CN109288845A - A kind of carbazoles STAT inhibitor maleate crystal form II drug combination compositions and preparation method thereof - Google Patents
A kind of carbazoles STAT inhibitor maleate crystal form II drug combination compositions and preparation method thereof Download PDFInfo
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- CN109288845A CN109288845A CN201811282914.6A CN201811282914A CN109288845A CN 109288845 A CN109288845 A CN 109288845A CN 201811282914 A CN201811282914 A CN 201811282914A CN 109288845 A CN109288845 A CN 109288845A
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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
- A61K31/395—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
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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
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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
- A61K31/395—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to medicinal chemistry arts, more particularly to compound 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1 with function of tumor, 3, a kind of novel crystal forms, preparation method, the composition comprising the crystal form of 5- triazine -2- amine maleate, and the purposes of the crystal form or the composition comprising the crystal form in medicine preparation, the II crystal form has good physical and chemical stability, solubility and bioavilability, is suitble to formulation development.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to the compound 4- (9- ethyl -9H- carbazole-with function of tumor
4- yl) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate
A kind of novel crystal forms, preparation method, the composition comprising the crystal form and the crystal form or the combination comprising the crystal form
Purposes of the object in medicine preparation.
Background technique
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.
Compound 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -
4- ketone group) -1,3,5-triazines -2- amine maleate, there is formula:
The Compound ira vitro cytoactive detection finds that it has good inhibitory activity to prostate gland cancer cell DU-145,
IC50Value is 9.0nM, also has good inhibitory activity, IC to human breast cancer cell MDA-MB-46850Value is 19.7nM, is had
Good application prospect.
This field knows that the difference of drug crystal forms will cause the difference of various physicochemical properties, as solubility, dissolution rate,
Fusing point, density, hardness, optical and electrical properties, steam pressure etc..These differences can be reflected in thermodynamic stability, as stable type,
Metastable type and instability mode；It can also be reflected on physical and chemical stability, such as hygroscopicity, crystal transfer, sample degradation.This
A little differences directly affect prescription preparation process, storage method, internal medicine the generation dynamic performance of drug, and then influence the safety of drug
Property and validity.
Therefore, 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color is studied
Alkene -4- ketone group) -1,3,5- triazine -2- amine maleate polymorphism and select significant and steady on clinical treatment
Fixed controllable crystal form tool is of great significance to.
Summary of the invention
To 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4-
Ketone group) -1,3,5-triazines -2- amine maleate crystal form research in, the present inventor has found tens kinds of crystal forms altogether, real
It tests and shows in obtained numerous crystal forms, wherein II crystal form has good physical and chemical stability, solubility and biological utilisation
Degree is suitble to formulation development.
For foregoing invention purpose, in a first aspect, the present invention provides a kind of taxols and carbazoles STAT inhibitor horse
Carry out hydrochlorate crystal form II drug combination compositions, includes active constituent and pharmaceutically acceptable auxiliary material, the active constituent
The STAT3 inhibitor crystal form II shown in taxol and formula (I) is formed, in the active constituent shown in taxol and formula (I)
The mass ratio of STAT3 inhibitor crystal form II is (0.14-0.22): 1；Wherein, the chemical name of STAT3 inhibitor shown in formula (I)
For 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,
5- triazine -2- amine mesylate, chemical formula are as follows:
4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl-provided by the invention
4H- chromene -4- ketone group) -1,3,5-triazines -2- amine maleate II crystal form, radiated using Cu-Ka, X-ray powder spreads out
Penetrate 2 θ of the angle of diffraction be 3.6 ± 0.2 °, 5.7 ± 0.2 °, 8.0 ± 0.2 °, 9.2 ± 0.2 °, 11.7 ± 0.2 °, 14.8 ± 0.2 °,
Characteristic peak is shown at 17.1 ± 0.2 °, 18.5 ± 0.2 °, 25.5 ± 0.2 °.
This field knows, when with the crystallization of X-ray diffraction measure compound, due to the instrument of measurement or condition of measurement etc.
Influence, for measured summit, there are the relative intensities of certain measurement error, especially x-ray diffraction pattern with test
The variation of condition and change.For example, the evaluated error of 2 θ values can be about ± 0.2 °, the evaluated error of relative intensity can for ±
20%.Therefore, when determining every kind of crystalline texture, it should take into account this error.It can be understood as any with the application's
There is II crystal form the crystal form of essentially identical or similar x-ray diffraction pattern to belong within scope of the present application.
Specifically, 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- provided by the invention
Methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine maleate II crystal form, it is radiated using Cu-Ka, X-ray powder
Diffraction 2 θ of the angle of diffraction be 3.6 ± 0.2 °, 5.7 ± 0.2 °, 7.1 ± 0.2 °, 8.0 ± 0.2 °, 9.2 ± 0.2 °, 10.5 ± 0.2 °,
11.7±0.2°、14.8±0.2°、15.7±0.2°、16.2±0.2°、17.1±0.2°、18.5±0.2°、22.4±0.2°、
Characteristic peak is shown at 25.5 ± 0.2 °.
4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl-provided by the invention
4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form have X- diffraction pattern as described in Figure 1.
Second aspect, the present invention provide 4- of the invention (9- ethyl -9H- carbazole -4- base) -6- (4- acrylyl aminobenzene
Base)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine maleate II crystal form preparation method, it is described
Method includes 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 and 4- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- ethyl-of formula (7)
The compound of formula (8) is made in 9H- carbazole reaction；
Step i: the compound reduction of formula (8) hydrogenates the compound that formula (9) are made；
Step j: the compound of formula (9) reacts the compound that formula (I) is made with acryloyl chloride；
Step k: the compound of formula (I) is reacted with maleic acid is made formula (I) compound maleate, by gained maleate
It is added in methanol or ethyl alcohol, reflux, 0-5 DEG C of crystallization is to get 4- (9- ethyl -9H- carbazole -4- base) -6- (4- acrylyl aminobenzene
Base)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine maleate II crystal form, reaction route is as follows:
The solvent that formula (I) compound is reacted with maleic acid in step k is selected from alcohol, ketone, ethyl acetate or their mixture；
Preferably, the solvent that formula (I) compound is reacted with maleic acid is selected from methanol, ethyl alcohol, acetone, ethyl acetate or their mixing
Object；It is further preferred that the solvent that formula (I) compound is reacted with maleic acid is methanol or ethyl alcohol.
The molar ratio that formula (I) compound is reacted with maleic acid in step k is about 1:0.5-0.55；Preferably, formula (I) chemical combination
The molar ratio that object is reacted with maleic acid is about 1:0.5.
The usage amount of methanol described in step F or ethyl alcohol is every gram of 4- (9- ethyl -9H- carbazole -4- base) -6- (4- alkene
Propionamido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate use methanol or ethyl alcohol
10-15mL；Preferably, the usage amount of methanol described in step F or ethyl alcohol is every gram of 4- (9- ethyl -9H- carbazole -4- base) -
6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleic acid uses methanol
Or ethyl alcohol 10mL.
The third aspect, the present invention provide pharmaceutical composition, and it includes 4- of the invention (9- ethyl -9H- carbazole -4- base) -
6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form,
Taxol and pharmaceutically acceptable carrier.By 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N-
(2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form, taxol with it is pharmaceutically acceptable
Carrier is prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication includes, but are not limited to intradermal, flesh
In interior, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, such as by defeated
It infuses or injects, applied by the approach that transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) absorb.Administration can be
It is whole body or local.The example of oral administration preparation includes solid or liquid dosage form, specifically, including tablet, pill, grain
Agent, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can be prepared by methods known in the art, and include medicine
The conventional use of carrier of object formulation art.
The third aspect, the present invention provides a kind of combinations of carbazoles STAT inhibitor maleate crystal form II combination medicine
Object, include active constituent and pharmaceutically acceptable auxiliary material, it is characterised in that: the active constituent by taxol, come that degree
The composition of STAT3 inhibitor crystal form A shown in amine, formula (I), STAT3 shown in taxol and formula (I) inhibits in the active constituent
The mass ratio of agent crystal form A is (0.09-0.21): (0.08-0.12): 1.
4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color of the invention
Alkene -4- ketone group) -1,3,5-triazines -2- amine maleate II crystal form is with good stability, solubility and bioavilability,
Suitable for pharmaceutical preparation is made.
Detailed description of the invention
Fig. 1 is 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -
4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form x-ray diffraction pattern.
Specific embodiment
The present invention is explained in more detail with reference to embodiments, the embodiment of the present invention is merely to illustrate technology of the invention
Scheme not limits the scope of the invention.
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]+。
The preparation of 4 4- of embodiment (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- ethyl -9H- carbazole
The preparation of the chloro- 9- ethyl -9H- carbazole of step 1 4-
4- chlorine carbazole (5.46mmol) is weighed in reaction flask, 20mL THF dissolution is added, is cooled to -10 DEG C, NaH is added
(14mmol), finishes, and after stirring 30 minutes, adds bromoethane (6mmol), finishes, reacts at room temperature 3h, and reaction terminates, and water quenching is added to go out,
Ethyl acetate extraction, dry, concentration is prepared chromatogram purification and obtains the chloro- 9- ethyl -9H- carbazole of 4-.
ES:M/Z 230 [M+H]+。
The preparation of step 2 4- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- ethyl -9H- carbazole
Weigh the chloro- 9- ethyl -9H- carbazole (1mmol) of step 1 gains 4-, connection pinacol borate (1.1mmol), vinegar
Sour potassium (2mmol) and 1,1'- bis(diphenylphosphino) ferrocene dichloropalladium (Pd (dppf) Cl2, 2mmol) and in reaction flask, add
Entering 5mL Isosorbide-5-Nitrae-dioxane, for 24 hours, after reaction, water is added in 100 DEG C of reactions under the conditions of nitrogen protection, and ethyl acetate extracts,
Merge organic phase, saturated common salt water washing merges organic phase, dries, filters, and is concentrated, and column chromatographic purifying obtains title compound.
5 4- of embodiment (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine preparation
Step 1 4- (9- ethyl -9H- carbazole -4- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine preparation
In 30ml microwave reaction bottle, embodiment 3 gained mixture 4- chloro- 6- (4- nitrobenzophenone)-N- (2- is sequentially added
Methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine (10mmol), 4 gains 4- (4,4,5,5- tetramethyl-of embodiment
1,3,2- dioxolane borine) -9- ethyl -9H- carbazole (10mmol), [bis- (diphenylphosphine) ferrocene of 1,1'-] dichloride
Palladium dichloromethane complex (0.1mmol), x-phos (0.4mmol), cesium carbonate (100mmol) and 1,4- dioxane/H2O
(60ml/10ml), dissolution, argon gas displacement, 105 DEG C of microwave reaction 90min, concentration, column chromatographic purifying obtain title compound.
ES:M/Z 575 [M+H]+。
Step 2 4- (9- ethyl -9H- carbazole -4- base) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine preparation
Weigh step 1 gains 4- (9- ethyl -9H- carbazole -4- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine (1mmol), 10%Pd-C (10mg) in reaction flask, be added 15ml methanol, at 1
Normal atmosphere pressure, H21h is restored, reaction is stopped, title compound is concentrated in filtering, is directly used in next step.
ES:M/Z 545 [M+H]+。
Step 3 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -
4- ketone group) -1,3,5- triazine -2- amine preparation
Weigh step 2 gains 4- (9- ethyl -9H- carbazole -4- base) -6- (4- aminophenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine (0.1mmol), diisopropylethylamine (0.3mmol) in reaction flask, be added 15ml
Anhydrous methylene chloride dissolution, 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), 8.12 (m, 1H), 7.80~7.82 (m, 2H),
7.78~7.79 (m, 1H), 7.67~7.69 (m, 2H), 7.50~7.52 (m, 2H), 7.43~7.45 (m, 2H), 7.31~
7.32 (m, 2H), 7.07~7.09 (m, 2H), 6.97~6.99 (m, 1H), 6.68~6.70 (m, 1H), 6.02~6.04 (m,
1H), 5.56 (s, 1H), 5.50~5.52 (m, 1H), 4.88 (s, 1H), 4.46~4.51 (m, 3H), 3.06~3.08 (m, 2H),
2.81~2.84 (m, 2H), 2.01~2.03 (brs, 2H), 1.91~1.93 (brs, 1H), 1.30~1.31 (t, 3H)
ES:M/Z 599 [M+H]+。
Embodiment 6:4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine maleate preparation
5 compound of embodiment (1mmol) is weighed in reaction flask, adds methanol 20mL, at room temperature after stirring and dissolving, horse is added
Come sour (0.5mmol), finish, flow back 0.5h, is cooled to room temperature, evaporating solvent under reduced pressure, and vacuum drying obtains titled at room temperature
Close object.
Embodiment 7:4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine maleate preparation
5 compound of embodiment (1mmol) is weighed in reaction flask, adds acetone 20mL, at room temperature after stirring and dissolving, horse is added
Come sour (0.55mmol), finish, flow back 0.5h, is cooled to room temperature, evaporating solvent under reduced pressure, and vacuum drying obtains titled at room temperature
Close object.
Embodiment 8:4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine maleate preparation
5 compound of embodiment (1mmol) is weighed in reaction flask, adds ethyl alcohol 20mL, at room temperature after stirring and dissolving, horse is added
Come sour (0.5mmol), finish, flow back 0.5h, is cooled to room temperature, evaporating solvent under reduced pressure, and vacuum drying obtains titled at room temperature
Close object.
Embodiment 9:4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form preparation
Weigh 10.0g4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine maleate is in reaction flask, and addition 100mL methanol, flow back 30min, natural cooling
To room temperature, 0-5 DEG C of crystallization is stayed overnight, and obtains 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- first
Base -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form.
Embodiment 10:4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form preparation
Weigh 10.0g4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine maleate is in reaction flask, and addition 150mL ethyl alcohol, flow back 30min, natural cooling
To room temperature, 0-5 DEG C of crystallization is stayed overnight, and obtains 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- first
Base -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form.
Embodiment 11:4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form preparation
Weigh 10.0g4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine maleate is in reaction flask, and addition 100mL ethyl alcohol, flow back 30min, natural cooling
To room temperature, 0-5 DEG C of crystallization is stayed overnight, and obtains 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- first
Base -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form.
4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- of above embodiments 9-11 preparation
(2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine maleate II crystal form through measurement there is essentially identical X to penetrate
Ray diffraction diagram spectrum, is shown in Fig. 1.
Embodiment 12: biological activity determination
Compound prepares: the compound that the full-automatic microwell plate pretreatment system of POD810 is prepared the embodiment of the present invention 6
It is added 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
In 96 orifice plates (5-10 × 104cells/well), handle 48h with the compound of embodiment 6, be added in every hole 20 μ l 3- (4,
5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromide (MTT) hatching 4h, 100 μ l DMSO in every hole is then added, sets and shakes
Low-speed oscillation 10min on bed, dissolves crystal sufficiently.The extinction in each hole is measured at enzyme-linked immunosorbent assay instrument OD 490nm
Value, handles to obtain homologous thread and IC using GraphPad Prism50Value, the results are shown in Table 1.
Table 1
The experimental results showed that 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -
4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate is to the active MDA-MB-468 of STAT3 with sustained activation
Cell, DU-145 cell have good inhibiting effect.
Embodiment 13: water solubility evaluation
By pharmacopeia four water-soluble experiments in 2015, experimental result was shown in Table 2.
Table 2
| Compound | It is water-soluble |
| 9 compound of embodiment | 40.28mg/ml |
Embodiment 14:4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form stability test
Weigh 3 parts of 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine maleate II crystal form 1.0g, it is laid in culture dish respectively, 1 part of opening is placed in light
It is placed under the conditions of being 4500Lx ± 500Lx according to illumination 30 days, 1 part of opening is placed under the conditions of being placed in 85% relative humidity of room temperature (RH)
30 days, 1 part of opening was placed 30 days under the conditions of being placed in 95% relative humidity of room temperature (RH), is sampled in the 0th, 10,30 day, and examination is maximum
Single miscellaneous, total impurities, crystal form and appearance variations, experimental result are shown in Table 3.
Table 3
Above-mentioned experimental result shows 4- of the invention (9- ethyl -9H- carbazole -4- base) -6- (4- acrylyl aminobenzene
Base)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form have good chemical stabilization
Property and physical stability.
Embodiment 15:4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form long term stability tests
Weigh 2 parts of 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine maleate II crystal form 1.0g opening be laid in weighing bottle, opening is placed in respectively
Separately sampled in 0,3,6 month under the conditions of 25 DEG C/60% relative humidity (RH) and 40 DEG C/75% relative humidity (RH), examination is most
Big single miscellaneous, total impurities, crystal form and appearance variations, the results are shown in Table 4,
Table 4
Above-mentioned experimental result shows 4- of the invention (9- ethyl -9H- carbazole -4- base) -6- (4- acrylyl aminobenzene
Base)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine maleate II crystal form have it is good steady in a long-term
Property.
Claims (8)
1. a kind of taxol and carbazoles STAT inhibitor maleate crystal form II drug combination compositions include active constituent
With pharmaceutically acceptable auxiliary material, it is characterised in that: active constituent STAT3 as shown in taxol and formula (I) inhibits
Agent crystal form II composition, the mass ratio of STAT3 inhibitor crystal form II shown in taxol and formula (I) is in the active constituent
(0.14-0.22): 1；Wherein, entitled 4- (9- ethyl -9H- carbazole -4- the base) -6- of chemistry of STAT3 inhibitor shown in formula (I)
(4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine mesylate, chemical formula
Are as follows:
2. a kind of taxol as described in claim 1 and STAT3 inhibitor crystal form I drug combination compositions, feature exist
In: 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,
The II crystal form of 3,5- triazine -2- amine maleates, is radiated using Cu-Ka, X-ray powder diffraction 2 θ of the angle of diffraction be 3.6 ±
0.2°、5.7±0.2°、8.0±0.2°、9.2±0.2°、11.7±0.2°、14.8±0.2°、17.1±0.2°、18.5±
Characteristic peak is shown at 0.2 °, 25.5 ± 0.2 °.
3. a kind of taxol as described in claim 1 and STAT3 inhibitor crystal form I drug combination compositions, feature exist
In: 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,
The II crystal form of 3,5- triazine -2- amine maleates, is radiated using Cu-Ka, X-ray powder diffraction 2 θ of the angle of diffraction be 3.6 ±
0.2°、5.7±0.2°、7.1±0.2°、8.0±0.2°、9.2±0.2°、10.5±0.2°、11.7±0.2°、14.8±
It is shown at 0.2 °, 15.7 ± 0.2 °, 16.2 ± 0.2 °, 17.1 ± 0.2 °, 18.5 ± 0.2 °, 22.4 ± 0.2 °, 25.5 ± 0.2 °
Characteristic peak.
4. a kind of taxol as described in claim 1 and STAT3 inhibitor crystal form I drug combination compositions, feature exist
In: 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,
The preparation method of the II crystal form of 3,5- triazine -2- amine maleates, includes 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 and 4- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- ethyl -9H- click of formula (7)
Azoles reacts 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) reacts the compound that formula (I) is made with acryloyl chloride；
Step k: the compound of formula (I) is reacted with maleic acid is made formula (I) compound maleate, and gained maleate is added
In methanol or ethyl alcohol, reflux, 0-5 DEG C of crystallization is to get 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl) -
N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine maleate II crystal form, reaction route are as follows:
5. preparation method as claimed in claim 3, it is characterised in that: formula (I) compound reacts molten with maleic acid in step k
Agent is selected from alcohol, ketone, ethyl acetate or their mixture；Preferably, the solvent that formula (I) compound is reacted with maleic acid is selected from first
Alcohol, ethyl alcohol, acetone, ethyl acetate or their mixture；It is further preferred that formula (I) compound reacts molten with maleic acid
Agent is methanol or ethyl alcohol.
6. preparation method as claimed in claim 3, it is characterised in that: what formula (I) compound was reacted with maleic acid in step k rubs
Your ratio is about 1:0.5-0.55；Preferably, the molar ratio that formula (I) compound is reacted with maleic acid is about 1:0.5.
7. preparation method as claimed in claim 3, it is characterised in that: the usage amount of methanol described in step F or ethyl alcohol is
Every gram of 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,
3,5- triazine -2- amine maleate uses methanol or ethyl alcohol 10-15mL；Preferably, methanol described in step F or ethyl alcohol make
Dosage is every gram of 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine maleic acid use methanol or ethyl alcohol 10mL.
8. a kind of carbazoles STAT inhibitor maleate crystal form II drug combination compositions, comprising active constituent and pharmaceutically
Acceptable auxiliary material, it is characterised in that: active constituent STAT3 as shown in taxol, lenalidomide, formula (I) inhibits
Agent crystal form A composition, the mass ratio of STAT3 inhibitor crystal form A shown in taxol and formula (I) is (0.09- in the active constituent
0.21): (0.08-0.12): 1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070060521A1 (en) * | 1999-01-27 | 2007-03-15 | The University Of South Florida, A Public Corporation Of The State Of Florida Corporation | Inhibition of STAT3 signal transduction for human cancer therapy |
| 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 |
-
2018
- 2018-10-31 CN CN201811282914.6A patent/CN109288845A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070060521A1 (en) * | 1999-01-27 | 2007-03-15 | The University Of South Florida, A Public Corporation Of The State Of Florida Corporation | Inhibition of STAT3 signal transduction for human cancer therapy |
| 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 |
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