CN109288847A - A kind of taxol and carbazoles STAT inhibitor Mesylate Form P drug combination compositions - Google Patents
A kind of taxol and carbazoles STAT inhibitor Mesylate Form P drug combination compositions Download PDFInfo
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- CN109288847A CN109288847A CN201811283146.6A CN201811283146A CN109288847A CN 109288847 A CN109288847 A CN 109288847A CN 201811283146 A CN201811283146 A CN 201811283146A CN 109288847 A CN109288847 A CN 109288847A
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- 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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Abstract
The present invention provides a kind of taxols and carbazoles STAT inhibitor Mesylate Form P drug combination compositions for this, include active constituent and pharmaceutically acceptable auxiliary material, active constituent STAT3 inhibitor crystal form P shown in taxol and formula (I) is formed, and the mass ratio of STAT3 inhibitor crystal form P shown in taxol and formula (I) is (0.09-0.21) in the active constituent: 1.The P crystal form has good physical and chemical stability, solubility and bioavilability, and particle size is suitable, and size distribution curve is in normal state Unimodal Distribution, 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 mesylate
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 mesylate, 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 8.4nM, is had a 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 mesylate 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 mesylate 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 P crystal form has good physical and chemical stability, solubility and biological utilisation
Degree, particle size is suitable, D50It is 35~40 μm, and size distribution curve is in normal state Unimodal Distribution, is suitble to formulation development.
In a first aspect, a kind of taxol and carbazoles STAT inhibitor Mesylate Form P drug combination compositions, packet
Containing active constituent and pharmaceutically acceptable auxiliary material, active constituent STAT3 inhibitor as shown in taxol and formula (I)
Crystal form P composition, the mass ratio of STAT3 inhibitor crystal form P shown in taxol and formula (I) is (0.09- in the active constituent
0.21): 1；Wherein, entitled 4- (9- ethyl -9H- carbazole -4- base) -6- (the 4- alkene of chemistry of STAT3 inhibitor shown in formula (I)
Propionamido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine mesylate, chemical formula are as follows:
The present invention provides 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 mesylate P crystal form, radiated using Cu-Ka, X-ray powder diffraction exists
2 θ of the angle of diffraction is to show characteristic peak at 12.2 ± 0.2 °, 16.9 ± 0.2 °, 23.1 ± 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 and the application P
There is 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 mesylate P crystal form, it is radiated using Cu-Ka, X-ray powder
Diffraction 2 θ of the angle of diffraction be 9.7 ± 0.2 °, 10.9 ± 0.2 °, 12.2 ± 0.2 °, 13.3 ± 0.2 °, 14.5 ± 0.2 °, 16.9 ±
It is shown at 0.2 °, 21.2 ± 0.2 °, 22.3 ± 0.2 °, 23.1 ± 0.2 °, 26.4 ± 0.2 °, 31.0 ± 0.2 °, 40.5 ± 0.2 °
Characteristic peak.
More specifically, 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-provided by the invention
N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine mesylate P crystal form, is radiated, X-ray using Cu-Ka
Powder diffraction 2 θ of the angle of diffraction be 9.7 ± 0.2 °, 10.9 ± 0.2 °, 12.2 ± 0.2 °, 13.3 ± 0.2 °, 13.7 ± 0.2 °,
14.5±0.2°、16.9±0.2°、17.6±0.2°、18.6±0.2°、21.2±0.2°、22.3±0.2°、23.1±0.2°、
Characteristic peak is shown at 26.4 ± 0.2 °, 31.0 ± 0.2 °, 40.5 ± 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 mesylate P 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 mesylate P crystal form preparation method, the side
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 methanesulfonic acid is made formula (I) compound methanesulfonic acid salt, by gained mesylate
It is added in methanol-acetone-isopropyl alcohol mixed solvent, 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 mesylate P crystal form, instead
Answer route as follows:
Preferably, the solvent that formula (I) compound is reacted with methanesulfonic acid in step k be selected from alcohol, ketone, ethyl acetate or they
Mixture；Preferably, the solvent that formula (I) compound is reacted with methanesulfonic acid be selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, acetone,
Methyl ethyl ketone, methyl iso-butyl ketone (MIBK), ethyl acetate or their mixture；It is further preferred that formula (I) compound and methylsulphur
The solvent of acid reaction is selected from methanol, ethyl alcohol, acetone, ethyl acetate or their mixture.
Preferably, the molar ratio that formula (I) compound is reacted with methanesulfonic acid in step k is about 1:1-1.1；Preferably, formula (I)
The molar ratio that compound is reacted with methanesulfonic acid is about 1:1.
Preferably, in methanol-acetone-isopropyl alcohol mixed solvent described in step k methanol, acetone and isopropanol volume
Than for 10~15:3:1；Preferably, methanol, acetone and isopropyl in methanol-acetone-isopropyl alcohol mixed solvent described in step k
The volume ratio of alcohol is 10:3:1.
Preferably, methanol-acetone-isopropyl alcohol mixed solvent usage amount described in step F 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
Mesylate uses methanol-acetone-isopropyl alcohol mixed solvent 25-40mL；Preferably, alcohol-water mixed solvent described in step F
Usage amount be 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 mesylate use methanol-acetone-isopropyl alcohol mixed solvent 30-35mL.
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 mesylate P 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 mesylate P crystal form, taxol and pharmaceutically acceptable load
Body is prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication include, but are not limited to it is intradermal, intramuscular,
In peritonaeum, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, for example, by infusion or
It injects, is applied by the approach that transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) absorb.Administration can be whole body
Or it is 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 drug
The conventional use of carrier of formulation art.
Fourth aspect, the present invention provides a kind of combinations of carbazoles STAT inhibitor Mesylate Form P combination medicine
Object includes active constituent and pharmaceutically acceptable auxiliary material, and the active constituent is shown in taxol, lenalidomide, formula (I)
STAT3 inhibitor crystal form A composition, the matter of STAT3 inhibitor crystal form A shown in taxol and formula (I) in the active constituent
Amount is than being (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 mesylate P crystal form is with good stability, solubility and bioavilability, grain
Diameter size is suitable, D50It is 35~40 μm, and size distribution curve is in normal state Unimodal Distribution, is suitble to formulation development.
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 mesylate P crystal form x-ray diffraction pattern；
Fig. 2 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 mesylate P crystal form particle size distribution figure (PSD).
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 mesylate preparation
5 compound of embodiment (0.5mmol) is weighed in reaction flask, adds ethyl alcohol 10mL, at room temperature after stirring and dissolving, is added dropwise
Methanesulfonic acid acetone soln (containing methanesulfonic acid 0.5mmol) 1mL, drop finish, continue to stir 0.5h, evaporating solvent under reduced pressure, room temperature at room temperature
Lower vacuum drying obtains title compound.
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 mesylate preparation
5 compound of embodiment (0.5mmol) is weighed in reaction flask, adds ethyl acetate 10mL, at room temperature after stirring and dissolving,
Methanesulfonic acid acetone soln (contain methanesulfonic acid 0.55mmol) 1mL is added dropwise, drop finishes, continue to stir 0.5h at room temperature, evaporating solvent under reduced pressure,
Vacuum drying obtains title compound at room temperature.
Instrument used in particle size analyzer (PSD analysis) is 7Microtrac FLEX S3500 laser particle size instrument.Detection ginseng
Number: dispersing agent is water；Dispersing agent flow velocity 55%, sample refractive index: 1.58, dispersing agent refractive index: 1.33, integral way: volume,
Laser source wavelength: 780nm (nanometer).
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 mesylate P crystal form preparation
Weigh 10g4- (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 mesylate in reaction flask, be added 300mL volume ratio be 10:3:1 methanol-the third
Ketone-isopropyl alcohol mixed solvent, flow back 30min, cooled to room temperature, and 0-5 DEG C of crystallization is stayed overnight, and obtains 4- (9- ethyl -9H- click
Azoles -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine methanesulfonic acid
Salt P crystal form, particle size distribution figure are shown in Fig. 2, D50It is 37.5 μm.
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 mesylate P crystal form preparation
Weigh 2.0g4- (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 mesylate in reaction flask, be added 50mL volume ratio be 15:3:1 methanol-the third
Ketone-isopropyl alcohol mixed solvent, flow back 30min, cooled to room temperature, and 0-5 DEG C of crystallization is stayed overnight, and obtains 4- (9- ethyl -9H- click
Azoles -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine methanesulfonic acid
Salt P crystal form, particle size distribution figure is similar with Fig. 2, D50It is 35.2 μm.
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 mesylate P crystal form preparation
Weigh 2.0g4- (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 mesylate in reaction flask, be added 80mL volume ratio be 12:3:1 methanol-the third
Ketone-isopropyl alcohol mixed solvent, flow back 30min, cooled to room temperature, and 0-5 DEG C of crystallization is stayed overnight, and obtains 4- (9- ethyl -9H- click
Azoles -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine methanesulfonic acid
Salt P crystal form, particle size distribution figure is similar with Fig. 2, D50It is 36.9 μm.
4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- of above embodiments 8-10 preparation
(2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine mesylate P crystal form through measurement there is essentially identical X to penetrate
Ray diffraction diagram spectrum, is shown in Fig. 1.
Embodiment 11: 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), 48h is handled with compound, 20 μ l3- (4,5- dimethyl thiophenes are added in every hole
Azoles -2) -2,5- diphenyltetrazolium bromide bromide (MTT) hatching 4h, 100 μ l DMSO in every hole is then added, sets low speed on shaking table and shakes
10min is swung, dissolves crystal sufficiently.The light absorption value that each hole is measured at enzyme-linked immunosorbent assay instrument OD 490nm, uses
GraphPad Prism handles to obtain homologous thread and IC50Value, 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 mesylate is to the active MDA-MB-468 of STAT3 with sustained activation
Cell, DU-145 cell have good inhibiting effect.
Embodiment 12: 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 |
| 8 compound of embodiment | 58.34mg/ml |
Embodiment 13:4- (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 mesylate P 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 mesylate P 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 10 days, 1 part of opening is placed under the conditions of being placed in 85% relative humidity of room temperature (RH)
10 days, 1 part of opening was placed 10 days under the conditions of being placed in 95% relative humidity of room temperature (RH), is sampled in the 0th, 5,10 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 mesylate P crystal form have good chemical stabilization
Property and physical stability.
Claims (10)
1. a kind of taxol and carbazoles STAT inhibitor Mesylate Form P 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 P composition, the mass ratio of STAT3 inhibitor crystal form P shown in taxol and formula (I) is (0.09- in the active constituent
0.21): 1；Wherein, entitled 4- (9- ethyl -9H- carbazole -4- base) -6- (the 4- alkene of chemistry of STAT3 inhibitor shown in formula (I)
Propionamido 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 carbazoles STAT inhibitor Mesylate Form P combination medicine group
Close object, it is characterised in that: 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 mesylate P crystal form, radiated using Cu-Ka, X-ray powder diffraction is being spread out
2 θ of firing angle is to show characteristic peak at 12.2 ± 0.2 °, 16.9 ± 0.2 °, 23.1 ± 0.2 °.
3. a kind of taxol as described in claim 1 and carbazoles STAT inhibitor Mesylate Form P combination medicine group
Close object, it is characterised in that: 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 mesylate P crystal form, radiated using Cu-Ka, X-ray powder diffraction is being spread out
2 θ of firing angle is 9.7 ± 0.2 °, 10.9 ± 0.2 °, 12.2 ± 0.2 °, 13.3 ± 0.2 °, 14.5 ± 0.2 °, 16.9 ± 0.2 °, 21.2
Characteristic peak is shown at ± 0.2 °, 22.3 ± 0.2 °, 23.1 ± 0.2 °, 26.4 ± 0.2 °, 31.0 ± 0.2 °, 40.5 ± 0.2 °.
4. a kind of taxol as described in claim 1 and carbazoles STAT inhibitor Mesylate Form P combination medicine group
Close object, it is characterised in that: 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 mesylate P crystal form, radiated using Cu-Ka, X-ray powder diffraction is being spread out
2 θ of firing angle is 9.7 ± 0.2 °, 10.9 ± 0.2 °, 12.2 ± 0.2 °, 13.3 ± 0.2 °, 13.7 ± 0.2 °, 14.5 ± 0.2 °, 16.9
±0.2°、17.6±0.2°、18.6±0.2°、21.2±0.2°、22.3±0.2°、23.1±0.2°、26.4±0.2°、31.0
Characteristic peak is shown at ± 0.2 °, 40.5 ± 0.2 °.
5. a kind of taxol as described in claim 1 and carbazoles STAT inhibitor Mesylate Form P combination medicine group
Close object, it is characterised in that: 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 mesylate P crystal form preparation method, include 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 methanesulfonic acid is made formula (I) compound methanesulfonic acid salt, and gained mesylate is added
In methanol-acetone-isopropyl alcohol mixed solvent, reflux, 0-5 DEG C of crystallization is to get 4- (9- ethyl -9H- carbazole -4- base) -6- (4- alkene
Propionamido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-triazines -2- amine mesylate P crystal form, reaction route
It is as follows:
6. a kind of taxol as described in claim 1 and carbazoles STAT inhibitor Mesylate Form P combination medicine group
Close object, it is characterised in that: the solvent that formula (I) compound is reacted with methanesulfonic acid in step k selected from alcohol, ketone, ethyl acetate or they
Mixture；Preferably, the solvent that formula (I) compound is reacted with methanesulfonic acid is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, third
Ketone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), ethyl acetate or their mixture；It is further preferred that formula (I) compound with
The solvent of methanesulfonic acid reaction is selected from methanol, ethyl alcohol, acetone, ethyl acetate or their mixture.
7. a kind of taxol as described in claim 1 and carbazoles STAT inhibitor Mesylate Form P combination medicine group
Close object, it is characterised in that: the molar ratio that formula (I) compound is reacted with methanesulfonic acid in step k is about 1:1-1.1；Preferably, formula
(I) molar ratio that compound is reacted with methanesulfonic acid is about 1:1.
8. a kind of taxol as described in claim 1 and carbazoles STAT inhibitor Mesylate Form P combination medicine group
Close object, it is characterised in that: the body of methanol, acetone and isopropanol in methanol-acetone-isopropyl alcohol mixed solvent described in step k
Product is than being 10~15:3:1；Preferably, methanol in methanol-acetone-isopropyl alcohol mixed solvent described in step k, acetone and different
The volume ratio of propyl alcohol is 10:3:1.
9. preparation method as claimed in claim 3, it is characterised in that: methanol-acetone described in step F-isopropanol mixing
The usage amount of solvent 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 mesylate use methanol-acetone-isopropyl alcohol mixed solvent 25-40mL；It is preferred that
Ground, alcohol-water mixed solvent usage amount described in step F are 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 mesylate using methanol-acetone-it is different
Propanol solvent mixture 30-35mL.
10. a kind of carbazoles STAT inhibitor Mesylate Form P 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 CN201811283146.6A patent/CN109288847A/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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