CN109172563A - A kind of thioxanthene ketone class taxol and STAT3 inhibitor drug combination compositions - Google Patents

A kind of thioxanthene ketone class taxol and STAT3 inhibitor drug combination compositions Download PDF

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CN109172563A
CN109172563A CN201811282938.1A CN201811282938A CN109172563A CN 109172563 A CN109172563 A CN 109172563A CN 201811282938 A CN201811282938 A CN 201811282938A CN 109172563 A CN109172563 A CN 109172563A
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formula
compound
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taxol
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郭程杰
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Nanjing Advanced Biomaterials And Process Equipment Research Institute Co Ltd
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Nanjing Advanced Biomaterials And Process Equipment Research Institute Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The present invention provides a kind of thioxanthene ketone class taxols and STAT3 inhibitor drug combination compositions, include active constituent and pharmaceutically acceptable auxiliary material, it is characterized by: active constituent STAT3 inhibitor shown in taxol and formula (I) forms, the mass ratio of STAT3 inhibitor shown in taxol and formula (I) is (0.18-0.32) in the active constituent: 1.The compound has good inhibiting effect to the active MDA-MB-468 cell of STAT3, DU-145 cell with sustained activation.

Description

A kind of thioxanthene ketone class taxol and STAT3 inhibitor drug combination compositions
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of STAT3 inhibitor and its application, and in particular to one kind has letter Number conduction and compound, the pharmaceutical composition containing the compound and the chemical combination of -3 inhibiting effect of activating transcription factor The purposes of object or pharmaceutical composition as cancer treatment drugs.
Technical background
Cancer is the general designation of a major class malignant tumour, its main feature is that without limitation, without end hyperplasia.Cancer cell makes patient's body Interior nutriment is largely consumed, while releasing a variety of toxin, and human body is made to generate a series of symptoms, cause human body it is thin, Inability, anaemia, loss of appetite, fever and serious organ function are impaired, cause necrotic hemorrhage concurrent infection, patient finally by It is dead in organ failure.
Signal transduction and (the Signal Transducer and Activator of of activating transcription factor -3 Transcription-3, STAT3) be a kind of GAP-associated protein GAP that can be activated by different cytokine receptors, cell because Carrier is served as during son-acceptor interaction, the inherence specificity for keeping signal to transmit in the cell, and pass through induction target The effect effect of biostimulation is expressed in genetic transcription, other than participating in angiogenesis and immune response, also with the increasing of cell It grows, survive, breaking up, the close associations such as anti-apoptotic.STAT3 is in kinds of tumor cells (including blood such as leukaemia, Huppert's disease A variety of entity tumors such as liquid tumour and lung cancer, breast cancer, prostate cancer) in abnormal expression increase, generation with malignant tumour, Develop closely related.
By inhibiting STAT3 activity to be expected to that cancer cell is made apoptosis occur to achieve the purpose that treating cancer, study recently It was found that inhibiting STAT3 signal that can overcome the chemical drug resistance including kinds of tumors such as retinoblastoma, lung cancer, leukaemia Property, successfully research and development are a new antitumor target to STAT3.Therefore, new STAT3 inhibitor is actively found for cancer Treatment have particularly important meaning.
Summary of the invention
The present invention the following technical schemes are provided:
In a first aspect, the present invention provides a kind of thioxanthene ketone class taxol and STAT3 inhibitor drug combination compositions, Include active constituent and pharmaceutically acceptable auxiliary material, it is characterised in that: the active constituent is shown in taxol and formula (I) STAT3 inhibitor composition, the mass ratio of STAT3 inhibitor shown in taxol and formula (I) is in the active constituent (0.18-0.32): 1；Wherein, the entitled 4- (dibenzo [b, d] thiophene -4- base)-of chemistry of STAT3 inhibitor shown in formula (I) 6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine, chemical formula are as follows:
Second aspect, the present invention also provides the preparation methods of STAT3 inhibitor shown in formula (I), comprising the following steps:
The compound of formula (1) is made in step a:2- hydroxy acetophenone acetylation；
Step b: the compound of formula (2) is made in the compound cyclization of formula (1)；
Step c: the compound of formula (3) is made in the compound bromo of formula (2)；
Step d: the compound amino of formula (3) replaces the compound that formula (4) are made；
The compound of formula (5) is made in step e:4- nitrobenzene methyl and biuret cyclization；
Step f: the compound of formula (6) is made in the compound chloro of formula (5)；
Step g: the compound of formula (6) reacts the compound that formula (7) are made with the compound of formula (4)；
Step h: the compound of formula (7) withReact the compound that formula (8) are made；
Step i: the compound reduction of formula (8) hydrogenates the compound that formula (9) are made；
Step j: the compound of formula (9) is reacted with acryloyl chloride is made STAT3 inhibitor shown in formula (I), reaction route It is as follows:
Preferably, the compound of formula (4) the preparation method comprises the following steps:
In step a, the compound of formula (1) the preparation method comprises the following steps: 2- hydroxy acetophenone, chloroacetic chloride and potassium carbonate are added anti- It answers in bottle, acetone is added, back flow reaction, after reaction, water, ethyl acetate extraction, anhydrous slufuric acid is added in evaporating solvent under reduced pressure Sodium is dry, concentration to get；
In step b, the compound of formula (2) the preparation method comprises the following steps: take 2- acetoxy acetophenone in reaction flask, be added DMSO dissolves, and sodium hydrogen is added portionwise at 0-5 DEG C, finishes, is warmed to room temperature stirring, after reaction, water is added into reaction solution, dilute Hydrochloric acid tune pH value is to faintly acid, and ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, adds into gained grease Enter acetic acid and concentrated hydrochloric acid, about, reaction terminates back flow reaction, and reaction solution is spin-dried for, and water, ethyl acetate extraction, anhydrous slufuric acid is added Sodium it is dry to get；
In step c, the compound of formula (3) the preparation method comprises the following steps: by the compound of formula (2), N-bromosuccinimide and Benzoyl peroxide is added in reaction flask, adds carbon tetrachloride to dissolve, back flow reaction, after reaction, reaction solution add water, acetic acid second Ester extraction, anhydrous sodium sulfate is dry, column chromatographic purifying to get；
In step d, the compound of formula (4) the preparation method comprises the following steps: the compound of formula (3) is added in reaction flask, DMF is added Dissolution is added ammonium hydroxide, is stirred at room temperature, and after reaction, water is added in reaction solution, and ethyl acetate extraction, anhydrous sodium sulfate is dry, mistake Filter, is spin-dried for, and ethyl acetate is added, and the ethyl acetate hydrogen chloride solution that saturation is added after stirring and dissolving is given birth to supernatant layer without precipitating At, filtering, it is dry to get.
Preferably, the compound of formula (7) the preparation method comprises the following steps:
In step e, the compound of formula (5) the preparation method comprises the following steps: weigh 4- nitrobenzoic acid in reaction flask, methanol is added Thionyl chloride is added dropwise in dissolution, drips and finishes back flow reaction, and after reaction, decompression is spin-dried for, and saturated sodium bicarbonate solution is added and adjusts pH To 7-8, ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to get 4- nitrobenzene methyl；Take biuret in reaction flask In, glycol dimethyl ether dissolution is added, sodium hydride is added portionwise at 0-5 DEG C, finishes, is stirred to react 1h at 50 DEG C, adds 4- Nitrobenzene methyl finishes, and is warming up to 85 DEG C of reactions, after reaction, reaction solution is poured into water, and adjusts pH with concentrated hydrochloric acid To acidity, filtering, filter cake drying to get；
In step f, the compound of formula (6) the preparation method comprises the following steps: by 6- (4- nitrobenzophenone) -1,3,5-triazines -2,4- (1H, 3H)-diketone is added in reaction flask, and phosphorus oxychloride, phosphorus pentachloride, 105 DEG C of reactions, after reaction, by reaction solution are added Be poured into water, methylene chloride extraction, anhydrous sodium sulfate it is dry to get；
In step g, the compound of formula (7) the preparation method comprises the following steps: the compound of modus ponens (6) in reaction flask, be added tetrahydro Furans dissolution, be added formula (4) compound, sodium carbonate, back flow reaction, filtering to get.
Preferably, in step h, the compound of formula (8) the preparation method comprises the following steps:
It takes thiosalicylic acid, chlorobenzene in reaction flask, is slowly added into the concentrated sulfuric acid, is reacted at 75 DEG C, it after reaction, will be anti- Liquid is answered to be poured slowly into 60 DEG C of water under stiring, ethyl acetate extraction, anhydrous sodium sulfate dries, filters, and is spin-dried for obtaining the chloro- 9- oxygen of 2- Generation -9H- thioxanthene；
Take the chloro- 9- oxo -9H- thioxanthene of 2-, two cyclopentadienyl of connection pinacol borate, potassium acetate and 1,1'- bis- (diphenyl phosphine) Isosorbide-5-Nitrae-dioxane is added in reaction flask in iron palladium chloride, and 100 DEG C of reactions are added after reaction under the conditions of nitrogen protection Water, ethyl acetate extraction merge organic phase, and saturated common salt water washing merges organic phase, dries, filters, and is concentrated, and column chromatography is pure Change to get 2- (4,4,5,5- tetramethyls -1,3,2- dioxolane borine) -9- oxo -9H- thioxanthene；
In microwave reaction bottle, the chloro- 6- of 4- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group)-is sequentially added 1,3,5- triazine -2- amine, 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- oxo -9H- thioxanthene, [1, Bis- (diphenylphosphine) ferrocene of 1'-] palladium chloride dichloromethane complex, x-phos, cesium carbonate and Isosorbide-5-Nitrae-dioxane/H2O, Dissolution, argon gas displacement, 105 DEG C of microwave reactions, concentration, column chromatographic purifying to get formula (8) compound.
Preferably, in step i, the compound of formula (9) the preparation method comprises the following steps: the compound of modus ponens (8), Pd-C in reaction flask In, methanol is added, is depressed in 1 normal atmosphere, H2Reduction reaction stops reaction, filters, concentration.
Preferably, in step j, the compound of formula (10) the preparation method comprises the following steps: compound, the diisopropyl second of modus ponens (9) Amine is added anhydrous methylene chloride dissolution, is slowly dropped into the dichloromethane solution dissolved with allyl acyl chlorides, react in reaction flask Completely, be concentrated, column chromatographic purifying to get.
The third aspect, the present invention provide pharmaceutical composition, and it includes the compound of the present invention or its is pharmaceutically acceptable Salt.
In some embodiments, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its pharmaceutically Acceptable salt, also comprising one or more selected from following composition: tyrosine protein enzyme inhibitor, EGFR inhibitor, VEGFR Inhibitor, Bcr-Abl inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, histone deacetylase Enzyme inhibitor, VEGF antibody, EGF antibody, HIV kinases inhibitor, HMG-CoA reductase inhibitor etc..
In some embodiments, the present invention provides the compound of the present invention or its pharmaceutically acceptable salt and comprising this The pharmaceutical composition of the compound of invention or its pharmaceutically acceptable salt, the compound or pharmaceutical composition are for treating And/or pre- anti-cancer.
Can by the compound of the present invention or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, diluent or Excipient is prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication include, but are not limited to it is intradermal, In intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, such as be passed through It is transfused or injects, applied by the approach that transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) absorb.Administration can be with It is whole body or local.The example of oral administration preparation includes solid or liquid dosage form, specifically, include tablet, pill, Granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can be prepared by methods known in the art, and include The conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
Fourth aspect, present invention offer general formula I compound represented of the present invention or its pharmaceutically acceptable salt, or comprising Purposes of its pharmaceutical composition in the drug of preparation treatment and/or pre- anti-cancer, wherein the cancer be selected from prostate, Breast cancer, melanoma, Papillary thyroid carcinoma, cholangiocarcinoma, colon cancer, oophoroma, lung cancer, malignant lymphatic tumor, Yi Jipi Skin, colon, thyroid gland, lung and ovary primary and recurrent solid tumor or leukaemia.
Fourth aspect, the present invention provide a kind of thioxanthene ketone class taxol and STAT3 inhibitor drug combination compositions, packet Containing active constituent and pharmaceutically acceptable auxiliary material, the active constituent is as shown in taxol, lenalidomide, formula (I) STAT3 inhibitor composition, the mass ratio of STAT3 inhibitor shown in taxol and formula (I) is (0.18- in the active constituent 0.32): (0.08-0.12): 1.
Specific embodiment
Representative embodiment is protection model and is not intended to limit the present invention in order to better illustrate the present invention below It encloses.
The preparation of 1 2- aminomethyl -4H- chromene -4- keto hydrochloride of embodiment
The preparation of step 1 2- acetoxy acetophenone
2- hydroxy acetophenone (100mmol), chloroacetic chloride (250mmol) and potassium carbonate (500mmol) are added in reaction flask, 300ml acetone is added, back flow reaction 12h, after reaction, water, ethyl acetate extraction, anhydrous sulphur is added in evaporating solvent under reduced pressure Sour sodium is dry, is concentrated to give grease, directly throws in next step.
The preparation of step 2 2- methyl -4H- chromene -4- ketone
2- acetoxy acetophenone (50mmol) is weighed in reaction flask, 100ml DMSO is added and dissolves, at 0-5 DEG C in batches It is added sodium hydrogen (150mmol), finishes, be warmed to room temperature stirring 3h and water, dilute hydrochloric acid tune pH are added into reaction solution after reaction It is worth faintly acid, ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, and 100ml second is added into gained grease Acid and 5 drop concentrated hydrochloric acids, back flow reaction about 3h, reaction terminate, reaction solution are spin-dried for, and water, ethyl acetate extraction, anhydrous slufuric acid is added Sodium is dry, and column chromatographic purifying obtains title compound.
ES:M/Z 161 [M+H]+。
The preparation of step 3 2- bromomethyl -4H- chromene -4- ketone
By step 2 gained 2- methyl -4H- chromene -4- ketone (10mmol), N-bromosuccinimide (NBS, 10mmol) and Benzoyl peroxide (BPO, 0.95mmol) is added in reaction flask, and 20ml carbon tetrachloride is added to dissolve, back flow reaction 12h, reaction knot Shu Hou, reaction solution add water, and ethyl acetate extraction, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains title compound.
ES:M/Z 239 [M+H]+。
The preparation of step 4 2- aminomethyl -4H- chromene -4- keto hydrochloride
Step 3 gained 2- bromomethyl -4H- chromene -4- ketone (0.5mmol) is added in reaction flask, it is molten that 5ml DMF is added Solution is added 2ml ammonium hydroxide, 12h is stirred at room temperature, and after reaction, water, ethyl acetate extraction is added in reaction solution, and anhydrous sodium sulfate is done Dry, filtering is spin-dried for, and ethyl acetate 5ml is added, and the ethyl acetate hydrogen chloride solution of saturation is added after stirring and dissolving to supernatant layer nothing Precipitating generates, and filters, dry, obtains title compound.
ES:M/Z 239 [M+H]+。
The preparation of chloro- 6- (4- the nitrobenzophenone) -1,3,5- triazine of 2 2,4- of embodiment bis-
The preparation of step 1 4- nitrobenzene methyl
4- nitrobenzoic acid (250mmol) is weighed in reaction flask, the dissolution of 300mL methanol is added, thionyl chloride is added dropwise (375mmol) drips and finishes back flow reaction 12h, and after reaction, decompression is spin-dried for, and saturated sodium bicarbonate solution is added and adjusts pH to 7- 8, ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give title compound, directly throws in next step.
The preparation of step 2 6- (4- nitrobenzophenone) -1,3,5- triazine -2,4- (1H, 3H)-diketone
Biuret (100mmol) is weighed in reaction flask, the dissolution of 150mL glycol dimethyl ether is added, adds in batches at 0-5 DEG C Enter sodium hydride (83.4mmol), finish, be stirred to react 1h at 50 DEG C, adds 4- nitrobenzene methyl (83.4mmol), add Finish, be warming up to 85 DEG C of reaction 20h and be after reaction poured into water reaction solution, adjusts pH to acidity with concentrated hydrochloric acid, filter, filter Cake drying, obtains title compound.
ES:M/Z 235 [M+H]+。
The preparation of step 3 2,4- bis- chloro- 6- (4- nitrobenzophenone) -1,3,5- triazine
6- (4- nitrobenzophenone) -1,3,5-triazines -2,4- (1H, 3H)-diketone (200mmol) is added in reaction flask, is added Entering 200mL phosphorus oxychloride, phosphorus pentachloride (800mmol), reaction solution is poured into water by 105 DEG C of reaction 12h after reaction, and two Chloromethanes extraction, anhydrous sodium sulfate is dry, is concentrated to give title compound.
ES:M/Z 275 [M+H]+。
The chloro- 6- of 3 4- of embodiment (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine Preparation
Chloro- 6- (4- the nitrobenzophenone) -1,3,5- triazine (50mmol) of 2 gains 2,4- of embodiment bis- is weighed in reaction flask In, the dissolution of 100mL tetrahydrofuran is added, 1 gains 2- aminomethyl -4H- chromene -4- keto hydrochloride 2- (trifluoro of embodiment is added Methyl)-pyridine -4- amine (55mmol), sodium carbonate (100mmol), back flow reaction 72h, filtering, column chromatographic purifying obtains title compound Object.
ES:M/Z 416 [M+H]+。
4 4- of embodiment (dibenzo [b, d] thiophene -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color Alkene -4- ketone group) -1,3,5- triazine -2- amine DE ZHIBEI
The preparation of the chloro- 9- oxo -9H- thioxanthene of step 1 2-
4.5g thiosalicylic acid, 12.5g chlorobenzene are weighed in reaction flask, the 40mL concentrated sulfuric acid is slowly added into, is reacted at 75 DEG C Reaction solution is poured slowly into 60 DEG C of water by 2h under stiring after reaction, and ethyl acetate extraction, anhydrous sodium sulfate is dry, mistake Filter, is spin-dried for obtaining title compound.
ES:M/Z 247 [M+H]+。
The preparation of step 2 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- oxo -9H- thioxanthene
Take the chloro- 9- oxo -9H- thioxanthene (1mmol) of 2-, connection pinacol borate (1.1mmol), potassium acetate (2mmol) With 1,1'- bis(diphenylphosphino) ferrocene dichloropalladium (Pd (dppf) Cl2, 2mmol) and in reaction flask, 5mL Isosorbide-5-Nitrae-two is added Six ring of oxygen, for 24 hours, after reaction, water is added in 100 DEG C of reactions under the conditions of nitrogen protection, and ethyl acetate extraction merges organic phase, Saturated common salt water washing merges organic phase, dries, filters, and is concentrated, column chromatographic purifying.
ES:M/Z 339 [M+H]+。
Step 3 4- (9- oxo -9H- thioxanthene -2- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone Base) -1,3,5- triazine -2- amine preparation
In 30ml microwave reaction bottle, the chloro- 6- of 4- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone is sequentially added Base) -1,3,5- triazine -2- amine (10mmol), 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- oxo - 9H- thioxanthene (10mmol), [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex (0.1mmol), x- Phos (0.4mmol), cesium carbonate (100mmol) and Isosorbide-5-Nitrae-dioxane/H2O (60ml/10ml), dissolution, argon gas displacement, 105 DEG C microwave reaction 90min, concentration, column chromatographic purifying obtain title compound.
ES:M/Z 592 [M+H]+。
Step 4 4- (9- oxo -9H- thioxanthene -2- base) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -4- ketone Base) -1,3,5- triazine -2- amine preparation
Weigh step 3 gains 4- (9- oxo -9H- thioxanthene -2- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- Chromene -4- ketone group) -1,3,5-triazines -2- amine (1mmol), 10%Pd-C (10mg) in reaction flask, be added 15ml methanol, 1 A normal atmosphere pressure, H21h is restored, reaction is stopped, title compound is concentrated in filtering, is directly used in next step.
ES:M/Z 562 [M+H]+。
Step 5 4- (dibenzo [b, d] thiophene -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color Alkene -4- ketone group) -1,3,5- triazine -2- amine preparation
Weigh step 4 gains 4- (9- oxo -9H- thioxanthene -2- base) -6- (4- aminophenyl)-N- (2- methyl -4H- Chromene -4- ketone group) -1,3,5-triazines -2- amine (0.1mmol), diisopropylethylamine (0.3mmol) in reaction flask, be added The dissolution of 15ml anhydrous methylene chloride, is slowly dropped into methylene chloride (1ml) solution dissolved with allyl acyl chlorides (0.12mmol), 10min fully reacting, concentration, column chromatographic purifying obtain title compound.
1H NMR(600MHz,CDCl3) (δ, ppm): 10.12 (s, 1H), 7.81~7.83 (m, 2H), 7.68~7.70 (m, 2H), 7.57~7.59 (m, 1H), 7.51~7.52 (m, 2H), 7.44~7.46 (m, 1H), 7.39~7.40 (m, 1H), 7.28 ~7.30 (m, 2H), 7.19~7.20 (m, 1H), 7.07~7.09 (m, 2H), 6.64~6.65 (m, 1H), 6.48~6.50 (m, 1H), 6.01~6.03 (m, 1H), 5.56 (s, 1H), 5.50~5.52 (m, 1H), 4.89 (s, 1H), 4.46~4.48 (m, 1H), 3.06~3.08 (m, 2H), 2.81~2.83 (m, 2H), 2.00~2.03 (brs, 2H), 1.91~1.92 (brs, 1H)
ES:M/Z 616 [M+H]+。
Experimental example 1: biological activity determination
Compound prepares: the full-automatic microwell plate pretreatment system of POD810 is added compound prepared by the embodiment of the present invention Enter in orifice plate, compound initial concentration is 100uM, and each compound does duplicate hole, 2 times of dilutions, 10 points.
The culture of cell: prostate gland cancer cell DU-145, human breast cancer cell MDA-MB-468 are used contain 15% tire respectively The RPMI-1640 culture medium of cow's serum (FBS) is cultivated in 37 degree of incubators, and logarithmic growth phase cell is for testing.
The experiment of MTT cells viability: prostate gland cancer cell DU-145, human breast cancer cell MDA-MB-468 are inoculated with respectively (5-10 × 10 in 96 orifice plates4Cells/well), 48h is handled with the compound of embodiment 6 to 11 respectively, is added 20 in every hole μ l3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromide (MTT) hatches 4h, and 100 μ in every hole are then added LDMSO sets low-speed oscillation 10min on shaking table, dissolves crystal sufficiently.It is measured at enzyme-linked immunosorbent assay instrument OD490nm each The light absorption value in hole handles to obtain homologous thread and IC using GraphPad Prism50Value, the results are shown in Table 1.
Table 1
The experimental results showed that the present invention is thin to the active MDA-MB-468 cell of STAT3, DU-145 with sustained activation There is born of the same parents good inhibiting effect, taxol and formula (I) compound combination to have more to MDA-MB-468 cell, DU-145 cell Excellent inhibiting effect.

Claims (8)

1. a kind of thioxanthene ketone class taxol and STAT3 inhibitor drug combination compositions comprising active constituent and pharmaceutically may be used The auxiliary material of receiving, it is characterised in that: active constituent STAT3 inhibitor shown in taxol and formula (I) forms, described The mass ratio of STAT3 inhibitor shown in taxol and formula (I) is (0.18-0.32) in active constituent: 1；Wherein, formula (I) institute Entitled 4- (dibenzo [b, d] thiophene -4- base) -6- (the 4- allyl amido phenyl)-N- (2- of chemistry of the STAT3 inhibitor shown Methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine, chemical formula are as follows:
2. a kind of thioxanthene ketone class taxol as described in claim 1 and STAT3 inhibitor drug combination compositions, feature It is: the following steps are included:
The compound of formula (1) is made in step a:2- hydroxy acetophenone acetylation；
Step b: the compound of formula (2) is made in the compound cyclization of formula (1)；
Step c: the compound of formula (3) is made in the compound bromo of formula (2)；
Step d: the compound amino of formula (3) replaces the compound that formula (4) are made；
The compound of formula (5) is made in step e:4- nitrobenzene methyl and biuret cyclization；
Step f: the compound of formula (6) is made in the compound chloro of formula (5)；
Step g: the compound of formula (6) reacts the compound that formula (7) are made with the compound of formula (4)；
Step h: the compound of formula (7) withReact the compound that formula (8) are made；
Step i: the compound reduction of formula (8) hydrogenates the compound that formula (9) are made；
Step j: the compound of formula (9) is reacted with acryloyl chloride is made STAT3 inhibitor shown in formula (I), and reaction route is as follows:
3. a kind of thioxanthene ketone class taxol as described in claim 1 and STAT3 inhibitor joint are used Pharmaceutical composition, it is characterised in that: the compound of formula (4) the preparation method comprises the following steps:
In step a, the compound of formula (1) the preparation method comprises the following steps: by 2- hydroxy acetophenone, chloroacetic chloride and potassium carbonate be added reaction flask In, acetone is added, water, ethyl acetate extraction is added in back flow reaction, after reaction, evaporating solvent under reduced pressure, and anhydrous sodium sulfate is done It is dry, concentration to get；
In step b, the compound of formula (2) the preparation method comprises the following steps: take 2- acetoxy acetophenone in reaction flask, it is molten that DMSO is added It solves, sodium hydrogen is added portionwise at 0-5 DEG C, finishes, is warmed to room temperature stirring, after reaction, water, dilute hydrochloric acid tune are added into reaction solution PH value is to faintly acid, and ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, acetic acid is added into gained grease And concentrated hydrochloric acid, about, reaction terminates back flow reaction, and reaction solution is spin-dried for, and water is added, and ethyl acetate extraction, anhydrous sodium sulfate is dry, To obtain the final product；
In step c, the compound of formula (3) the preparation method comprises the following steps: by the compound, N-bromosuccinimide and peroxide of formula (2) Change benzoyl to be added in reaction flask, carbon tetrachloride is added to dissolve, back flow reaction, after reaction, reaction solution add water, ethyl acetate extraction Take, anhydrous sodium sulfate is dry, column chromatographic purifying to get；
In step d, the compound of formula (4) the preparation method comprises the following steps: the compound of formula (3) is added in reaction flask, it is molten that DMF is added Solution is added ammonium hydroxide, is stirred at room temperature, and after reaction, water is added in reaction solution, and ethyl acetate extraction, anhydrous sodium sulfate is dry, mistake Filter, is spin-dried for, and ethyl acetate is added, and the ethyl acetate hydrogen chloride solution that saturation is added after stirring and dissolving is given birth to supernatant layer without precipitating At, filtering, it is dry to get.
4. a kind of thioxanthene ketone class taxol as described in claim 1 and STAT3 inhibitor joint are used Pharmaceutical composition, it is characterised in that: the compound of formula (7) the preparation method comprises the following steps:
In step e, the compound of formula (5) the preparation method comprises the following steps: weigh 4- nitrobenzoic acid in reaction flask, it is molten that methanol is added Solution, be added dropwise thionyl chloride, drip finish back flow reaction, after reaction, decompression is spin-dried for, be added saturated sodium bicarbonate solution adjust pH to 7-8, ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to get 4- nitrobenzene methyl；Take biuret in reaction flask, Glycol dimethyl ether dissolution is added, sodium hydride is added portionwise at 0-5 DEG C, finishes, is stirred to react 1h at 50 DEG C, add 4- nitro Methyl benzoate finishes, and is warming up to 85 DEG C of reactions, after reaction, reaction solution is poured into water, and adjusts pH to acid with concentrated hydrochloric acid Property, filtering, filter cake drying to get；
In step f, the compound of formula (6) the preparation method comprises the following steps: by 6- (4- nitrobenzophenone) -1,3,5-triazines -2,4- (1H, 3H)-diketone is added in reaction flask, and phosphorus oxychloride, phosphorus pentachloride is added, and after reaction, reaction solution is poured into for 105 DEG C of reactions In water, methylene chloride extraction, anhydrous sodium sulfate it is dry to get；
In step g, the compound of formula (7) the preparation method comprises the following steps: the compound of modus ponens (6) in reaction flask, be added tetrahydrofuran Dissolution, be added formula (4) compound, sodium carbonate, back flow reaction, filtering to get.
5. a kind of thioxanthene ketone class taxol as described in claim 1 and STAT3 inhibitor joint are used Pharmaceutical composition, it is characterised in that: in step h, the compound of formula (8) the preparation method comprises the following steps:
It takes thiosalicylic acid, chlorobenzene in reaction flask, is slowly added into the concentrated sulfuric acid, is reacted at 75 DEG C, after reaction, by reaction solution It is poured slowly into 60 DEG C of water under stiring, ethyl acetate extraction, anhydrous sodium sulfate dries, filters, and is spin-dried for obtaining the chloro- 9- oxo-of 2- 9H- thioxanthene；
Take the chloro- 9- oxo -9H- thioxanthene of 2-, connection pinacol borate, potassium acetate and 1,1'- bis- (diphenyl phosphine) ferrocene two Isosorbide-5-Nitrae-dioxane is added in reaction flask in palladium chloride, and water is added after reaction in 100 DEG C of reactions under the conditions of nitrogen protection, Ethyl acetate extraction merges organic phase, and saturated common salt water washing merges organic phase, dries, filters, and is concentrated, column chromatographic purifying, Up to 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- oxo -9H- thioxanthene；
In microwave reaction bottle, the chloro- 6- of 4- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -1,3 is sequentially added, 5- triazine -2- amine, 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- oxo -9H- thioxanthene, [1,1'- is bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, x-phos, cesium carbonate and Isosorbide-5-Nitrae-dioxane/H2O, dissolution, Argon gas displacement, 105 DEG C of microwave reactions, concentration, column chromatographic purifying to get formula (8) compound.
6. a kind of thioxanthene ketone class taxol as described in claim 1 and STAT3 inhibitor joint are used Pharmaceutical composition, it is characterised in that: in step i, the compound of formula (9) the preparation method comprises the following steps: compound, the Pd-C of modus ponens (8) In reaction flask, methanol is added, is depressed in 1 normal atmosphere, H2Reduction reaction stops reaction, filters, concentration.
7. a kind of thioxanthene ketone class taxol as described in claim 1 and STAT3 inhibitor joint are used Pharmaceutical composition, it is characterised in that: in step j, the compound of formula (10) the preparation method comprises the following steps: the compound of modus ponens (9), two different Propylethylamine is added anhydrous methylene chloride dissolution, it is molten to be slowly dropped into the methylene chloride dissolved with allyl acyl chlorides in reaction flask Liquid, fully reacting, concentration, column chromatographic purifying to get.
8. a kind of thioxanthene ketone class taxol and STAT3 inhibitor drug combination compositions comprising active constituent and pharmaceutically may be used The auxiliary material of receiving, it is characterised in that: active constituent STAT3 inhibitor as shown in taxol, lenalidomide, formula (I) Composition, the mass ratio of STAT3 inhibitor shown in taxol and formula (I) is (0.18-0.32): (0.08- in the active constituent 0.12): 1.
CN201811282938.1A 2018-10-31 2018-10-31 A kind of thioxanthene ketone class taxol and STAT3 inhibitor drug combination compositions Withdrawn CN109172563A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101854802A (en) * 2007-09-10 2010-10-06 波士顿生物医药公司 Novel compositions and methods for cancer treatment
CN102884062A (en) * 2009-12-23 2013-01-16 嘉世高制药公司 Aminopyrimidine kinase inhibitors
US20140045908A1 (en) * 2011-02-25 2014-02-13 Synta Pharmaceuticals Corp. Hsp90 inhibitory compounds in treating jak/stat signaling-mediated cancers
CN105640939A (en) * 2016-01-27 2016-06-08 湖北医药学院 Application of compound separated and extracted from burdock to serving as STAT3 inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101854802A (en) * 2007-09-10 2010-10-06 波士顿生物医药公司 Novel compositions and methods for cancer treatment
CN102884062A (en) * 2009-12-23 2013-01-16 嘉世高制药公司 Aminopyrimidine kinase inhibitors
US20140045908A1 (en) * 2011-02-25 2014-02-13 Synta Pharmaceuticals Corp. Hsp90 inhibitory compounds in treating jak/stat signaling-mediated cancers
CN105640939A (en) * 2016-01-27 2016-06-08 湖北医药学院 Application of compound separated and extracted from burdock to serving as STAT3 inhibitor

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