, 40 DEG C； (f) halides, potassium carbonate, potassium iodide, acetone, 60 DEG C；(g) Anhydrous potassium carbonate, potassium iodide, bromoacetate, 1N hydrochloric acid, third Ketone, ethyl alcohol, 60 DEG C；(h) EDCI (1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride), HOBt (1- hydroxy benzo Triazole), n,N-Dimethylformamide, room temperature；(i) 4- (N, TMSDMA N dimethylamine base) benzaldehyde, sodium ethoxide, dehydrated alcohol, room temperature.
It is further preferred that formula (III) compound the preparation method comprises the following steps: formula M-1a and replace aldehyde reaction, obtain compound III -1a~III -1h, formula M-1a react to obtain intermediate 3, compound shown in formula 3 and bromoacetate with aluminum trichloride (anhydrous) Intermediate 4 is reacted to obtain, compound shown in formula 3 is reacted with halides, obtains intermediate M-2a~M-2e, intermediate M-2a~M-2e It being reacted with 4- (N, TMSDMA N dimethylamine base) benzaldehyde, obtains the target compound -2e of III -2a~III, compound shown in formula 4 is reacted with amine, The reaction of intermediate M-3a~M-3d, intermediate M-3a~M-3d and 4- (N, TMSDMA N dimethylamine base) benzaldehyde is obtained, target compound is obtained - the 3d of III -3a~III, compound shown in formula 3 are reacted with 2- chloroacetamide, obtain target compound III -4；Wherein, halides areAmine is Replace aldehyde be
Preferably, specific synthesis step is as follows:
(1) 2,3- chlorophenesic acid is dissolved in toluene, 50% potassium hydroxide solution, 30min is slowly dropped under stirring condition Afterwards, dimethyl suflfate is at the uniform velocity instilled.100 DEG C of reaction 5h are slowly dropped into 50% potassium hydroxide solution, continue back flow reaction 1h.It crosses Filter, filtrate are extracted with ethyl acetate three times, combined ethyl acetate, successively use saturated sodium carbonate solution, and saturated sodium chloride solution is washed It washs three times, anhydrous sodium sulfate dries, filters, and solvent is evaporated off in filtrate decompression, intermediate 2a is obtained, wherein 2,3- chlorophenesic acids, sulfuric acid The molar ratio of dimethyl ester is 1:2.
(2) 2,3- chlorophenesic acid is dissolved in toluene, 50% potassium hydroxide solution, 30min is slowly dropped under stirring condition Afterwards, dithyl sulfate is at the uniform velocity instilled.100 DEG C of reaction 5h are slowly dropped into 50% potassium hydroxide solution, continue back flow reaction 1h.It crosses Filter, filtrate are extracted with ethyl acetate three times, combined ethyl acetate, successively use saturated sodium carbonate solution, and saturated sodium chloride solution is washed It washs three times, anhydrous sodium sulfate dries, filters, and solvent is evaporated off in filtrate decompression, intermediate 2b is obtained, wherein 2,3- chlorophenesic acids, sulfuric acid The molar ratio of diethylester is 1:2.
(3) under condition of ice bath, alchlor is added in the dichloromethane solution of intermediate 2；It finishes, substitution is slowly added dropwise Acyl chlorides after reacting 3h, reacts at room temperature 8h.Reaction is finished, and under condition of ice bath, reaction solution is poured into excessive 1M hydrochloric acid solution, dichloro Methane extracts three times, merges methylene chloride, saturated sodium bicarbonate solution washing, and water and saturated sodium chloride solution are washed three times, nothing Aqueous sodium persulfate dries, filters, and solvent is evaporated off in filtrate decompression, and (elution system is petrol ether/ethyl acetate=8:1 to silica gel column chromatography ~5:1) intermediate M-1, wherein alchlor, intermediate 2, replace acyl chlorides molar ratio be 1.5:1:1.5, the intermediate In M-1, R1 is methyl or ethyl；R2 is hydrogen, methyl or ethyl.
(4) intermediate M-1 is dissolved in ethyl alcohol, 1M potassium hydroxide solution is added dropwise, finishes, be added and replace aldehyde.It is stirred at room temperature 24h.Reaction is finished, and filtering, filter cake washs with methanol, obtains target product II, wherein intermediate M-1, potassium hydroxide, replace rubbing for aldehyde You are than being 1:1.2:1, in the target product II, R1For methyl or ethyl；R2For hydrogen, methyl or ethyl；R3For substituted benzene ring, Pyridine and furans heterocycle；
(5) amine will be replaced to be dissolved in n,N-Dimethylformamide, Anhydrous potassium carbonate is added, be warming up to 80 DEG C, stirring 4- fluorobenzaldehyde is then added in 30min, and 80 DEG C of reactions are for 24 hours.Reaction system is poured into ice water, is extracted with ethyl acetate three times, Combined ethyl acetate, saturated sodium chloride solution are washed three times, and anhydrous sodium sulfate dries, filters, and solvent, silica gel is evaporated off in filtrate decompression Column chromatography (elution system is petrol ether/ethyl acetate=5:1), obtains intermediate Y, wherein replacing amine, Anhydrous potassium carbonate, 4- fluorobenzene The molar ratio of formaldehyde is 3:3:1；Wherein substitution amine is
(6) ethanol solution is added in metallic sodium, alcohol sodium solution is made in stirring and dissolving, and intermediate M-1a is then added in Mesosome Y replaces aldehyde, and 24~36h is stirred at room temperature.Reaction is finished, and is precipitated if any solid, filtering, and a small amount of methanol washing of filter cake obtains Target product III -1a~III -1h adds water if solid is not precipitated, and is extracted with ethyl acetate three times, combined ethyl acetate, with saturation Sodium chloride solution washs three times, and anhydrous sodium sulfate dries, filters, and filtrate decompression is evaporated off solvent, and (elution system is silica gel column chromatography Petrol ether/ethyl acetate=2:1) to get.Wherein the molar ratio of intermediate M-1a, intermediate Y or substitution aldehyde is 1:1, the mesh It marks in product III -1a~III -1h, R4 is 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 5-1H- indyl, 4- (N, TMSDMA N dimethylamine Base) phenyl, 4- (N- pyrrole radicals) phenyl, 4- [1- (N-methyl piperazine base)] phenyl or 4- (1- morpholinyl) phenyl；R5 is methyl.
(7) under condition of ice bath, aluminum trichloride (anhydrous) is added dissolved in the dichloromethane solution of steaming again of intermediate M-1a.Add Finish, 40 DEG C of reactions are for 24 hours.Reaction is finished, and reaction solution is poured into cold 1M hydrochloric acid solution, is extracted with dichloromethane three times, is merged two Chloromethanes successively uses saturated sodium bicarbonate solution, and three times, anhydrous sodium sulfate dries, filters for water and saturated sodium chloride solution washing, Solvent is evaporated off in filtrate decompression, is recrystallized with petrol ether/ethyl acetate, obtain intermediate 3, wherein alchlor, intermediate M-1a Molar ratio is 3:1.
(8) intermediate 3 is dissolved in 20mL acetone, addition Anhydrous potassium carbonate, potassium iodide, after 60 DEG C of stirring 30min, is added Halides react 20h.Reaction is finished, evaporating solvent under reduced pressure, silica gel column chromatography (elution system is petrol ether/ethyl acetate=3: 1) intermediate M-2a~M-2e, is obtained, wherein intermediate 3, Anhydrous potassium carbonate, potassium iodide, the molar ratio of halides are 1:3:0.2: In 2, the intermediate M-2a~M-2e, R6 is ethyl alcohol base, acetonitrile-base, methoxy ethyl, ethyl piperidine base, ethyl morpholine base.
(9) ethanol solution is added in metallic sodium, alcohol sodium solution is made in stirring and dissolving, and intermediate M-2a~M- is then added 2e and 4- dimethylaminobenzaldehyde, is stirred at room temperature 24~36h.Reaction is finished, and is precipitated if any solid, and filtering, a small amount of methanol of filter cake is washed It washs, obtains target product III -2a~III -2e if solid is not precipitated and add water, be extracted with ethyl acetate three times, merge acetic acid second Ester is washed three times with saturated sodium chloride solution, and anhydrous sodium sulfate dries, filters, and solvent, silica gel column chromatography is evaporated off in filtrate decompression (elution system be petrol ether/ethyl acetate=2:1) to get.Wherein intermediate M-2a~M-2e, 4- dimethylaminobenzaldehyde Molar ratio is 1:1.In the target product III -2a~III -2e, R4 is 4- (N, TMSDMA N dimethylamine base) phenyl；R6 is ethyl alcohol base, second Itrile group, methoxy ethyl, ethyl piperidine base, ethyl morpholine base.
(10) intermediate 3 is dissolved in acetone, Anhydrous potassium carbonate, potassium iodide is added, 60 DEG C of stirring 10min instill bromine second Acetoacetic ester reacts 6h.Reaction is finished, and evaporating solvent under reduced pressure, silica gel column chromatography obtains crude product.Above-mentioned crude product is dissolved in 10mL ethyl alcohol, Potassium hydroxide solution is added, reacts at room temperature 3h.Reaction is finished, and is removed ethyl alcohol under reduced pressure, is about 1 with 1M hydrochloric acid solution tune pH, is filtered, and is done Dry intermediate 4, wherein intermediate 3, Anhydrous potassium carbonate, potassium iodide, bromoacetate, potassium hydroxide molar ratio be 1:3: 0.2:2:1.2。
(11) intermediate 4 is dissolved in n,N-Dimethylformamide, under condition of ice bath, EDCI, HOBt is added.Continue to stir After 1h, amine is added.It finishes, reacts at room temperature 4h.Reaction solution is poured into ice water by end of reaction, three times with ether extraction, merges second Ether successively uses water, and saturated sodium chloride solution is washed three times, and anhydrous sodium sulfate dries, filters, and solvent is evaporated off in filtrate decompression, obtains slightly Product obtain intermediate M-3a~M-3d with petroleum ether/acetone recrystallization, wherein intermediate 4, EDCI, HOBt, amine molar ratio be 1:1.2:1.2:1.In the intermediate M-3a~M-3d, R7 is N- methyl vinyl amido, n,N-dimethylacetamide base, acetyl Pyrrole radicals, acetyl morphine base.
(12) ethanol solution being added in metallic sodium, alcohol sodium solution is made in stirring and dissolving, subsequent addition intermediate M-3a~ M-3d and 4- dimethylaminobenzaldehyde, is stirred at room temperature 24~36h.Reaction is finished, and is precipitated if any solid, filtering, a small amount of methanol of filter cake Washing, obtains target product III -3a~III -3d if solid is not precipitated and adds water, is extracted with ethyl acetate three times, merges acetic acid second Ester is washed three times with saturated sodium chloride solution, and anhydrous sodium sulfate dries, filters, and solvent, silica gel column chromatography is evaporated off in filtrate decompression (elution system be petrol ether/ethyl acetate=2:1) to get.Wherein intermediate M-3a~M-3d, 4- dimethylaminobenzaldehyde Molar ratio is 1:1, and in the target product III -3a~III -3d, R4 is 4- (N, TMSDMA N dimethylamine base) phenyl；R7 is N- methyl second Amide groups, n,N-dimethylacetamide base, acetyl pyrrole base or acetyl morphine base.
(13) intermediate 3 is dissolved in 20mL acetone, addition Anhydrous potassium carbonate, potassium iodide, after 60 DEG C of stirring 30min, is added Enter 2- chloroacetamide, reacts 20h.Reaction is finished, and evaporating solvent under reduced pressure, (elution system is petrol ether/ethyl acetate to silica gel column chromatography =3:1), intermediate M-4 is obtained, wherein intermediate 3, Anhydrous potassium carbonate, potassium iodide, the molar ratio of chloroacetamide are 1:3:0.2:2.
(14) ethanol solution is added in metallic sodium, alcohol sodium solution is made in stirring and dissolving, and intermediate M-4 and 4- is then added 24~36h is stirred at room temperature in dimethylaminobenzaldehyde.Reaction is finished, and is precipitated if any solid, filtering, and a small amount of methanol washing of filter cake obtains Target product III -4 adds water if solid is not precipitated, and is extracted with ethyl acetate three times, and combined ethyl acetate is molten with saturated sodium-chloride Liquid washs three times, and anhydrous sodium sulfate dries, filters, and filtrate decompression is evaporated off solvent, silica gel column chromatography (elution system be petroleum ether/ Ethyl acetate=2:1) to get.Wherein the molar ratio of intermediate M-4,4- dimethylaminobenzaldehyde is 1:1.
The third aspect of the present invention provide a kind of above compound or its pharmaceutically acceptable salt preparation prevention and/ Or the purposes in the drug for the treatment of tumour.
Preferably, the tumour is lymphoma mantle cell.
The fourth aspect of the present invention provides a kind of pharmaceutical composition, and comprising above compound or its is pharmaceutically acceptable Salt.
It preferably, further include excipient and/or diluent.
The fifth aspect of the present invention provides a kind of pharmaceutical preparation, includes effective component and pharmaceutically acceptable auxiliary material And/or carrier, the effective component are above compound or its pharmaceutically acceptable salt or aforementioned pharmaceutical compositions.
Auxiliary material used can be solid-state or liquid.The preparation of solid-state form includes pulvis, tablet, discrete particles, capsule, medicine Ball and suppository.Pulvis and tablet can include about the active constituent of 5% to about 95%.Solid adjuvant material appropriate can be magnesium carbonate, Magnesium stearate, talcum powder, sugar or lactose.Tablet, pulvis, pill and capsule are suitable for solid dosage for oral use.Liquid shape The preparation of formula includes solution, suspension and lotion, can be parenteral injection aqueous solution or water-propylene glycol solution, can also be with Add the oral administration solution of sweetener and contrast agent.In addition, may also be fabricated which the small water needle of injection, injection freeze-dried powder, big infusion Or primary infusion.
Preferably, the pharmaceutical preparation is solid orally ingestible, liquid oral medicine or injection.
It is further preferred that the pharmaceutical preparation is tablet, dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, sugar-coat Agent, granule, dry powder doses, oral solution, the small water needle of injection, injection freeze-dried powder, big infusion or primary infusion.
The invention has the benefit that
Experimental data of the invention proves that the compound of preparation all has MCL cell growth inhibiting activity, and wherein certain A little compounds, such as II o, III -1a, III -1b, III -1c, III -4 etc. are much higher than MCL cell growth inhibiting activity and replace according to Shandong Buddhist nun is expected to as the alternatives to medication for replacing Buddhist nun according to Shandong.
Specific embodiment
It is noted that described further below be all exemplary, it is intended to provide further instruction to the disclosure.Unless another It indicates, all technical and scientific terms used herein has usual with disclosure person of an ordinary skill in the technical field The identical meanings of understanding.
It should be noted that term used herein above is merely to describe specific embodiment, and be not intended to restricted root According to the illustrative embodiments of the disclosure.As used herein, unless the context clearly indicates otherwise, otherwise singular Also it is intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet Include " when, indicate existing characteristics, step, operation, device, component and/or their combination.
In order to enable those skilled in the art can clearly understand the technical solution of the disclosure, below with reference to tool The technical solution of the disclosure is described in detail in the embodiment of body.
Embodiment 1: the preparation of target compound II a~II q
(1) synthesis of intermediate 2
2,3- chlorophenesic acid (0.1mol) is dissolved in 10mL toluene, it is molten that 50% potassium hydroxide is slowly dropped under stirring condition Liquid (0.2mol), after 30min, at the uniform velocity instillation dimethyl suflfate or dithyl sulfate (0.2mol).100 DEG C of reaction 5h.Reaction is finished, It is slowly dropped into 50% potassium hydroxide solution (0.2mol), continues back flow reaction 1h.Filtering, filtrate extract three with 50mL ethyl acetate Secondary, combined ethyl acetate is successively saturated Na with 200ml2CO3Solution, saturated sodium chloride solution are washed three times, and anhydrous sodium sulfate is dry Dry, filtering, filtrate decompression is evaporated off solvent, obtains intermediate 2a or 2b.
The chloro- 3- methoxybenzene (2a) of 1,2- bis-
White solid, yield 96.6%,1H NMR (400MHz, DMSO-d6) δ (ppm): 7.35 (t, J=8.4Hz, 1H), 7.21 (dd, J1=8.4Hz, J2=1.2Hz, 1H), 7.15 (d, J=8.4Hz, 1H), 3.88 (s, 3H), MS (ESI) m/ z:177[M+H]+.
The chloro- 3- ethoxybenzene (2b) of 1,2- bis-
White solid, yield 90.8%, MS (ESI) m/z:191 [M+H]+
(2) synthesis of intermediate M-1
Under condition of ice bath, the methylene chloride of steaming again that intermediate 2 (20mmol) is added in alchlor (30mmol) by several times is molten In liquid；It finishes, is slowly added dropwise and replaces acyl chlorides (30mmol), after reacting 3h, react at room temperature 8h.Reaction is finished, will be anti-under condition of ice bath Liquid is answered to be poured into excessive 1M hydrochloric acid solution, 100mL methylene chloride extracts three times, merges methylene chloride, successively uses the saturation of 300mL Three times, anhydrous sodium sulfate dries, filters, and filtrate decompression is evaporated off for sodium bicarbonate solution washing, water and saturated sodium chloride solution washing Solvent, silica gel column chromatography obtain intermediate M-1.Elution system is petrol ether/ethyl acetate=8:1~5:1.
The chloro- 4- methoxyacetophenone (M-1a) of 2,3- bis-
White solid.Yield is 81%, MS (ESI) m/z:219 [M+H]+
The chloro- 4- methoxybenzene acetone (M-1b) of 2,3- bis-
White solid.Yield is 51.5%, MS (ESI) m/z:233 [M+H]+
The chloro- 4- methoxybenzene butanone (M-1c) of 2,3- bis-
White solid.Yield is 92.3%, MS (ESI) m/z:247 [M+H]+
The chloro- 4- ethoxybenzene butanone (M-1d) of 2,3- bis-
White solid, yield 86.1%, MS (ESI) m/z:261 [M+H]+
(3) synthesis of target product II
Take sodium block (1.2mmol) to be added in 4mL ethanol solution, be stirred at room temperature and all dissolved to sodium block, successively will in Mesosome M-1 (1mmol) replaces aldehyde (1mmol) to be added in the alcohol sodium solution of above-mentioned brand-new, is stirred at room temperature for 24 hours.Reaction is finished, mistake Filter, filtrate decompression are evaporated off solvent, obtain grease.Silica gel column chromatography, elution system are petrol ether/ethyl acetate=15/1~10/ 1, crude product is obtained, with recrystallizing methanol, obtains target compound II.
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (2- ethyl -3- phenyl) acryloyl] } phenyl ether (II a)
White solid, yield 84.8%, mp:124~128 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.45-7.40 (m, 6H), 7.27 (d, J=8.8Hz, 1H), 7.06 (s, 1H), 3.95 (s, 3H), 2.65 (q, J=7.2Hz, 2H), 1.18 (t, J=7.2Hz, 3H)
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (2- methoxyphenyl)] acryloyl } } phenyl ether (II b)
Yellowish solid, yield 77.8%, mp:103~106 DEG C,1H NMR(600MHz,DMSO-d6)δ(ppm): 7.43-7.31 (m, 3H), 7.27 (d, J=8.4Hz, 1H), 7.16 (s, 1H), 7.05-7.04 (m, 2H), 3.96 (s, 3H), 3.71 (s, 3H), 2.54 (q, J=7.2Hz, 2H), 1.14 (t, J=7.2Hz, 3H) .MS (ESI) m/z:365 [M+H]+
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (3- methoxyphenyl)] acryloyl } } phenyl ether (II c)
Yellowish solid, yield 65.9%, mp:115~120 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.43 (d, J=8.4Hz, 1H), 7.38 (t, J=8.0Hz, 1H), 7.27 (d, J=8.0Hz, 1H), 7.05 (s, 1H), 7.02- 6.95 (m, 3H), 3.95 (s, 3H), 3.76 (s, 3H), 2.63 (q, J=7.2Hz, 2H), 1.18 (t, J=7.2Hz, 3H)
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- methoxyphenyl)] acryloyl } } phenyl ether (II d)
Yellow solid, yield 27.8%, mp:105~107 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.44 (d, J=8.8Hz, 2H), 7.39 (d, J=8.8Hz, 1H), 7.25 (d, J=8.8Hz, 1H), 7.02 (d, J=8.8Hz, 2H), 7.00 (s, 1H), 3.95 (s, 3H), 3.79 (s, 3H), 2.66 (q, J=7.6Hz, 2H), 1.17 (t, J=7.6Hz, 3H) .MS (ESI)m/z:365[M+H]+.
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- dimethylamino phenyl)] acryloyl } } phenyl ether (II e)
Yellowish solid, yield 26.5%, mp:143~145 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.34-7.32 (m, 3H), 7.24 (d, J=8.8Hz, 1H), 6.91 (s, 1H), 6.74 (d, J=8.8Hz, 2H), 3.95 (s, 3H), 2.97 (s, 6H), 2.69 (q, J=7.2Hz, 2H), 1.17 (t, J=7.2Hz, 3H) .MS (ESI) m/z:378 [M+H]+
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- cyano-phenyl)] acryloyl } } phenyl ether (II f)
White solid, yield 41.7%, mp:108~110 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.91 (d, J=8.4Hz, 2H), 7.61 (d, J=8.4Hz, 2H), 7.47 (d, J=8.4Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 7.12 (s, 1H), 3.95 (s, 3H), 2.59 (q, J=7.2Hz, 2H), 1.16 (t, J=7.2Hz, 3H)
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- nitrobenzophenone)] acryloyl } } phenyl ether (II g)
Yellow oil, yield 50%, mp:86~90 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):8.28 (d, J=8.8Hz, 2H), 7.70 (d, J=8.8Hz, 2H), 7.49 (d, J=8.4Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 7.17 (s, 1H), 3.96 (s, 3H), 2.61 (q, J=7.2Hz, 2H), 1.17 (t, J=7.2Hz, 3H)
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- fluorophenyl)] acryloyl } } phenyl ether (II h)
White solid, yield 79.5%, mp:125~128 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.52-7.49 (m, 2H), 7.43 (d, J=8.4Hz, 1H), 7.30-7.24 (m, 3H), 7.06 (s, 1H), 3.95 (s, 3H), 2.62 (q, J=7.2Hz, 2H), 1.17 (t, J=7.2Hz, 3H)
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- chlorphenyl)] acryloyl } } phenyl ether (II i)
White solid, yield 45.4%, 120~121 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.52- 7.45 (m, 4H), 7.44 (d, J=8.4Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 7.05 (s, 1H), 3.95 (s, 3H), 2.63 (q, J=7.6Hz, 2H), 1.16 (t, J=7.6Hz, 3H)
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- bromophenyl)] acryloyl } } phenyl ether (II j)
White solid, yield 64%, mp:98~100 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.65(d, J=8.4Hz, 2H), 7.43 (d, J=8.4Hz, 1H), 7.39 (d, J=8.4Hz, 2H), 7.26 (d, J=8.4Hz, 1H), 7.03 (s, 1H), 3.95 (s, 3H), 2.62 (q, J=7.2Hz, 2H), 1.16 (t, J=7.2Hz, 3H)
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (furans -2- base)] acryloyl } } phenyl ether (II k)
Yellowish solid, yield 49.4%, mp:145~148 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.96 (d, J=1.6Hz, 1H), 7.38 (d, J=8.4Hz, 1H), 7.26 (d, J=8.4Hz, 1H), 6.99 (d, J=3.2Hz, 1H), 6.79 (s, 1H), 6.69 (q, J=1.6Hz, 1H), 3.95 (s, 3H), 2.78 (q, J=7.2Hz, 2H), 1.11 (t, J= 7.2Hz,3H).
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (pyridin-4-yl)] acryloyl } } phenyl ether (II l)
White solid, yield 58.9%, mp:120~124 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):8.64 (d, J=6.0Hz, 2H), 7.48 (d, J=8.4Hz, 1H), 7.38 (d, J=6.0Hz, 2H), 7.28 (d, J=8.4Hz, 1H), 7.03 (s, 1H), 3.96 (s, 3H), 2.59 (q, J=7.2Hz, 2H), 1.15 (t, J=7.2Hz, 3H)
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (naphthalene -1- base)] acryloyl } } phenyl ether (II m)
White solid, yield 84.2%, mp:135~138 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.99-7.96 (m, 2H), 7.69-7.67 (m, 1H), 7.61-7.55 (m, 5H), 7.50 (d, J=7.2Hz, 1H), 7.33 (d, J =8.4Hz, 1H), 3.96 (s, 3H), 2.48 (q, J=7.2Hz, 2H), 1.08 (t, J=7.2Hz, 3H)
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (2,3- dioxane simultaneously [b] [1,4] -6- base)] propylene Acyl } } phenyl ether (II n)
Yellow solid, yield 64.3%, mp:88~90 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.38 (d, J=8.4Hz, 1H), 7.25 (d, J=8.4Hz, 1H), 6.98-6.90 (m, 4H), 4.28-4.24 (m, 4H), 3.95 (s, 3H), 2.65 (q, J=7.2Hz, 2H), 1.16 (t, J=7.2Hz, 3H)
(E)-methyl-[the chloro- 4- of 2,3- bis- (3- phenylacryloyl)] phenyl ether (II o)
White solid, yield 91.8%, mp:149~153 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.78-7.76 (m, 2H), 7.62 (d, J=8.4Hz, 1H), 7.49-7.43 (m, 4H), 7.31-7.27 (m, 2H), 3.94 (s, 3H).MS(ESI)m/z:307[M+H]+.
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (2- methyl -3- phenyl) acryloyl] } phenyl ether (II p)
Yellow solid, yield 84.4%, mp:132~134 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.50-7.39 (m, 6H), 7.27 (d, J=8.4Hz, 1H), 7.11 (s, 1H), 3.96 (s, 3H), 2.16 (s, 3H) .MS (ESI) m/z:321[M+H]+.
(E)-ethyl-{ the chloro- 4- of 2,3- bis- [3- (2- ethyl -3- phenyl) acryloyl] } phenyl ether (II q)
White solid, yield 74.7%, mp:100~104 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.45-7.39 (m, 6H), 7.25 (d, J=8.4Hz, 1H), 7.06 (s, 1H), 4.25 (q, J=7.2Hz, 2H), 2.65 (q, J= 7.2Hz, 2H), 1.41 (t, J=7.2Hz, 3H), 1.18 (t, J=7.2Hz, 3H)
Embodiment 2: the preparation of target compound III -1a~III -1h
(1) synthesis of intermediate Y
Amine (30mmol) will be replaced to be dissolved in 10mL n,N-Dimethylformamide, be added Anhydrous potassium carbonate (30mmol), risen Temperature stirs 30min, 4- fluorobenzaldehyde (10mmol) then is added to 80 DEG C, and 80 DEG C of reactions are for 24 hours.Reaction system is poured into 100mL In ice water, three times with the extraction of 100mL ethyl acetate, combined ethyl acetate, 100mL saturated sodium chloride solution is washed three times, anhydrous Sodium sulphate dries, filters, and solvent, silica gel column chromatography is evaporated off in filtrate decompression, and elution system is petrol ether/ethyl acetate=5/1, obtains Intermediate Y.Wherein substitution amine is
4- (pyrroles -1- base)-benzaldehyde (Ya)
White solid, yield 72.6%,1H NMR(400MHz,CDCl3)δ(ppm):9.75(s,1H),7.70(d, 2H, J=8.4Hz), 6.55 (d, 2H, J=8.4Hz), 3.39 (m, 4H), 2.08 (m, 4H)；MS(ESI)m/z:176[M+H]+.
4- (4- methylpiperazine-1-yl)-benzaldehyde (Yb)
Yellow oil, yield 53.9%,1H NMR(400MHz,CDCl3)δ(ppm):9.76(s,1H),7.72(d, J=8.0Hz, 2H), 6.90 (d, J=8.0Hz, 2H), 3.41-3.39 (m, 4H), 2.55-2.53 (m, 4H), 2.34 (s, 3H) .MS(ESI)m/z:205[M+H]+.
4- (morpholine -1- base)-benzaldehyde (Yc)
White light yellow complexion solid, yield 78.5%,1H NMR(400MHz,DMSO-d6)δ(ppm):9.73(s,1H), 7.73 (d, J=8.8Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 3.73-3.72 (m, 4H), 3.34-3.33 (m, 4H) .MS (ESI)m/z:192[M+H]+.
(2) synthesis of target compound III -1a~III -1h
4mL dehydrated alcohol is added in sodium block (1.2mmol) first, alcohol sodium solution is made in stirring and dissolving, then in addition Mesosome M-1a (0.5mmol) and intermediate Y replaces aldehyde (0.5mmol), and 24~36h is stirred at room temperature.Reaction is finished, and is analysed if any solid Out, it filters, a small amount of methanol washing of filter cake obtains target product III -1a~III -1h；If solid is not precipitated, add water 20mL, uses 20mL ethyl acetate extracts three times, and combined ethyl acetate is washed three times with 20mL saturated sodium chloride solution, and anhydrous sodium sulfate is dry Dry, solvent, silica gel column chromatography is evaporated off in filtering, filtrate decompression, and elution system is petrol ether/ethyl acetate=2:1 to get targeted Close object III -1a~III -1h.
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (2- pyridyl group) acryloyl] } phenyl ether (III -1a)
Yellowish solid, yield 46.8%, mp:110~113 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 8.67 (d, J=4.7Hz, 1H), 7.88 (td, J=7.6,1.8Hz, 1H), 7.81 (d, J=7.8Hz, 1H), 7.64 (d, J= 8.6Hz, 1H), 7.56 (d, J=15.8Hz, 1H), 7.49-7.42 (m, 2H), 7.30 (d, J=8.7Hz, 1H), 3.98 (s, 3H).13C NMR(100MHz,DMSO-d6)δ(ppm):192.19(s),157.91(s),151.60(s),150.69(s), 145.01(s),137.78(s),132.31(s),130.27(s),129.47(s),129.26(s),125.88(s),125.47 (s),121.67(s),111.41(s),57.19(s).
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (3- pyridyl group) acryloyl] } phenyl ether (III -1b)
Yellowish solid.Yield is 91%, mp:170~173 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):8.93 (s, 1H), 8.62 (d, J=6.0Hz, 1H), 8.26 (d, J=8.0Hz, 1H), 7.66 (d, J=8.6Hz, 1H), 7.55 (d, J= 16.2Hz, 1H), 7.50-7.43 (m, 2H), 7.30 (d, J=8.7Hz, 1H), 3.99 (s, 3H)13C NMR(100MHz,DMSO- d6)δ(ppm):191.65(s),157.92(s),151.79(s),150.82(s),142.72(s),135.55(s),132.36 (s),130.56(s),129.31(s),128.33(s),124.43(s),121.76(s),111.45(s),57.49(s).
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (4- pyridyl group) acryloyl] } phenyl ether (III -1c)
Light yellow solid.Yield is 30.1%, mp:117~119 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 8.65 (d, J=5.9Hz, 2H), 7.74 (d, J=5.9Hz, 2H), 7.68 (d, J=8.7Hz, 1H), 7.57 (d, J=16.1Hz, 1H), 7.47 (d, J=16.1Hz, 1H), 7.30 (d, J=8.7Hz, 1H), 3.99 (s, 3H)13C NMR(100MHz,DMSO- d6)δ(ppm):191.65(s),158.10(s),150.88(s),142.95(s),141.84(s),132.08(s),130.61 (d, J=13.0Hz), 129.53 (s), 122.89 (s), 121.82 (s), 111.48 (s), 57.53 (s)
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (5-1H- indyl) acryloyl] } phenyl ether (III -1d)
Light yellow solid, yield 50.6%, mp:193~195 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 11.40 (s, 1H), 7.94 (s, 1H), 7.56 (dd, J=14.2,6.3Hz, 3H), 7.44 (d, J=10.3Hz, 2H), 7.28 (d, J=8.6Hz, 1H), 7.16 (d, J=15.9Hz, 1H), 6.49 (s, 1H), 3.98 (s, 3H)13C NMR(100MHz,DMSO- d6)δ(ppm):191.95(s),157.20(s),149.56(s),137.93(s),133.15(s),130.19(s),128.74 (s),128.46(s),127.23(s),125.72(s),123.68(s),123.28–123.08(m),121.85(s),121.49 (s),112.62(s),111.34(s),102.73(s),57.41(s).
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [4- (N, TMSDMA N dimethylamine base) phenyl] acryloyl } } phenyl ether (III -1e)
Light yellow solid, yield 77.1%, mp:124~126 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.57 (d, J=8.8Hz, 2H), 7.50 (d, J=8.6Hz, 1H), 7.28 (dd, J=23.0,12.2Hz, 2H), 6.94 (d, J= 15.8Hz, 1H), 6.71 (d, J=8.9Hz, 2H), 3.96 (s, 3H), 3.00 (s, 6H)13C NMR(100MHz,DMSO-d6)δ (ppm):191.85(s),156.93–156.74(m),152.97(s),147.64(s),133.64(s),130.94(s), 130.05(s),128.71(s),121.73(s),121.38(s),121.08(s),112.23(s),111.45(s),57.38 (s).
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [4- (N- pyrrole radicals) phenyl] acryloyl } } phenyl ether (III -1f)
Yellow solid, yield 94.4%, mp:170~172 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.56 (d, J=8.7Hz, 2H), 7.49 (d, J=8.6Hz, 1H), 7.27 (dd, J=21.1,12.2Hz, 2H), 6.91 (d, J= 15.8Hz, 1H), 6.55 (d, J=8.7Hz, 2H), 3.96 (s, 3H), 3.33-3.28 (m, 4H), 1.96 (q, J=6.4Hz, 4H).13C NMR(100MHz,DMSO-d6)δ(ppm):191.71(s),156.79(s),150.68(s),147.80(s), 133.55(s),131.15(s),129.60(s),127.84(s),121.45(s),120.19(s),112.26(s),110.91 (s),56.69(s),47.49(s),25.08(s).
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- { 4- [1- (N-methyl piperazine base)] phenyl } acryloyl } } phenyl ether (III- 1g)
Yellow solid, yield 82.3%, mp:154~156 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.59 (d, J=8.6Hz, 2H), 7.52 (d, J=8.6Hz, 1H), 7.33 (d, J=15.9Hz, 1H), 7.26 (d, J=8.6Hz, 1H), 7.01 (d, J=15.9Hz, 1H), 6.94 (d, J=8.6Hz, 2H), 3.96 (s, 3H), 3.28 (d, J=4.5Hz, 4H), 2.41 (d, J=4.4Hz, 4H), 2.21 (s, 3H)13C NMR(100MHz,DMSO-d6)δ(ppm):191.72(s),157.14(s), 153.18(s),147.23(s),133.57(s),131.10(s),129.81(s),129.09(s),123.92–123.73(m), 122.33(s),115.05(s),111.43(s),57.31(s),54.50(s),47.17(s),45.69(s).
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [4- (1- morpholinyl) phenyl] acryloyl } } phenyl ether (III -1h)
Yellow solid, yield 76.5%, mp:124~126 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.62 (d, J=8.8Hz, 2H), 7.53 (d, J=8.6Hz, 1H), 7.35 (d, J=15.9Hz, 1H), 7.26 (d, J=8.7Hz, 1H), 7.04 (d, J=15.9Hz, 1H), 6.96 (d, J=8.8Hz, 2H), 3.96 (s, 3H), 3.77-3.66 (m, 4H), 3.29-3.17 (m,4H).13C NMR(100MHz,DMSO-d6)δ(ppm):192.40(s),157.69(s),153.56(s),147.16(s), 133.11(s),131.15(s),130.13–129.93(m),128.46(s),124.56(s),122.37(s),121.24(s), 114.42(s),110.92(s),66.34(s),57.40(s),47.70(s).
Embodiment 3: target compound III -2a~III -2e, III -3a~III -3d, III -4 synthesis
(1) synthesis of intermediate 3
Under condition of ice bath, 10mL is added dissolved with intermediate M-1a (33.46mmol) in aluminum trichloride (anhydrous) (100.0mmol) The dichloromethane solution of steaming again in.It finishes, 40 DEG C of reactions are for 24 hours.Reaction is finished, and reaction solution is poured into cold 1M hydrochloric acid solution, is used 100mL methylene chloride extracts three times, merges methylene chloride, successively uses 100mL saturated sodium bicarbonate solution, water and saturated sodium-chloride Solution washs three times, and anhydrous sodium sulfate dries, filters, and solvent is evaporated off in filtrate decompression, crude product is obtained, with petrol ether/ethyl acetate weight Crystallization, obtains intermediate 3.
Bis- chloro- 4-hydroxyacetophenone (3) of 2,3-
White solid, yield 72.9%,1H NMR(400MHz,DMSO-d6)δ(ppm):11.38(s,1H),7.62 (d, J=8.4Hz, 1H), 7.02 (d, J=8.8Hz, 1H), 2.54 (s, 3H) .MS (ESI) m/z:205 [M+H]+
(2) synthesis of intermediate M-2a~M-2e
Intermediate 3 (1mmol) is dissolved in 20mL acetone, Anhydrous potassium carbonate (3mmol), potassium iodide (0.2mmol) is added, It after 60 DEG C of stirring 30min, is added halides (2mmol), reacts 20h.Reaction is finished, evaporating solvent under reduced pressure, and silica gel column chromatography obtains Mesosome M-2a~M-2e.
2,3- bis- chloro- 4- (2- hydroxyl-oxethyl) acetophenone (M-2a)
Yellow oil, yield 72.6%,1H NMR (400MHz, DMSO-d6) δ (ppm): 7.74 (d, J=8.8Hz, 1H), 7.27 (d, J=8.8Hz, 1H), 4.97 (t, J=5.3Hz, 1H), 4.20 (t, J=4.9Hz, 2H), 3.84-3.67 (m, 2H),2.57(s,3H).
2- (4- acetyl group -2,3- dichlorophenoxy) acetonitrile (M-2b)
Yellow solid, yield 68.8%,1H NMR(400MHz,DMSO-d6)δ(ppm):11.40(s,1H),7.63 (d, J=8.6Hz, 1H), 7.01 (d, J=8.6Hz, 1H), 2.54 (s, 3H)
2,3- bis- chloro- 4- (2- methoxy ethoxy) acetophenone (M-2c)
Brown solid object, yield 53.2%,1H NMR (400MHz, DMSO-d6) δ (ppm): 7.84 (d, J=8.8Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 5.42 (s, 2H), 2.60 (s, 3H)
The chloro- 4- of 2,3- bis- (2- (1- piperidyl) ethyoxyl) acetophenone (M-2d)
White solid, yield 60.7%,1H NMR (400MHz, DMSO-d6) δ (ppm): 7.74 (d, J=8.8Hz, 1H), 7.27 (d, J=8.8Hz, 1H), 4.26 (t, J=5.6Hz, 2H), 2.71 (t, J=5.6Hz, 2H), 2.57 (s, 3H), 2.45(s,4H),1.48-1.36(m,6H).
The chloro- 4- of 2,3- bis- [2- (N- morpholinyl) ethyoxyl] acetophenone (M-2e)
Light yellow solid, yield 87.1%,1H NMR (400MHz, DMSO-d6) δ (ppm): 7.75 (d, J=8.8Hz, 1H), 7.28 (d, J=8.8Hz, 1H), 4.29 (t, J=5.6Hz, 2H), 3.62-3.52 (m, 4H), 2.76 (t, J=5.6Hz, 2H),2.57(s,3H).
(3) synthesis of target compound III -2a~III -2e
4mL dehydrated alcohol is added in sodium block (1.2mmol), stirring and dissolving is made alcohol sodium solution, intermediate is then added M-2a~M-2e (0.5mmol) and 4- dimethylaminobenzaldehyde (0.5mmol), are stirred at room temperature 24~36h.Reaction is finished, if any solid Body is precipitated, filtering, and a small amount of methanol washing of filter cake obtains the target product -2e of III -2a~III if solid is not precipitated and adds water 20mL, Three times with the extraction of 20mL ethyl acetate, combined ethyl acetate is washed three times with 20mL saturated sodium chloride solution, and anhydrous sodium sulfate is dry Dry, solvent is evaporated off in filtering, filtrate decompression, and silica gel column chromatography (elution system is petrol ether/ethyl acetate=2:1) is to get target Product III -2a~III -2e.
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethyl alcohol (III -2a)
Brown solid, yield 35.6%, mp:160~164 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.57 (d, J=8.8Hz, 2H), 7.47 (d, J=8.6Hz, 1H), 7.29 (dd, J=16.4,12.3Hz, 2H), 6.94 (d, J= 15.8Hz, 1H), 6.71 (d, J=8.8Hz, 2H), 4.96 (t, J=5.3Hz, 1H), 4.19 (t, J=4.8Hz, 2H), 3.79 (dd, J=9.8,5.0Hz, 2H), 3.00 (s, 6H)13C NMR(100MHz,DMSO-d6)δ(ppm):191.87(s),156.60 (s),152.90(s),147.46(s),133.39(s),131.31(s),129.73(s),128.16(s),121.66(s), 120.97 (s), 114.92 (s), 112.35 (d, J=6.9Hz), 71.65 (s), 59.35 (s)
(E) the chloro- 4- of -2,3- two [3- (4- dimethylaminophenyl) acryloyl] phenoxyacetonitrile (III -2b)
Yellow-brown solid, yield 47.3%.Mp:147~150 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.58 (d, J=8.7Hz, 3H), 7.40 (d, J=8.7Hz, 1H), 7.32 (d, J=15.9Hz, 1H), 6.95 (d, J= 15.9Hz, 1H), 6.71 (d, J=8.8Hz, 2H), 5.42 (s, 2H), 3.00 (s, 6H)13C NMR(100MHz,DMSO-d6)δ (ppm):191.76(s),154.25(s),152.78(s),148.41(s),135.63(s),131.43(s),130.12(s), 128.44(s),122.06(s),121.69(s),120.85(s),116.38(s),112.90(s),112.20(s),54.93 (s).
(E)-methyl -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethylether (III -2c)
Yellow solid, yield 69.7%.Mp:108~110 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.57 (d, J=8.5Hz, 2H), 7.47 (d, J=8.5Hz, 1H), 7.29 (dd, J=19.6,12.2Hz, 2H), 6.94 (d, J= 15.8Hz, 1H), 6.71 (d, J=8.5Hz, 2H), 4.30 (s, 2H), 3.73 (s, 2H), 3.00 (s, 6H)13C NMR (100MHz,DMSO-d6)δ(ppm):191.62(s),156.25(s),152.48(s),147.74(s),133.52(s), 131.31(s),130.18(s),128.22(s),121.97(s),120.41(s),112.33(s),70.56(s),69.35(d, ), J=10.4Hz 58.79 (d, J=6.5Hz)
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethyl piperidine (III -2d)
Yellow solid, yield 46.8%, mp:99~101 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.57 (d, J=8.8Hz, 2H), 7.46 (d, J=8.6Hz, 1H), 7.29 (dd, J=15.9,12.3Hz, 2H), 6.94 (d, J= 15.8Hz, 1H), 6.71 (d, J=8.8Hz, 2H), 4.26 (t, J=5.7Hz, 2H), 3.00 (s, 6H), 2.73 (t, J= 5.7Hz, 2H), 2.47 (m, 4H), 1.49 (m, 4H), 1.38 (d, J=5.0Hz, 2H)13C NMR(100MHz,DMSO-d6)δ (ppm):191.71(s),156.58(s),153.28(s),148.01(s),133.32(s),131.36(s),129.61(s), 128.27(s),122.16(s),119.91(s),112.22(s),68.77(s),57.61(s),54.52(s),25.78(s), 23.60(s).
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethyl morpholine (III -2e)
Brown solid, yield 72.7%, mp:140~142 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.57 (d, J=8.8Hz, 2H), 7.47 (d, J=8.6Hz, 1H), 7.29 (dd, J=14.5,12.4Hz, 2H), 6.94 (d, J= 15.8Hz, 1H), 6.71 (d, J=8.8Hz, 2H), 4.32-4.24 (m, 2H), 3.61-3.52 (m, 4H), 3.00 (s, 6H), 2.77 (t, J=5.3Hz, 2H), 2.52 (dd, J=4.4,3.3Hz, 4H)13C NMR(100MHz,DMSO-d6)δ(ppm): 191.59(s),156.52(s),152.71(s),148.13(s),133.80(s),131.10(s),130.12(s),128.31 (s), 121.65 (s), 120.94 (s), 112.32 (d, J=19.3Hz), 68.24 (s), 66.71 (s), 57.13 (s), 54.12 (s).
The synthesis of intermediate 2- (4- acetyl group -2,3- dichlorophenoxy) acetic acid (4)
Intermediate 33 (10mmol) is dissolved in 20mL acetone, Anhydrous potassium carbonate (30mmol), potassium iodide is added (2mmol), 60 DEG C of stirring 10min are instilled bromoacetate (20mmol), react 6h.Reaction is finished, evaporating solvent under reduced pressure, silica gel Column chromatography, obtains crude product.
Above-mentioned crude product (4mmol) is dissolved in 10mL ethyl alcohol, is added potassium hydroxide solution (12mmol), 3h is reacted at room temperature. Reaction is finished, and is removed ethyl alcohol under reduced pressure, is about 1 with 1M hydrochloric acid solution tune pH, is filtered, dry yellowish solid, yield 88.6% ,1H NMR (400MHz, DMSO-d6) δ (ppm): 13.26 (br, 1H), 7.71 (d, J=8.8Hz, 1H), 7.16 (d, J= 8.8Hz,1H),4.96(s,2H),2.57(s,3H),MS(ESI)m/z:261[M-H]+.
(4) synthesis of intermediate M-3a~M-3d
Intermediate 4 (0.5mmol) is dissolved in 2mL n,N-Dimethylformamide, and under condition of ice bath, EDCI is added (0.6mmol), HOBt (0.6mmol).Continue after stirring 1h, is added amine (0.5mmol).It finishes, reacts at room temperature 4h.It has reacted Finish, reaction solution is poured into 20mL ice water, three times with the extraction of 20mL ether, merges ether, successively use 20mL water, saturated sodium-chloride Solution washs three times, and anhydrous sodium sulfate dries, filters, and solvent is evaporated off in filtrate decompression, obtains crude product, with petroleum ether/acetone recrystallization, Obtain intermediate M-3a~M-3d.
2- (4- acetyl group -2,3- dichlorophenoxy)-N- methylacetamide (M-3a)
Brown oil, yield 71%,1H NMR(400MHz,DMSO-d6)δ(ppm):7.96(s,1H),7.73(d, J=8.8Hz, 1H), 7.10 (d, J=8.8Hz, 1H), 4.74 (s, 2H), 2.65 (d, J=4.6Hz, 3H), 2.57 (s, 3H)
2- (4- acetyl group -2,3- dichlorophenoxy)-DMAC N,N' dimethyl acetamide (M-3b)
Brown solid, yield 54%,1H NMR (400MHz, DMSO-d6) δ (ppm): 7.68 (d, J=8.8Hz, 1H), 7.10 (d, J=8.8Hz, 1H), 5.14 (s, 2H), 2.99 (s, 3H), 2.84 (s, 3H), 2.57 (s, 3H), 2.09 (s, 1H)
N- [(4- acetyl group -2,3- dichlorophenoxy) acetyl group] -2- (pyrroles -1- base) ethyl ketone (M-3c)
Light tan solid, yield 42.4%,1H NMR (400MHz, DMSO-d6) δ (ppm): 7.69 (d, J=8.8Hz, 1H), 7.11 (d, J=8.9Hz, 1H), 5.03 (s, 2H), 3.46 (t, J=6.8Hz, 2H), 3.37-3.25 (m, 5H), 2.57 (s,3H),2.09(s,2H),1.95–1.87(m,2H),1.83–1.72(m,2H).
N- [(4- acetyl group -2,3- dichlorophenoxy) acetyl group] -2- morpholinyl ethyl ketone (M-3d)
Light yellow solid, yield 75.3%,1H NMR (400MHz, DMSO-d6) δ (ppm): 7.70 (d, J=8.8Hz, 1H), 7.12 (d, J=9.2Hz, 1H), 5.15 (s, 2H), 3.63-3.57 (m, 4H), 3.43 (s, 4H), 2.56 (s, 3H)
(5) synthesis of target compound III -3a~III -3d
4mL dehydrated alcohol is added in sodium block (1.2mmol), stirring and dissolving is made alcohol sodium solution, intermediate is then added M-3a~M-3d (0.5mol) and 4- dimethylaminobenzaldehyde (0.5mol), are stirred at room temperature 24~36h.Reaction is finished, if any solid It is precipitated, filtering, a small amount of methanol washing of filter cake obtains the target product -3d of III -3a~III, if solid is not precipitated, adds water 20mL, uses 20mL ethyl acetate extracts three times, and combined ethyl acetate is washed three times with 20mL saturated sodium chloride solution, and anhydrous sodium sulfate is dry Dry, solvent is evaporated off in filtering, filtrate decompression, and silica gel column chromatography (elution system is petrol ether/ethyl acetate=2:1) is to get target - the 3d of compound III -3a~III.
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group }-N- methylacetamide (III - 3a)
White solid, yield 56.1%, mp:173~175 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.97 (d, J=4.2Hz, 1H), 7.57 (d, J=8.8Hz, 2H), 7.47 (d, J=8.6Hz, 1H), 7.31 (d, J=15.8Hz, 1H), 7.11 (d, J=8.7Hz, 1H), 6.94 (d, J=15.8Hz, 1H), 6.71 (d, J=8.8Hz, 2H), 4.73 (s, 2H), 3.00 (s, 6H), 2.67 (d, J=4.6Hz, 3H)13C NMR(100MHz,DMSO-d6)δ(ppm):191.77(s),167.51(s), 156.11(s),152.74–152.54(m),147.67(s),134.34(s),131.41(s),130.14(s),128.35(s), 121.77 (d, J=19.0Hz), 120.95 (s), 112.43 (s), 112.14 (s), 68.44 (s), 25.88 (s)
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group }-DMAC N,N' dimethyl acetamide (Ⅲ-3b)
White solid, yield 43.2%, mp:120~123 DEG C,1H NMR (DMSO-d6) δ (ppm): δ 7.58 (d, J= 8.3Hz, 2H), 7.44 (d, J=8.6Hz, 1H), 7.32 (d, J=15.8Hz, 1H), 7.10 (d, J=8.6Hz, 1H), 6.95 (d, J=15.8Hz, 1H), 6.71 (d, J=8.3Hz, 2H), 5.11 (s, 2H), 3.00 (s, 9H), 2.86 (s, 3H)13C NMR (100MHz,DMSO-d6)δ(ppm):191.77(s),166.63–166.43(m),156.05(s),152.22(s),147.64 (s),134.08(s),131.01(s),129.85(s),127.83(s),121.71(s),121.43(s),121.00(s), 112.59(s),112.22(s),66.91(s),35.81(s),35.41(s).
(E) the chloro- 4- of -2- acetyl pyrrole base -2,3- two [3- (4- dimethylaminophenyl) acryloyl] phenyl ether (III -3c)
Brown solid, yield 46.6%, mp:147~150 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.58 (d, J=8.9Hz, 2H), 7.44 (d, J=8.6Hz, 1H), 7.32 (d, J=15.8Hz, 1H), 7.12 (d, J=8.7Hz, 1H), 6.94 (d, J=15.8Hz, 1H), 6.71 (d, J=9.0Hz, 2H), 5.01 (s, 2H), 3.48 (t, J=6.8Hz, 2H), 3.33 (t, J=6.9Hz, 2H), 3.00 (s, 6H), 1.91 (p, J=6.8Hz, 2H), 1.84-1.72 (m, 2H)13C NMR(100MHz, DMSO-d6)δ(ppm):191.28(s),165.56(s),156.37(s),152.22(s),147.58(s),133.96(s), 131.16(s),130.03(s),127.44(s),121.65(s),121.37(s),120.96(s),112.60(s),112.23 (s),99.55(s),67.50(s),46.14(s),44.89(s),26.21(s),24.46(s).
(E) the chloro- 4- of -2- acetyl morphine base -2,3- two [3- (4- dimethylaminophenyl) acryloyl] phenyl ether (III -3d)
Brown solid, yield 53.1%, mp:186~188 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm):7.57 (d, J=8.8Hz, 2H), 7.45 (d, J=8.6Hz, 1H), 7.32 (d, J=15.8Hz, 1H), 7.13 (d, J=8.7Hz, 1H), 6.95 (d, J=15.8Hz, 1H), 6.71 (d, J=8.8Hz, 2H), 5.14 (s, 2H), 3.61 (d, J=22.1Hz, 4H), 3.46 (s,4H),3.00(s,6H).13C NMR(100MHz,DMSO-d6)δ(ppm):191.97(s),165.60(s),155.56(s), 151.98(s),147.46(s),133.90(s),131.15(s),129.95(s),128.17(s),121.75(s),121.50 (s),121.00(s),112.57(s),112.23(s),99.79(s),67.39(s),66.50(s),44.98(s),42.21 (s).
(6) synthesis of intermediate M-4
Intermediate 3 is dissolved in 20mL acetone, Anhydrous potassium carbonate (3mmol), potassium iodide (0.2mmol) is added, 60 DEG C are stirred It after mixing 30min, is added 2- chloroacetamide (2mmol), reacts 20h.Reaction is finished, evaporating solvent under reduced pressure, silica gel column chromatography (elution system System is petrol ether/ethyl acetate=3:1), obtain intermediate M-4.
4- amino -2,3- dichloroacetophenone (M-4)
Brown solid, yield 78.5%,1H NMR (400MHz, DMSO-d6) δ (ppm): 7.58 (d, J=8.7Hz, 1H), 6.77 (d, J=8.7Hz, 1H), 6.43 (s, 2H), 2.49 (s, 3H) .MS (ESI) m/z:204 [M+H]+
(7) synthesis of target compound III -4
4mL dehydrated alcohol is added in sodium block (1.2mmol), stirring and dissolving is made alcohol sodium solution, intermediate is then added M-4 (0.5mmol) and 4- dimethylaminobenzaldehyde (0.5mmol), are stirred at room temperature 24~36h.Reaction is finished, and is precipitated if any solid, Filtering, a small amount of methanol washing of filter cake, obtains target product 40, if solid is not precipitated, adds water, be extracted with ethyl acetate three times, close And ethyl acetate, it is washed three times with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and solvent, silica gel is evaporated off in filtrate decompression Column chromatography (elution system is petrol ether/ethyl acetate=2:1) is to get target compound III -4.
(E) the chloro- 4- of -2,3- two [3- (4- dimethylaminophenyl) acryloyl] aniline (III -4)
Brown-red solid, yield 30.2%, mp:128~130 DEG C,1H NMR(400MHz,DMSO-d6)δ(ppm): 7.56 (d, J=8.6Hz, 2H), 7.35 (dd, J=18.2,12.1Hz, 2H), 7.02 (d, J=15.7Hz, 1H), 6.82 (d, J =8.5Hz, 1H), 6.71 (d, J=8.6Hz, 2H), 6.22 (s, 2H), 2.99 (s, 6H)13C NMR(100MHz,DMSO-d6)δ (ppm):190.52–190.33(m),152.51(s),148.62(s),145.54(s),130.87(s),130.49(s), 129.33(s),128.00(s),122.17(s),121.01(s),116.20(s),112.99(s),112.02(s).
Experimental example: the biological activity determination of compound
(1) growth inhibitory activity measurement experiment of the compound to MCL cell strain
Experimental material and instrument: people lymphoma mantle cell cell strain Mino, Rec-1, Jeko-1, Maver-1, Z-138, Granta-519, JVM-2, JVM-13 (American type culture collection-American Type Culture Collection, ATCC), RPMI-1640 culture medium (Sigma Co., USA), fetal calf serum (Sigma Co., USA), HEPES Buffer (CORNING company, the U.S.), penicillin receive (10000units/mL)-streptomycin sulphate (10mg/mL) (U.S. Sigma Company), trypan blue reagent-Trypan blue solution (Sigma Co., USA), the inverted light microscope (U.S. Fisher Scientific company), cell incubator (NUAIER company, the U.S.), superclean bench (NUAIER company, the U.S.), Cell counter-TC20TMAutomated Cell Counter) (Bio-Rad company, the U.S.), the electric-heated thermostatic water bath (U.S. Fisher Scientific company), desk centrifuge (Thermo Scientific company, the U.S.), microplate reader (BioTek Synergy HTX multi-tester), ultra low temperature freezer (Thermo Scientific company, the U.S.).
Experimental method: logarithmic growth phase MCL cell strain is inoculated in 96 well culture plates, and cell number is 1 × 104/ hole, Be added the surveyed compound of various concentration cell culture fluid, make its final concentration of 0.93-60 μM, at the same set up positive controls with DMSO blank control group adjusts DMSO concentration≤1 ‰.Each concentration sets 3 multiple holes, finishes, and sets 37 DEG C, 5%CO2Constant temperature incubation 72h is incubated in case.Then 30 μ L are added in every holeReagent, with the multi-functional detection of BioTek Synergy HTX Instrument (BioTek, USA) detector measures its luminance value under 570nm wavelength, institute's value and feminine gender DMSO control group into Row normalized calculates IC using 6.0 software of Prism (GraphPad Software, USA)50Value.Compound inhibiting rate by Formula: inhibiting rate (IR%)=(blank group OD value-administration group OD value)/blank group OD value × 100% calculates, further according to inhibition Rate concentration curve obtains IC50 value.
Growth inhibitory activity of 1. II series compound of table to MCL
aNumerical value is the average value of three groups of independent experiments
Growth inhibitory activity of 2. III series compound of table to MCL
aNumerical value is the average value of three groups of independent experiments
1 experimental data of table shows R1For methyl, R2When for ethyl, R3Phenyl ring it is unsubstituted when, MCL cell growth inhibition is living Property it is lower, when face, contraposition have methoxy substitution when, face position and compared with meta position methoxy substitution, contraposition replace to a certain extent Improve the inhibitory activity to MCL.Benzo [1,4] dioxane with it is little with the monosubstituted active difference of contraposition methoxyl group.
In para-orientating group, activity sequence are as follows: dimethylamino > nitro > methoxyl group > cyano > halogen.
By R1It is little to activity influence that middle methyl replaces with ethyl.And R2Transformation it is huge to activity influence, be H > > methyl > Ethyl.
2 experimental data of table shows that compared with unsubstituted II o of phenyl ring, pyridine ring has been obviously improved the suppression of the growth to MCL cell System activity, 3- pyridine and 4- pyridine replace activity more preferably compared with 2- pyridine activity.
The outer nitrogen-atoms of ring individually at saturated heterocyclic ring except 4- methyl piperazine analog derivative activity is a small amount of reduce it is outer, pyrroles with Quinoline derivant loses the growth inhibitory activity to MCL.Indole ring activity ratio is also remained to MCL growth inhibitory activity, though It is so slightly reduced compared with 4 methyl piperazine class activity, activity is still suitable with IBN activity in certain cell strains.
R1The extension transformation of bit substituent considerably reduces compound to the growth inhibitory activity of MCL, only compound III -2a, III -2d and III -3b remain with some growth inhibitory activity, the IC of the growth inhibitory activity of remaining compound50It is all larger than 60μM。
The foregoing is merely preferred embodiment of the present disclosure, are not limited to the disclosure, for the skill of this field For art personnel, the disclosure can have various modifications and variations.It is all within the spirit and principle of the disclosure, it is made any to repair Change, equivalent replacement, improvement etc., should be included within the protection scope of the disclosure.

Claims (10)

1. a kind of formula (I) compound represented or its pharmaceutically acceptable salt, characterized in that
Wherein A is B is hydrogen, methyl or ethyl；C is to take For phenyl ring, pyridine and furans heterocycle, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 5-1H- indyl, 4- (N, TMSDMA N dimethylamine base) Phenyl, 4- (N- pyrrole radicals) phenyl, 4- [1- (N-methyl piperazine base)] phenyl or 4- (1- morpholinyl) phenyl.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, characterized in that A is B is H；C is to dimethylamino phenyl, p-nitrophenyl, to methoxyl group Phenyl, to cyano-phenyl, p-fluorophenyl, rubigan, p-bromophenyl, 2- pyridyl group, 3- pyridyl group or 4- pyridyl group.
3. compound as described in claim 1 or its pharmaceutically acceptable salt, characterized in that the compound has formula (II) structure shown in:
Wherein, wherein R1For methyl or ethyl；R2For hydrogen, methyl or ethyl；R3It is miscellaneous for phenyl ring, substituted benzene ring, pyridine and furans Ring；
Preferably, R1For methyl, R2For hydrogen, R3For phenyl ring, substituted benzene ring, pyridine and furans heterocycle；
Or, the compound has structure shown in formula (III):
Wherein, R4For 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 5-1H- indyl, 4- (N, TMSDMA N dimethylamine base) phenyl, 4- (N- Pyrrole radicals) phenyl, 4- [1- (N-methyl piperazine base)] phenyl or 4- (1- morpholinyl) phenyl；R5For
4. compound as described in claim 1 or its pharmaceutically acceptable salt, characterized in that include following compound:
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (2- ethyl -3- phenyl) acryloyl] } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (2- methoxyphenyl)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (3- methoxyphenyl)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- methoxyphenyl)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- dimethylamino phenyl)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- cyano-phenyl)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- nitrobenzophenone)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- fluorophenyl)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- chlorphenyl)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (4- bromophenyl)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (furans -2- base)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (pyridin-4-yl)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (naphthalene -1- base)] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [2- ethyl -3- (2,3- dioxane simultaneously [b] [1,4] -6- base)] acryloyl } } Phenyl ether；
(E)-methyl-[the chloro- 4- of 2,3- bis- (3- phenylacryloyl)] phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (2- methyl -3- phenyl) acryloyl] } phenyl ether；
(E)-ethyl-{ the chloro- 4- of 2,3- bis- [3- (2- ethyl -3- phenyl) acryloyl] } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (2- pyridyl group) acryloyl] } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (3- pyridyl group) acryloyl] } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (4- pyridyl group) acryloyl] } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- [3- (5-1H- indyl) acryloyl] } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [4- (N, TMSDMA N dimethylamine base) phenyl] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [4- (N- pyrrole radicals) phenyl] acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- { 4- [1- (N-methyl piperazine base)] phenyl } acryloyl } } phenyl ether；
(E)-methyl-{ the chloro- 4- of 2,3- bis- { 3- [4- (1- morpholinyl) phenyl] acryloyl } } phenyl ether；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethyl alcohol；
(E) the chloro- 4- of -2,3- two [3- (4- dimethylaminophenyl) acryloyl] phenoxyacetonitrile；
(E)-methyl -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethylether；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethyl piperidine；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group } ethyl morpholine；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group }-N- methylacetamide；
(E) -2- { the chloro- 4- of 2,3- bis- [3- (4- dimethylaminophenyl) acryloyl] phenoxy group }-DMAC N,N' dimethyl acetamide；
(E) the chloro- 4- of -2- acetyl pyrrole base -2,3- two [3- (4- dimethylaminophenyl) acryloyl] phenyl ether；
(E) the chloro- 4- of -2- acetyl morphine base -2,3- two [3- (4- dimethylaminophenyl) acryloyl] phenyl ether；
(E) the chloro- 4- of -2,3- two [3- (4- dimethylaminophenyl) acryloyl] aniline.
5. a kind of preparation method of any compound of Claims 1 to 4, characterized in that including being that starting is former with intermediate 1 Material prepares formula (I) compound by following reaction route:
Wherein, A is B is hydrogen, first Base or ethyl；C is substituted benzene ring, pyridine and furans heterocycle, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 5-1H- indyl, 4- (N, TMSDMA N dimethylamine base) phenyl, 4- (N- pyrrole radicals) phenyl, 4- [1- (N-methyl piperazine base)] phenyl or 4- (1- morpholinyl) benzene Base；R2For hydrogen, methyl or ethyl；R5For
6. preparation method as claimed in claim 5, characterized in that the reaction route of formula (II) compound is as follows:
R1For methyl or ethyl；R2For hydrogen, methyl or ethyl；R3For phenyl ring, substituted benzene ring, pyridine and furans heterocycle；
Preferably, formula (II) compound the preparation method comprises the following steps: with 2,3- chlorophenesic acid (1) is starting material, with dimethyl suflfate Or dithyl sulfate reaction, midbody compound 2,2 compound represented of formula and substitution acyl chloride reaction are obtained, formula M-1 is obtained Shown compound, compound shown in formula M-1 and substitution aldehyde reaction, obtain formula (II) compound represented；Wherein replace acyl chlorides ForReplace aldehyde be
Or, the reaction route of formula (III) compound is as follows:
Wherein, R4For 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 5-1H- indyl, 4- (N, TMSDMA N dimethylamine base) phenyl, 4- (N- Pyrrole radicals) phenyl, 4- [1- (N-methyl piperazine base)] phenyl or 4- (1- morpholinyl) phenyl；R6For ethyl alcohol base, acetonitrile-base, methoxy Base ethyl, ethyl piperidine base, ethyl morpholine base；R7For N- methyl vinyl amido, n,N-dimethylacetamide base, acetyl pyrrole base Or acetyl morphine base；
Preferably, formula (III) compound the preparation method comprises the following steps: formula M-1a and replace aldehyde reaction, obtain compound III -1a~III - 1h, formula M-1a react to obtain intermediate 3 with aluminum trichloride (anhydrous), and compound shown in formula 3 and bromoacetate react intermediate Body 4, compound shown in formula 3 are reacted with halides, obtain intermediate M-2a~M-2e, intermediate M-2a~M-2e and 4- (N, N- Dimethylamino) benzaldehyde reaction, the target compound -2e of III -2a~III is obtained, compound shown in formula 4 is reacted with amine, obtains intermediate M- The reaction of 3a~M-3d, intermediate M-3a~M-3d and 4- (N, TMSDMA N dimethylamine base) benzaldehyde, obtains III -3a~III of target compound - 3d, compound shown in formula 3 are reacted with 2- chloroacetamide, obtain target compound III -4；Wherein, halides areAmine is Replace aldehyde be
7. a kind of Claims 1 to 4 any compound or its pharmaceutically acceptable salt are in preparation prevention and/or treatment Purposes in the drug of tumour；
Preferably, the tumour is lymphoma mantle cell.
8. a kind of pharmaceutical composition, characterized in that comprising any compound of Claims 1 to 4 or its can pharmaceutically connect The salt received；
It preferably, further include excipient and/or diluent.
9. a kind of pharmaceutical preparation, characterized in that described to have comprising effective component and pharmaceutically acceptable auxiliary material and/or carrier Imitating ingredient is the Claims 1 to 4 any compound or its pharmaceutically acceptable salt or medicine according to any one of claims 8 Compositions.
10. pharmaceutical preparation as claimed in claim 9, characterized in that the pharmaceutical preparation is solid orally ingestible, liquid oral Preparation or injection；
Preferably, the pharmaceutical preparation be tablet, dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, sugar-coat agent, granule, The small water needle of dry powder doses, oral solution, injection, injection freeze-dried powder, big infusion or primary infusion.
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