CN109288830A - A kind of taxol and novel phthalazines ketone compounds drug combination compositions - Google Patents
A kind of taxol and novel phthalazines ketone compounds drug combination compositions Download PDFInfo
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Abstract
A kind of taxol provided by the invention and novel phthalazines ketone compounds drug combination compositions, include active constituent and pharmaceutically acceptable auxiliary material, it is characterized by: active constituent phthalazines ketone compounds shown in taxol and N crystal form Formulas I form, the mass ratio of phthalazines ketone compounds shown in taxol and Formulas I is (0.1-0.3) in the active constituent: 1；Wherein, entitled [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] the benzyl ester mesylate of chemistry of phthalazines ketone compounds shown in Formulas I.Pharmaceutical composition anticancer therapeutic of the present invention is good.Present invention discover that can greatly improve the bioactivity of neoplasm growth after phthalazines ketone compound combination shown in taxol and N crystal form Formulas I, the two combination has the synergistic effect of antitumor proliferation, thirsts for exploitation into the fiest-tire medication of clinically anti-pancreatic cancer.
Description
Technical field
The invention belongs to chemical medicine, a kind of taxol and the combination of novel phthalazines ketone compounds combination medicine
Object.
Background technique
Bu Ludun histidine kinase (Bruton's tyrosine kinase, BTK) belongs to the member of Tec family.It is by only
N- terminal domains, that is, PH (pleckstrin homology) structural domain, TH (Tec homology) homologous region, SH3 (Src of spy
Homology3) structural domain, SH2 (Src homology2) structural domain and catalyst structure domain, also referred to as SH1/TK
(Srchomologyl/Tyrosine kinase) structural domain or kinase domain composition (Akinleye et al:
Ibrutinib and novel BTK inhibitors in clinical development.Journal of
Hematology&Oncology2013,6:59).In bone-marrow-derived lymphocyte development process, BTK gene difference protein domain
Correct expression has key effect in the function of B cell and a variety of transduction pathway.
It is B cell class tumour such as leukaemia, hair property myeloma based on BTK signal transduction pathway exploitation small molecule targeted drug
And the treatment of B cell para-immunity disease provides a completely new approach.The evidence of effect of the BTK in autoimmune disease is
(Kil LP, et al:Bruton's tyrosine is provided by BTK- deletion form mouse and BTK- abundance type mouse model experiment
kinase mediated signaling enhances leukemogenesis in a mouse model for
Chronic lymphocytic leukemia.Am J Blood Res2013,3 (1): 71-83.).It is white in chronic lymphocytic
In blood disease (CLL) mouse model, BTK- deletion form mouse abrogates chronic lymphocytic leukemia completely, and BTK overexpression can add
Fast leukaemia morbidity, increases the death rate.Currently, several BTK inhibitor are developed, however, unsatisfactory curative effect.
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, [8- is fluoro- by carbamic acid -4- for research [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -
(2H)-phthalazines -1- ketone group] benzyl ester mesylate polymorphism and select significant and stably and controllable on clinical treatment
Crystal form tool be of great significance to.
In addition, although the combination of anticancer agent has been demonstrated there is great progress in modality of cancer treatment, for difficulty
Treatment to treat or show to the conventional anti-neoplastic agent as monotherapy the cancer for the treatment of resistance, still has and some does not meet
Demand and improve cancer drug therapy space.Although for example, there is the joint based on gemcitabine in clinical treatment
Chemotherapeutic regimen, but to eventually lead to cancer of pancreas prognosis very poor for drug resistance of tumor, and median survival interval is only 3-6 months, is survived within 5 years
Rate is less than 5%.Therefore, novel compositions approach of the exploitation for delivering the known anticancer agents with different role mechanism is this field
Important advance.Although being related to that there is the scheme of the anticancer agent combination of different role mechanism can issue in the case where certain combinations
The effect of waving, but identical mode may not work for other combinations of anticancer agent, and such combination may not be produced always
The raw combination with beneficial therapeutic effect.
Summary of the invention
Technical problem: in order to solve the defects of prior art, the present invention provides a kind of taxols and novel phthalazines ketone
Compound drug combination compositions.
Technical solution: a kind of taxol provided by the invention and novel phthalazines ketone compounds drug combination compositions,
Comprising active constituent and pharmaceutically acceptable auxiliary material, active constituent phthalazone as shown in taxol and N crystal form Formulas I
Class compound composition, the mass ratio of phthalazines ketone compounds shown in taxol and Formulas I is (0.1- in the active constituent
0.3): 1；Wherein, entitled [2 (1H)-but-2-ene acyl group -3, the 4- dihydro isoquinolines of chemistry of phthalazines ketone compounds shown in Formulas I
Quinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate, chemical formula are as follows:
As an improvement, the N crystal form of phthalazines ketone compounds shown in I, is radiated, X-ray powder diffraction using Cu-Ka
2 θ of the angle of diffraction be 7.6 ± 0.2 °, 9.7 ± 0.2 °, 10.9 ± 0.2 °, 11.7 ± 0.2 °, 14.0 ± 0.2 °, 15.0 ± 0.2 °,
15.2±0.2°、19.8±0.2°、22.6±0.2°、25.0±0.2°、26.7±0.2°、29.0±0.2°、30.9±0.2°、
Characteristic peak is shown at 35.1 ± 0.2 °, 35.7 ± 0.2 °.
As an improvement, the N crystal form of phthalazines ketone compounds shown in I, is radiated, X-ray powder diffraction using Cu-Ka
2 θ of the angle of diffraction be 7.6 ± 0.2 °, 9.7 ± 0.2 °, 10.9 ± 0.2 °, 11.7 ± 0.2 °, 14.0 ± 0.2 °, 15.0 ± 0.2 °,
15.2±0.2°、15.7±0.2°、19.8±0.2°、20.3±0.2°、21.2±0.2°、22.6±0.2°、25.0±0.2°、
26.7±0.2°、26.8±0.2°、27.6±0.2°、29.0±0.2°、30.9±0.2°、31.8±0.2°、34.3±0.2°、
35.1±0.2°、35.7±0.2°、37.0±0.2°、39.4±0.2°、40.2±0.2°、44.0±0.2°、45.2±0.2°、
Characteristic peak is shown at 49.5 ± 0.2 °, 50.1 ± 0.2 °, 50.3 ± 0.2 °.
As an improvement, the preparation method of phthalazines ketone compounds shown in N crystal form Formulas I, comprising the following steps:
Step A: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；
Step B: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；
Step C: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
Step D: the compound of formula (6) reacts to obtain compound of formula I with acryloyl chloride；
Step E: formula (I) compound is reacted with methanesulfonic acid is made formula (I) compound methanesulfonic acid salt, and reaction route is as follows:
Step F: formula (I) compound methanesulfonic acid salt obtained by step E is added in ethanol-dichloromethane-water mixed solvent, is returned
Stream, 0-5 DEG C of crystallization is to get N crystal form [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8-
Fluoro- (2H)-phthalazines -1- ketone group] benzyl ester mesylate.
The volume ratio of ethyl alcohol, methylene chloride and water is 10 in ethanol-dichloromethane-water mixed solvent described in step F
~20:5::3~5.
The volume ratio of ethyl alcohol, methylene chloride and water is 15 in ethanol-dichloromethane-water mixed solvent described in step F:
5:3.
Ethanol-dichloromethane-water mixed solvent usage amount described in step F is every gram of [2 (1H)-but-2-ene acyls
Base -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate use second
Alcohol-methylene chloride-water mixed solvent 3-10mL.
Ethanol-dichloromethane described in step F-water mixed solvent usage amount is every gram of [2 (1H)-but-2-ene acyl groups-
3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate use ethyl alcohol -
Methylene chloride-water mixed solvent 5-8mL.
The utility model has the advantages that compared with prior art, pharmaceutical composition anticancer therapeutic of the present invention is good.Present invention discover that purple
The bioactivity of neoplasm growth, the two connection can be greatly improved after phthalazines ketone compound combination shown in the pure and mild N crystal form Formulas I of China fir
With the synergistic effect with antitumor proliferation, exploitation is thirsted for into the fiest-tire medication of clinically anti-pancreatic cancer.
Detailed description of the invention
Fig. 1 is [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalein of 8-
Piperazine -1- ketone group] benzyl ester mesylate N crystal form x-ray diffraction pattern；
Specific embodiment
The present invention is further illustrated below.
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.
Embodiment 1 [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- fluoro- (2H) -
Phthalazines -1- ketone group] benzyl ester preparation
Step 1: weighing -2 (1H)-t-butyl formate (50mmol) of 5- amino -3,4- dihydro-isoquinoline and DIPEA
(100mmol) is added methylene chloride 300ml, is stirred at room temperature down and chloro-carbonic acid is slowly added dropwise to benzyl chloride ester in reaction flask
(51mmol), drop finish, and continue to stir 1h at room temperature, stop reaction, and ethyl acetate 70ml, dilute salt is added in concentrated reaction mixture
Aqueous acid (0.2-0.3N) and saturated common salt water washing, anhydrous sodium sulfate dry, filter, and are concentrated to give (3,4- dihydro-isoquinolines-
2 (1H)-t-butyl formate -5- bases)-carbamic acid to benzyl chloride ester, is directly used in next step, ESI-MS:[M+H]+m/z417。
Step 2: weighing the fluoro- 1- dimethoxy-methyl benzene (500mmol) of 3- in reaction flask, tetrahydrofuran is added
(800ml) dissolution, 60 DEG C, under nitrogen protection, be added s-BuLi (565mmol), reaction solution is stirred into 1h at -60 DEG C；It weighs
Dry ice (50mmol) is added tetrahydrofuran (200ml) in another reaction flask, is added n-BuLi (5ml), stirred under nitrogen atmosphere
After 2h, said mixture is added, continues to stir 30min, stops reaction, water 1000ml is added, adjusts pH to 2 with concentrated hydrochloric acid, point
From organic phase, water phase is extracted with ethyl acetate, and merges organic phase, and saturated common salt water washing, anhydrous sodium sulfate is dry, recrystallizes
To the fluoro- 2- dimethoxy-methyl benzoic acid of 6-；Weigh the fluoro- 2- dimethoxy-methyl benzoic acid (400mmol) of 6-, acetic acid
(93mmol), hydrazine (600mmol) are in reaction flask, addition isopropanol 300ml, and under nitrogen protection, 100 DEG C of back flow reaction 2h stop
It only reacts, ethyl acetate 300ml, water 500ml is added, extraction merges organic phase, and anhydrous sodium sulfate is dry, and outstanding dry, column chromatography is pure
Change to obtain the fluoro- 2H- phthalazines -1- ketone of 8-, ESI-MS:[M+H]+m/z 165。
Step 3: weighing the fluoro- 2H- phthalazines -1- ketone (150mmol) of 8-, (3,4- dihydro-isoquinoline -2 (the 1H)-tertiary fourth of formic acid
Ester -5- base) in reaction flask, DMF100ml is added to benzyl chloride ester (195mmol) in-carbamic acid, and it reacts at 55 DEG C overnight, stops
Water 100ml, methylene chloride 200ml is added in reaction, and extraction separates organic phase, and water phase continues that (3* is extracted with dichloromethane
50ml), merge organic phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains (- 2 (1H)-t-butyl formate-of 3,4- dihydro-isoquinoline
5- yl)-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester.
Step 4: weighing (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base) -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] in reaction flask, addition trifluoroacetic acid 20ml stirs 1h at room temperature, depressurizes dense benzyl ester (50mmol)
It is reduced to dry, addition ethyl acetate 80ml, successively with 1.5M disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate
It dries, filters, intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) fluoro- 2- of carbamic acid -8- (2H)-phthalazines-is concentrated under reduced pressure to obtain
1- ketone group benzyl ester；Weigh gained intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) fluoro- 2- of carbamic acid -8- (2H)-phthalazines -
1- ketone group benzyl ester (20mmol) is added methylene chloride 100ml dissolution, DIEA (40mmol) is added at 0 DEG C, stirring in reaction flask
After 30min, continuing that acryloyl chloride (20mmol) is added dropwise at 0 DEG C, drop finishes, and is stirred at room temperature 3h, stops reaction, add water 100ml, two
Chloromethanes extracts (3*50ml), merges organic phase, and anhydrous sodium sulfate is dry, and column chromatographic purifying obtains [2 (1H)-but-2-ene acyl groups-
3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.10 (s, 1H), 7.88~7.85 (m, 1H),
7.77~7.75 (m, 1H), 7.54~7.52 (m, 3H), 7.34~7.32 (m, 2H), 7.21~7.18 (m, 3H), 6.57~
6.55 (m, 1H), 6.41~6.39 (m, 1H), 4.65 (s, 2H), 4.22 (s, 2H), 3.61~3.59 (m, 2H), 3.13~3.11
(m, 2H), 2.05~2.03 (m, 3H)
ESI–MS:[M+H]+m/z 513。
Embodiment 2:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate preparation
1 compound of embodiment (0.5mmol) is weighed in reaction flask, acetone 5mL is added to stir 0.5h at room temperature, methylsulphur is added dropwise
Sour acetone soln (containing methanesulfonic acid 0.55mmol) 1mL, drop finish, continue to stir 1h at room temperature, solvent is evaporated off in pressurization, at room temperature vacuum
It is dry to obtain title compound.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H disappear after heavy water exchange), 8.10 (s, 1H), 7.88
~7.85 (m, 1H), 7.77~7.75 (m, 1H), 7.54~7.52 (m, 3H), 7.34~7.32 (m, 2H), 7.21~7.18 (m,
3H), 6.57~6.55 (m, 1H), 6.41~6.39 (m, 1H), 5.17 (s, 2H), 4.22 (s, 2H), 3.61~3.59 (m, 2H),
3.13~3.11 (m, 2H), 2.84~2.81 (s, 3H), 2.05~2.03 (m, 3H)
Embodiment 3:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate N crystal form preparation
Weighing 1.0g [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate in reaction flask, be added 5mL volume ratio be 15:5:3 ethanol-dichloromethane -
Water mixed solution, flow back 30min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains [2 (1H)-but-2-ene acyl groups -3,4-
Dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate N crystal form.
Embodiment 4:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate N crystal form preparation
Weighing 2.0g [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate in reaction flask, be added 20mL volume ratio be 2:1:1 ethanol-dichloromethane -
Water mixed solution, flow back 30min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains [2 (1H)-but-2-ene acyl groups -3,4-
Dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate N crystal form.
Embodiment 5:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate N crystal form preparation
Weighing 0.5g [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate in reaction flask, be added 4mL volume ratio be 15:5:3 ethanol-dichloromethane -
Water mixed solution, flow back 30min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains [2 (1H)-but-2-ene acyl groups -3,4-
Dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate N crystal form.
Embodiment 6:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate N crystal form preparation
Weighing 0.5g [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate in reaction flask, be added 3mL volume ratio be 10:5:3 ethanol-dichloromethane -
Water mixed solution, flow back 30min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains [2 (1H)-but-2-ene acyl groups -3,4-
Dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate N crystal form.
[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid-of above embodiments 3-6 preparation
4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate N crystal form has essentially identical X ray diffracting spectrum through measurement,
See Fig. 1.
Grain size analysis: 2.03 μm of partial size D10,8.82 μm of D50,30.21 μm of D90 of statistics.
[8- is fluoro- by carbamic acid -4- for embodiment 7 [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -
(2H)-phthalazines -1- ketone group] benzyl ester mesylate N crystal form stability test
Weigh 2 parts of [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- fluoro- (2H) -
Phthalazines -1- ketone group] benzyl ester mesylate N crystal form 0.5g, it is laid in culture dish respectively, it is opposite that 1 part of opening is placed in room temperature 75%
Place 60 days under the conditions of humidity (RH), 1 part of opening is placed 60 days under the conditions of being placed in 95% relative humidity of room temperature (RH), in the 0th, 5,
10, it samples within 30,60 days, examines or check the variation of largest single impurity, total impurities, crystal form and appearance, experimental result is shown in Table 1.
Table 1
Above-mentioned experimental result shows [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-ammonia of the invention
Base formic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate N crystal form has good chemical stability and physics steady
It is qualitative.
The evaluation of 8 vitro kinase activity of experimental example
Prepare composition:
Composition 1: phthalazines ketone compounds shown in the taxol and Formulas I that mass ratio is 0.1:1；
Composition 2: phthalazines ketone compounds shown in the taxol and Formulas I that mass ratio is 0.3:1；
Composition 3: phthalazines ketone compounds shown in the taxol and Formulas I that mass ratio is 0.2:1；
Control group 1: taxol；
Control group 2: phthalazines ketone compounds shown in Formulas I.
After combination of the above object and control group are diluted to 10mM with DMSO, be successively diluted to 1uM, 100nM, 10nM, 1nM,
0.1nM、0.01nM。
Take the 10 μ l of compound solution of each concentration into 96 orifice plates, addition 90 μ l1 × kinase buffer liquid (50mMHEPES,
PH7.5,0.0015%Brij-35,10mMMgCl2,2mM DTT, prepared before use)；Set up DMSO control group and without enzyme simultaneously
Control group living, contains only 10 μ lDMSO and 90 μ l1 × kinase buffer liquid.Each group mixes 10min at room temperature, then shifts respectively
5 μ l are into 384 orifice plates；Kinase b TK is dissolved in 1 × kinase buffer liquid, is configured to 2.5 × kinase solution, then shifts 10 μ l2.5
× kinase solution is into above-mentioned 384 orifice plates containing each concentration compound；10 μ l2.5 × kinase solution is added in DMSO control group；Nothing
1 × kinase buffer liquid that 10 μ l are free of kinases is added in enzyme activity control group.It is incubated for 10min at room temperature；By FAM label polypeptide and
ATP is dissolved in 1 × kinase buffer liquid, is configured to 2.5 × substrate solution, then shifts 10 μ l2.5 × substrate solution to above-mentioned 384 hole
In plate, 28 DEG C of incubation 1hr；25 μ l (100mMHEPES, pH7.5,0.015%Brij-35,0.2% are added in each hole
CoatingReagent#3,50mMEDTA prepared before use), terminate liquid terminates reaction；It is placed on LabChipEZReader and reads
Conversion data, and inhibiting rate I% is calculated, calculation formula is I%=(Max-Conversion)/(Max-Min) × 100,
Middle Max is the conversion ratio of DMSO control group, and Min is the conversion ratio of no enzyme activity control group, and Conversion is compound processing group
Conversion ratio, data handle through XLfit, are fitted to obtain IC50。IC50Value indicates that compound presses down with not plus compared with compound processing group
Make corresponding compound concentration when 50% enzyme activity.IC50 the results are shown in Table 1.
Table 1
| Test-compound | IC50(nM) | Test-compound | IC50(nM) |
| Composition 1 | 0.8 | Control group 1 | 1.0 |
| Composition 2 | 0.7 | Control group 2 | 9.6 |
| Composition 3 | 0.7 |
The evaluation of the external Romas cell activity of experimental example 2
It takes in exponential phase of growth in good condition one bottle of Raji cell, collects cell, low speed desk centrifuge, 1500
Turn/min, is centrifuged 3min.Supernatant is abandoned, 5mL complete medium is added with pipettor and carries out cell resuspension.Use cell count instrument meter
Number, complete medium are diluted, adjustment cell density to 5 × 104A/mL.It is inoculated on 96 orifice plates using the volley of rifle fire, 100 μ L/
Constant temperature CO is set in hole2It is cultivated 24 hours in incubator.Compound sample-adding, which is carried out, using nanoliter sample adding instrument adds CCK-8 after 72 hours,
Its light absorption value is detected in 10 holes μ L/ at Envision microplate reader 450nm after 2 hours, calculate inhibiting rate, and calculate IC50, as a result see
Table 2.
Table 2
| Test-compound | IC50(nM) | Test-compound | IC50(nM) |
| Composition 1 | 1.6 | Control group 1 | 2.0 |
| Composition 2 | 1.5 | Control group 2 | 11.6 |
| Composition 3 | 1.2 |
Claims (8)
1. a kind of taxol and novel phthalazines ketone compounds drug combination compositions, can comprising active constituent and pharmaceutically connect
The auxiliary material received, it is characterised in that: active constituent phthalazines ketone compounds shown in taxol and N crystal form Formulas I form,
The mass ratio of phthalazines ketone compounds shown in taxol and Formulas I is (0.1-0.3) in the active constituent: 1；Wherein, Formulas I institute
Entitled [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid-of chemistry of the phthalazines ketone compounds shown
4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate, chemical formula are as follows:
2. a kind of taxol according to claim 1 and novel phthalazines ketone compounds drug combination compositions, special
Sign is: the N crystal form of phthalazines ketone compounds shown in I is radiated using Cu-Ka, and X-ray powder diffraction is in 2 θ of the angle of diffraction
For 7.6 ± 0.2 °, 9.7 ± 0.2 °, 10.9 ± 0.2 °, 11.7 ± 0.2 °, 14.0 ± 0.2 °, 15.0 ± 0.2 °, 15.2 ± 0.2 °,
19.8±0.2°、22.6±0.2°、25.0±0.2°、26.7±0.2°、29.0±0.2°、30.9±0.2°、35.1±0.2°、
Characteristic peak is shown at 35.7 ± 0.2 °.
3. a kind of taxol according to claim 1 and novel phthalazines ketone compounds drug combination compositions, special
Sign is: radiated using Cu-Ka, X-ray powder diffraction 2 θ of the angle of diffraction be 7.6 ± 0.2 °, 9.7 ± 0.2 °, 10.9 ±
0.2°、11.7±0.2°、14.0±0.2°、15.0±0.2°、15.2±0.2°、15.7±0.2°、19.8±0.2°、20.3±
0.2°、21.2±0.2°、22.6±0.2°、25.0±0.2°、26.7±0.2°、26.8±0.2°、27.6±0.2°、29.0±
0.2°、30.9±0.2°、31.8±0.2°、34.3±0.2°、35.1±0.2°、35.7±0.2°、37.0±0.2°、39.4±
It is shown at 0.2 °, 40.2 ± 0.2 °, 44.0 ± 0.2 °, 45.2 ± 0.2 °, 49.5 ± 0.2 °, 50.1 ± 0.2 °, 50.3 ± 0.2 °
Characteristic peak.
4. a kind of taxol according to claim 1 and novel phthalazines ketone compounds drug combination compositions, special
Sign is: the preparation method of phthalazines ketone compounds shown in N crystal form Formulas I, comprising the following steps:
Step A: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；
Step B: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；
Step C: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
Step D: the compound of formula (6) reacts to obtain compound of formula I with acryloyl chloride；
Step E: formula (I) compound is reacted with methanesulfonic acid is made formula (I) compound methanesulfonic acid salt, and reaction route is as follows:
Step F: formula (I) compound methanesulfonic acid salt obtained by step E is added in ethanol-dichloromethane-water mixed solvent, reflux,
[8- is fluoro- by carbamic acid -4- to get N crystal form [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-for 0-5 DEG C of crystallization
(2H)-phthalazines -1- ketone group] benzyl ester mesylate.
5. a kind of taxol according to claim 1 and novel phthalazines ketone compounds drug combination compositions, special
Sign is: in ethanol-dichloromethane-water mixed solvent described in step F the volume ratio of ethyl alcohol, methylene chloride and water be 10~
20:5::3~5.
6. a kind of taxol according to claim 1 and novel phthalazines ketone compounds drug combination compositions, special
Sign is: the volume ratio of ethyl alcohol, methylene chloride and water is 15 in ethanol-dichloromethane-water mixed solvent described in step F:
5:3.
7. a kind of taxol according to claim 1 and novel phthalazines ketone compounds drug combination compositions, special
Sign is: ethanol-dichloromethane-water mixed solvent usage amount described in step F is every gram of [2 (1H)-but-2-ene acyl groups-
3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate use ethyl alcohol -
Methylene chloride-water mixed solvent 3-10mL.
8. a kind of taxol according to claim 1 and novel phthalazines ketone compounds drug combination compositions, special
Sign is: ethanol-dichloromethane described in step F-water mixed solvent usage amount be every gram [2 (1H)-but-2-ene acyl group -3,
4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate use ethyl alcohol-two
Chloromethanes-water mixed solvent 5-8mL.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140107151A1 (en) * | 2011-05-17 | 2014-04-17 | Principia Biophama Inc. | Tyrosine kinase inhibitors |
| CN104812746A (en) * | 2012-11-16 | 2015-07-29 | 弗·哈夫曼-拉罗切有限公司 | Inhibitors of bruton's tyrosine kinase |
| WO2016123504A1 (en) * | 2015-01-30 | 2016-08-04 | Pharmacyclics Llc | Btk inhibitor combinations and multidrug-resistance |
| CN109180642A (en) * | 2018-10-04 | 2019-01-11 | 南京先进生物材料与过程装备研究院有限公司 | Phthalazines ketone BTK inhibitor and its application |
| CN109336864A (en) * | 2018-10-04 | 2019-02-15 | 南京先进生物材料与过程装备研究院有限公司 | Phthalazines ketone compound crystal form N and preparation method thereof |
-
2018
- 2018-10-04 CN CN201811164055.0A patent/CN109288830A/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140107151A1 (en) * | 2011-05-17 | 2014-04-17 | Principia Biophama Inc. | Tyrosine kinase inhibitors |
| CN104812746A (en) * | 2012-11-16 | 2015-07-29 | 弗·哈夫曼-拉罗切有限公司 | Inhibitors of bruton's tyrosine kinase |
| WO2016123504A1 (en) * | 2015-01-30 | 2016-08-04 | Pharmacyclics Llc | Btk inhibitor combinations and multidrug-resistance |
| CN109180642A (en) * | 2018-10-04 | 2019-01-11 | 南京先进生物材料与过程装备研究院有限公司 | Phthalazines ketone BTK inhibitor and its application |
| CN109336864A (en) * | 2018-10-04 | 2019-02-15 | 南京先进生物材料与过程装备研究院有限公司 | Phthalazines ketone compound crystal form N and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 孟繁浩等 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN109223759A (en) * | 2018-10-31 | 2019-01-18 | 南京先进生物材料与过程装备研究院有限公司 | A kind of taxol and novel phthalazines ketone BTK inhibitor drug combination compositions and its application |
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