CN109276571A - A kind of taxol and novel nitro phthalazone BTK inhibitor drug combination compositions and its application - Google Patents
A kind of taxol and novel nitro phthalazone BTK inhibitor drug combination compositions and its application Download PDFInfo
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
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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
Abstract
It include active constituent and pharmaceutically acceptable auxiliary material the present invention provides a kind of taxol and novel nitro phthalazone BTK inhibitor drug combination compositions, active constituent BTK inhibitor shown in taxol and formula (I) forms, and the molar ratio of BTK inhibitor shown in taxol and formula (I) is (0.14-0.20) in the active constituent: 1.The pharmaceutical composition can be used for preparing prevention and/or treatment disease medicament relevant to bruton's tyrosine kinase, therapeutic effect are good.
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to phthalazines ketone BTK inhibitor and its application, and in particular to phthalazines ketone
BTK inhibitor, preparation method, the pharmaceutical composition containing such compound and its treatment bruton's tyrosine kinase
Purposes in related disease.
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 (Src
Homologyl/Tyrosine kinase) structural domain or kinase domain form (Akinleye et al:Ibrutinib
and novel BTK inhibitors in clinical development.Journal of Hematology&
Oncology2013,6:59).In bone-marrow-derived lymphocyte development process, the correct expression of BTK gene difference protein domain is in B
There is key effect in the function of 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.
The selectivity for being currently known BTK inhibitor is undesirable, in addition to inhibiting BTK, also inhibit other a variety of kinases (such as ETK,
EGF, BLK, FGR, HCK, YES, BRK and JAK3 etc.), to generate more side effect；Meanwhile BTK binding site occurs to dash forward
It frequently can lead to the generation of drug resistance after change.Therefore more BTK inhibitor are clinically needed, for treating the diseases such as tumour,
Such adverse events can be overcome simultaneously.
Summary of the invention
The present invention the following technical schemes are provided:
In a first aspect, a kind of taxol provided by the invention and novel nitro phthalazone BTK inhibitor combination medicine group
Object is closed, includes active constituent and pharmaceutically acceptable auxiliary material, active constituent BTK as shown in taxol and formula (I)
Inhibitor composition, the molar ratio of BTK inhibitor shown in taxol and formula (I) is (0.14-0.20) in the active constituent: 1；
Wherein, the BTK inhibitor, shown in chemical formula such as formula (I),
Wherein, the preparation method of the BTK inhibitor, includes 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) and substituted alkene acyl chloride reaction obtain compounds of formula I, and reaction route is as follows:
Preferably, in step A,
It takes 3- nitro -1- dimethoxy-methyl benzene in reaction flask, is added tetrahydrofuran dissolution, 60 DEG C, under nitrogen protection,
S-BuLi is added, reaction solution is stirred to react at -60 DEG C；It takes dry ice in reaction flask, tetrahydrofuran is added, n- is added
BuLi, stirred under nitrogen atmosphere add the reaction solution after being stirred to react at -60 DEG C, continue to stir, and stop reaction, and water is added,
PH to 2 is adjusted with concentrated hydrochloric acid, separates organic phase, water phase is extracted with ethyl acetate, and merges organic phase, saturated common salt water washing, nothing
Aqueous sodium persulfate is dry, is recrystallized to give the compound of formula (8)；
The compound, acetic acid, hydrazine of formula (8) are weighed in reaction flask, isopropanol is added, under nitrogen protection, 100 DEG C of reflux are anti-
It answers, stops reaction, addition ethyl acetate, water, extraction merges organic phase, and anhydrous sodium sulfate is dry, hangs and does, column chromatographic purifying obtains
The compound of formula (4).
Preferably, in step B,
Triphosgene is weighed in reaction flask, toluene is added, the tetrahydrofuran for being dissolved with parachlorophenol and pyridine is added dropwise at 0 DEG C
Solution, drop finish, and the reaction was continued at room temperature, concentration of reaction solution, and methylene chloride is added, and hang and do, and chloro-carbonic acid is made to benzyl chloride ester, directly
For in next step；
- 2 (1H)-t-butyl formate of 5- amino -3,4- dihydro-isoquinoline and DIPEA are weighed in reaction flask, dichloro is added
Methane is stirred at room temperature down and chloro-carbonic acid is slowly added dropwise to benzyl chloride ester, and drop finishes, continues to stir at room temperature, stops reaction, and concentration reaction is mixed
Close object, ethyl acetate be added, diluted hydrochloric acid aqueous solution and saturated common salt water washing, anhydrous sodium sulfate dry, filter, concentration to get
The compound of formula (3).
Preferably, in step C, the compound of modus ponens (4), formula (3) compound in reaction flask, DMF is added, at 55 DEG C
Reaction overnight, stops reaction, and water, methylene chloride is added, and extraction separates organic phase, and water phase continues to be extracted with dichloromethane, and merges
Organic phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains the compound of formula (5).
Preferably, in step D, the compound of modus ponens (5) is added trifluoroacetic acid, stirs at room temperature in reaction flask, depressurizes
It being concentrated to dryness, ethyl acetate is added, successively use disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate is dry,
Filtering, be concentrated under reduced pressure formula (6) compound.
Preferably, in step E, the compound of modus ponens (6) is added methylene chloride 100ml and dissolves, at 0 DEG C in reaction flask
DIEA is added, after stirring, continues that but-2-ene acyl chlorides is added dropwise at 0 DEG C, drop finishes, is stirred at room temperature, and stops reaction, adds water, dichloromethane
Alkane extraction merges organic phase, and anhydrous sodium sulfate is dry, and column chromatographic purifying obtains the compound of formula (I).
The present invention also provides a kind of novel nitro phthalazines class BTK inhibitor drug combination compositions, comprising activity at
Divide and pharmaceutically acceptable auxiliary material, active constituent BTK inhibitor group as shown in taxol, lenalidomide, formula (I)
Molar ratio at BTK inhibitor shown in, taxol in the active constituent, lenalidomide, formula (I) is (0.14-0.20):
(0.08-0.12): 1.
Pharmaceutical composition of the invention and pharmaceutically acceptable carrier, diluent or excipient can be prepared by mixing into
Pharmaceutical preparation, to be suitable for oral or parenteral.Medication includes, but are not limited in intradermal, intramuscular, peritonaeum, vein
Interior, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, such as by being transfused or inject, pass through through
The approach application that epithelium or mucocutaneous (such as oral mucosa or rectum etc.) absorb.Administration can be whole body or local.
The example of oral administration preparation includes solid or liquid dosage form, specifically, include tablet, pill, granula, pulvis, capsule,
Syrup, emulsion, suspension etc..The preparation can be prepared by methods known in the art, and include field of pharmaceutical preparations routine
Carrier, diluent or the excipient used.
The pharmaceutical composition can be in preparation prevention and/or treatment disease medicament relevant to bruton's tyrosine kinase
Application, the compound of the logical formula (I) of the present invention is applied including the tumor disease patient that over-expresses to bruton's tyrosine kinase
Or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug or compound comprising the logical formula (I) of the present invention or
The pharmaceutical composition of its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, effectively to inhibit Bu Ludun junket ammonia
Acid kinase overexpression, prevents disease progression.
Specific embodiment
The preparation of 1 8- nitro -2H- phthalazines -1- ketone of embodiment
Step 1: weighing 3- nitro -1- dimethoxy-methyl benzene (500mmol) 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.
Step 2: dry ice (50mmol) is weighed in reaction flask, is added tetrahydrofuran (200ml), is added n-BuLi (5ml),
After stirred under nitrogen atmosphere 2h, the mixture of step 1 is added, continues to stir 30min, stops reaction, water 1000ml is added, use is dense
Salt acid for adjusting pH separates organic phase, water phase is extracted with ethyl acetate, and merges organic phase, saturated common salt water washing, anhydrous sulphur to 2
Sour sodium is dry, is recrystallized to give 3- nitro -2- dimethoxy-methyl benzoic acid.
Step 3: weighing step 2 gains (400mmol), acetic acid (93mmol), hydrazine (600mmol) in reaction flask, add
Entering isopropanol 300ml, under nitrogen protection, 100 DEG C of back flow reaction 2h stop reaction, ethyl acetate 300ml, water 500ml is added,
Extraction merges organic phase, and anhydrous sodium sulfate is dry, hangs and does, column chromatographic purifying obtains title compound.
ESI–MS:[M+H]+m/z 192。
Embodiment 2 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base) preparation of-carbamic acid to benzyl chloride ester
Triphosgene (5mmol) is weighed in reaction flask, toluene 100ml is added, is added dropwise at 0 DEG C and is dissolved with parachlorophenol
The tetrahydrofuran solution 20ml of (5mmol) and pyridine (10ml), drop finish, the reaction was continued at room temperature 8h, concentration of reaction solution, addition two
Chloromethanes 40ml is hanged and is done, and chloro-carbonic acid is made to benzyl chloride ester, is directly used in next step.
Weigh -2 (1H)-t-butyl formate (50mmol) of 5- amino -3,4- dihydro-isoquinoline and DIPEA (100mmol) in
In reaction flask, methylene chloride 300ml is added, is stirred at room temperature down and chloro-carbonic acid is slowly added dropwise to benzyl chloride ester (51mmol), drop finishes, room temperature
Under continue stir 1h, stop reaction, concentrated reaction mixture, be added ethyl acetate 70ml, diluted hydrochloric acid aqueous solution (0.2-0.3N)
With saturated common salt water washing, anhydrous sodium sulfate is dried, filtered, and is concentrated to give title compound, is directly used in next step.
ESI–MS:[M+H]+m/z 417。
Embodiment 3 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- [8- nitro -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
Weigh 8- nitro -2H- phthalazines -1- ketone and (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-amino
Formic acid in reaction flask, is added DMF100ml, is reacted overnight at 55 DEG C, stop reaction, water is added to benzyl chloride ester (195mmol)
100ml, methylene chloride 200ml, extraction separate organic phase, and water phase continues to be extracted with dichloromethane (3*50ml), merge organic
Phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains title compound.
ESI–MS:[M+H]+m/z 572。
Embodiment 4 [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- nitro -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
Weigh (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- [8- nitro-(2H)-phthalein
Piperazine -1- ketone group] in reaction flask, addition trifluoroacetic acid 20ml stirs 1h at room temperature, is concentrated to dryness benzyl ester (50mmol),
Ethyl acetate 80ml is added, successively uses 1.5M disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate is dry, mistake
Filter, is concentrated under reduced pressure to obtain intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) carbamic acid -2- (2H)-phthalazines -1- ketone group benzyl ester,
It directly throws in next step.
Weigh intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) carbamic acid -2- (2H)-phthalazines -1- ketone group benzyl ester
(20mmol) is added methylene chloride 100ml dissolution, DIEA (40mmol) is added at 0 DEG C in reaction flask, after stirring 30min, after
Continue dropwise addition but-2-ene acyl chlorides (20mmol) at 0 DEG C, drop finishes, and 3h is stirred at room temperature, and stops reaction, adds water 100ml, methylene chloride
It extracts (3*50ml), merges organic phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains title compound.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.40~8.39 (m, 1H), 8.16~8.15 (m,
1H), 8.10 (s, 1H), 8.03~8.01 (m, 1H), 7.54~7.53 (m, 2H), 7.34~7.33 (m, 2H), 7.21~7.18
(m, 3H), 6.57~6.55 (m, 1H), 6.40~6.38 (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 540。
The evaluation of 1 the compound of the present invention vitro kinase activity of experimental example
The compound of the present invention of above embodiments preparation successively dilutes after each compound is diluted to 10mM with DMSO
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
The external Romas cell activity evaluation of 2 the compound of the present invention of experimental example
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 1
Claims (9)
1. a kind of taxol and novel nitro phthalazone BTK inhibitor drug combination compositions, it is characterised in that: include activity
Ingredient and pharmaceutically acceptable auxiliary material, it is characterised in that: active constituent BTK as shown in taxol and formula (I) suppression
Preparation composition, the molar ratio of BTK inhibitor shown in taxol and formula (I) is (0.14-0.20) in the active constituent: 1；Its
In, the BTK inhibitor, shown in chemical formula such as formula (I),
2. a kind of taxol according to claim 1 and novel nitro phthalazone BTK inhibitor drug combination compositions,
It is characterized by: the preparation method of the BTK inhibitor, includes the following steps:
Step A: the compound substitution reaction of formula (7) obtains the compound of formula (8), and the compound and hydrazine reaction of formula (8) obtain formula (4)
Compound；
Step B: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；
Step C: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；
Step D: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
Step E: the compound of formula (6) and substituted alkene acyl chloride reaction obtain compounds of formula I, and reaction route is as follows:
3. a kind of taxol according to claim 1 and novel nitro phthalazone BTK inhibitor drug combination compositions,
It is characterized by: in step A,
It takes 3- nitro -1- dimethoxy-methyl benzene in reaction flask, is added tetrahydrofuran dissolution, 60 DEG C, under nitrogen protection, be added
Reaction solution is stirred to react by s-BuLi at -60 DEG C；It takes dry ice in reaction flask, tetrahydrofuran is added, n-BuLi, nitrogen is added
It is stirred under gas shielded, adds the reaction solution after being stirred to react at -60 DEG C, continue to stir, stop reaction, water is added, with dense salt
Acid for adjusting pH separates organic phase, water phase is extracted with ethyl acetate, and merges organic phase, saturated common salt water washing, anhydrous slufuric acid to 2
Sodium is dry, is recrystallized to give the compound of formula (8)；
The compound, acetic acid, hydrazine of formula (8) are weighed in reaction flask, isopropanol is added, under nitrogen protection, 100 DEG C of back flow reactions,
Stop reaction, addition ethyl acetate, water, extraction merges organic phase, and anhydrous sodium sulfate is dry, hangs and does, column chromatographic purifying obtains formula
(4) compound.
4. a kind of taxol according to claim 1 and novel nitro phthalazone BTK inhibitor drug combination compositions,
It is characterized by: in step B,
Triphosgene is weighed in reaction flask, toluene is added, it is molten that the tetrahydrofuran dissolved with parachlorophenol and pyridine is added dropwise at 0 DEG C
Liquid, drop finish, and the reaction was continued at room temperature, concentration of reaction solution, and methylene chloride is added, and hang and do, and chloro-carbonic acid is made to benzyl chloride ester, directly uses
In in next step；
- 2 (1H)-t-butyl formate of 5- amino -3,4- dihydro-isoquinoline and DIPEA are weighed in reaction flask, methylene chloride is added,
It being stirred at room temperature down and chloro-carbonic acid is slowly added dropwise to benzyl chloride ester, drop finishes, continues to stir at room temperature, stops reacting, concentrated reaction mixture,
Ethyl acetate is added, diluted hydrochloric acid aqueous solution and saturated common salt water washing, anhydrous sodium sulfate dry, filter, and are concentrated to get formula (3)
Compound.
5. a kind of taxol according to claim 1 and novel nitro phthalazone BTK inhibitor drug combination compositions,
It is characterized by: in step C, the compound of modus ponens (4), formula (3) compound in reaction flask, DMF is added, is reacted at 55 DEG C
Overnight, stop reaction, water, methylene chloride is added, extraction separates organic phase, and water phase continues to be extracted with dichloromethane, and merges organic
Phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains the compound of formula (5).
6. a kind of taxol according to claim 1 and novel nitro phthalazone BTK inhibitor drug combination compositions,
It is characterized by: the compound of modus ponens (5) is added trifluoroacetic acid, stirs at room temperature in reaction flask in step D, it is concentrated under reduced pressure
To doing, ethyl acetate is added, is successively dried, filtered with disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate,
Be concentrated under reduced pressure formula (6) compound.
7. a kind of taxol according to claim 1 and novel nitro phthalazone BTK inhibitor drug combination compositions,
It is characterized by: the compound of modus ponens (6) is added methylene chloride 100ml dissolution, is added at 0 DEG C in reaction flask in step E
DIEA after stirring, continues that but-2-ene acyl chlorides is added dropwise at 0 DEG C, and drop finishes, is stirred at room temperature, and stops reaction, adds water, methylene chloride extraction
It takes, merges organic phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains the compound of formula (I).
8. drug combination compositions described in claim 1 are in preparation prevention and/or treat and bruton's tyrosine kinase phase
Application in the disease medicament of pass.
9. a kind of novel nitro phthalazines class BTK inhibitor drug combination compositions, it is characterised in that: include active constituent and medicine
Acceptable auxiliary material on, it is characterised in that: active constituent BTK as shown in taxol, lenalidomide, formula (I) suppression
Preparation composition, taxol in the active constituent, lenalidomide, BTK inhibitor shown in formula (I) molar ratio be (0.14-
0.20): (0.08-0.12): 1.
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