CN105777759A - Bruton's tyrosine kinase inhibitor - Google Patents
Bruton's tyrosine kinase inhibitor Download PDFInfo
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- CN105777759A CN105777759A CN201610286399.3A CN201610286399A CN105777759A CN 105777759 A CN105777759 A CN 105777759A CN 201610286399 A CN201610286399 A CN 201610286399A CN 105777759 A CN105777759 A CN 105777759A
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- 0 CCC(C(*(CCC1)CC1*(*=C([C@]1C(C)=CC(CC2C3C=CC=CC23)=CC1)C=C(CC=CC)C(C)C)C(C)=C)O)=C Chemical compound CCC(C(*(CCC1)CC1*(*=C([C@]1C(C)=CC(CC2C3C=CC=CC23)=CC1)C=C(CC=CC)C(C)C)C(C)=C)O)=C 0.000 description 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention provides a Bruton's tyrosine kinase inhibitor, a medicinal composition comprising the same and application of the Bruton's tyrosine kinase inhibitor in preparation of antitumor drugs. The compound has anti-proliferative effect on tumor cell strains such as A549, SGC7901, MCF-7, HL-60 and PC9-IR, and can be applied to drugs for treating human or animal cell proliferation related solid tumors or leukemia; the compound has good pharmacokinetics property and can be applied to oral medication for human or animal cell proliferation related solid tumors or leukemia or autoimmune diseases; the compound has double-locus response characteristics.
Description
Technical field
The invention belongs to field of medicaments, specificallyA kind of bruton's tyrosine kinase inhibitor, containing its pharmaceutical composition and application in preparing antitumor drug thereof.
Background technology
Little molecule covalent inhibitor (covalent inhibitors), also referred to as irreversible inhibitor (irreversible inhibitors), it is by covalent bond and target protein residue generation irreversible fixation, thus plays a class inhibitor of its biological function.Covalency inhibitor medicaments in the past few decades in human health is made that significant contribution.Relative to non-covalent inhibitor, covalency inhibitor by being combined, with target protein, the affinity enhanced with target with covalent bond, and this is the basic reason that covalency inhibitor shows its high bioactivity.In recent years, owing to non-covalent anti-tumor drugs targeting is particularly a large amount of for the kinase whose generation for Buddhist nun's class Drug-resistant, people are made to increasingly focus on again covalency inhibitor medicaments.In recent years, many big drug firms have all been carried out the research and development of the covalency inhibitor for certain enzyme target spot, have some covalent inhibitor at present and enter clinical trial, including Afatinib, Cl 1033, HKI-272 etc..Wherein, Afatinib is used for treating the Metastatic Nsclc of EGF-R ELISA (EGFR) gene mutation on July 12nd, 2013 by U.S. FDA official approval, becomes the irreversible inhibitor new drug of the first treatment pulmonary carcinoma ratified by FDA.Additionally, the covalent drug of antiviral is also study hotspot in recent years, and achieved with the biggest progress, such as, two anti-hepatitis c virus covalency inhibitor medicaments of FDA approved in 2011, i.e. telaprevir and boceprevir.These researchs demonstrate irreversible inhibitor and can be effectively used for the treatment of disease.
Bruton's tyrosine kinase (Bruton's tyrosine kinase, Btk), the member of a kind of nonreceptor tyrosine kinase Tec family, is except T lymphocyte and natureKillThe key signal enzyme expressed in all hematopoetic cell types outside cell.Btk plays the part of vital role in connection cell surface B-cell receptor (B-cell receptor, BCR) stimulation to the B cell signal transduction path of response in downstream cellular.Btk is B cell growth, activation, signal conduction and the key regulators of survival.Additionally, Bkt works in other hematopoietic cell signal transduction paths numerous, the TNF-α generation of the such as Toll-like receptor in macrophage (Toll like receptor, TLR) and cytokine receptor mediation, IgE receptor (Fc ε R1) the signal conduction in mastocyte, the conduction of suppression Fas/APO-1 apoptotic signal and the platelet aggregation of collagen stimulation in B-pedigree lymphoid cell.See for example C.A.Jeffries etc., J.Bio.Chem. (2003) 278:26258-26264, N.J.Horwood etc., J.Exp.Med. (2003) 197:1603-1611.Recent study shows, Btk signal path is current non-Hodgkin lymphoma (NHL), particularly the new focus in chronic lymphocytic leukemia (CLL), B cell lymphoma and the research of autoimmune disease clinical treatment.Little molecule Btk inhibitor, by acting on BCR signal path, is combined with Btk and suppresses Btk autophosphorylation, stops the activation of Btk, thus blocks cell conductance inducing cell apoptosis.Btk inhibitor selectivity is strong, and toxic and side effects is low, and particularly her cloth replaces the listing of Buddhist nun, is set to " breakthrough " new drug by FDA, and its research and development have a extensive future.Yi Bu reacts for the sulfydryl of Buddhist nun with Btk enzyme cysteine (Cys481) residue, and forms covalent bond, makes Btk enzyme inactivation play curative effect.But, Yi Bu replaces Buddhist nun in administration process for Buddhist nun, easily it is metabolized (being metabolized oxydasis be metabolized to dihydroxylated product or inactivated containing attacks such as the enzyme of sulfydryl, cysteine, glutathion by other) and affects drug effect (seeing below formula), its clinical administration dosage has reached 560mg/ days, and make patient's burden, therefore still need to the treatment developing the highly efficient BTK inhibitor of a class for relevant disease.
The present inventor's early stage patent reports a class dibit point BTK irreversible inhibitor and optical isomer thereof or its pharmaceutically acceptable salt or solvate (number of patent application: 201510242552.8), withFollowing formula InHZ-003 be representation compound.Compared with this compounds replaces Buddhist nun with her cloth, at 2 introducing halogen substiuted of acryloyl group, improve medicine and move character, BTK inhibitory activity, and notable to part entity tumor inhibition, but its water solublity is have impact on due to the introducing of halogen atom.Therefore, for its this characteristic, ensureing that it is highly active while, find that the dibit point BTK irreversible inhibitor that a class water solublity improves has great importance.
Summary of the invention
The dibit point BTK irreversible inhibitor with good solubility that it is an object of the invention to provide novelty, that have no document and report and optical isomer thereof or its pharmaceutically acceptable salt or solvate.
Replace passway of metabolism analysis and the structure activity relationship of Buddhist nun based on her cloth, we remain the halogen of acrylamide 2 so that it is continue the irreversible inhibitory activity of BTK with good pharmacokinetics and dibit point.In its aromatic rings, introduce nitrogen-atoms, improve its dissolubility.
The present invention adopts the following technical scheme that:
BTK inhibitor provided by the present invention has a logical formula I structure:
And optical isomer or its pharmaceutically acceptable salt or solvate, wherein: Ra, Rb, RcIndependent ChoosingFrom H, halogen ,-CF3、-CN、-NO2、OH、NH2、-L-C1-C6Alkyl ,-L-C1-C6The substituted or non-substituted aryl of thiazolinyl, heteroaryl substituted or non-substituted for-L-or-L-, wherein L is key, O, S ,-S (=O) ,-S (=O)2、NH、C(O)、CH2,-NHC (O) O ,-NHC (O) or-C (O) NH, X be selected from fluorine, chlorine and bromine, Y1,Y2Selected from C, N, Y1,Y2At least one is selected from N.
Further, currently preferred compound has a logical formula (II) structure:
And optical isomer or its pharmaceutically acceptable salt or solvate, wherein: each RdIndependentGround is H, halogen ,-CF3、-CN、-NO2、-OH、C1-C3Alkoxyl or-NH2, X is selected from fluorine, chlorine and bromine, Y1,Y2Selected from C, N, Y1,Y2At least one is selected from N.
Further, currently preferred compound has a logical formula (III) structure:
And optical isomer or its pharmaceutically acceptable salt or solvate, wherein: X is selected from fluorine, chlorine and bromine, Y1,Y2Selected from C, N, Y1,Y2At least one is selected from N.
Term illustrates: terms used herein " aryl " refers to full carbon monocycle or the fused polycycle group of 5 to 12 carbon atoms, has the pi-electron system of total conjugated.The limiting examples of aromatic ring has: phenyl ring, naphthalene nucleus and anthracene nucleus.Aromatic ring can be unsubstituted or substituted.The substituent group of aromatic ring is selected from halogen, nitro, amino, C1-C6Alkyl, C1-C6Alkoxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl；
Terms used herein " heteroaryl " refers to the undersaturated carbocyclic ring of 5 to 12 annular atomses, and wherein one or more carbon are replaced by hetero atom such as oxygen, nitrogen, sulfur etc..Hetero-aromatic ring can be monocycle, it is also possible to be dicyclo, is i.e. condensed by two rings and forms.Concrete heterocyclic aryl may is that pyridine radicals, pyrimidine radicals, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl and imidazole radicals etc..Heterocyclic aryl can be unsubstituted or substituted.The substituent group of heterocyclic aryl is selected from halogen, nitro, amino, C1-C6Alkyl, C1-C6Alkoxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl；
Terms used herein " heterocycle " refers to monocycle or fused ring group, has 5 to 9 annular atomses in ring, and wherein one or two annular atoms is selected from N, O or S (O)mThe hetero atom of (wherein m is the integer of 0 to 2), remaining annular atoms is C.These rings can have one or more double bond, but these rings do not have the pi-electron system of total conjugated.Unsubstituted Heterocyclylalkyl can be that pyrrolidinyl, piperidyl, piperazinyl, morpholino base, thiomorpholine are for base, homopiperazine base etc..Heterocycle can be unsubstituted or substituted.The substituent group of heterocycle is selected from halogen, nitro, amino, C1-C6Alkyl, C1-C6Alkoxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl.
Terms used herein " alkoxyl " refers to-O-alkyl group, and wherein alkyl is as defined above.The example of " alkoxyl " used herein includes but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy and tert-butoxy." alkoxyl " also includes substituted alkoxy.Alkoxyl can optionally be optionally substituted by halogen one or many.
Term " thiazolinyl " refers to a class alkyl, and wherein two initial atoms of alkyl form double bond, and this double bond is not the ingredient of aromatic radical.It is to say, thiazolinyl starts from atom-C (R)=C (R)-R, wherein R refers to the remainder of thiazolinyl, and each R can be identical or different.Alkenyl part can be side chain, straight chain or ring-type (in the case, it also can be referred to as " cycloalkenyl group ").According to structure, thiazolinyl can be monoradical or double add group (i.e. alkenylene).Thiazolinyl can be optionally substituted.The limiting examples of thiazolinyl includes-CH=CH2、-C(CH3)=CH2,-CH=CHCH3、-C(CH3)=CHCH3.Alkenylene includes but not limited to-CH=CH-,-C (CH3)=CH-,-CH=CHCH2-,-CH=CHCH2CH2-and-C (CH3)=CHCH2-.Thiazolinyl can have 2-10 carbon atom.Thiazolinyl alternatively has " low-grade alkenyl " of 2-6 carbon atom.
Term " pharmaceutically acceptable derivant " refers to salt and the solvate of selected compounds.
Terms used herein " solvate " refers to the complex of the varying chemical metering formed by solute (such as: the logical formula (I) of the present invention～logical formula (III) compound) and solvent.For the purposes of the present invention, described solvent can not disturb the biologic activity of solute.The suitably example of solvent includes but not limited to water, methanol, ethanol and acetic acid.The solvent being preferably used is pharmaceutical acceptable solvents.Suitably pharmaceutical acceptable solvents includes but not limited to water, ethanol and acetic acid.It is highly preferred that solvent for use is water.
The present invention uses method well-known to those skilled in the art can prepare the salt of compound of the present invention.Described salt can be acylate, inorganic acid salt etc., and described acylate includes citrate, fumarate, oxalates, malate, lactate, camsilate, tosilate, mesylate etc.；Described inorganic acid salt includes halogen acid salt, sulfate, phosphate, nitrate etc..Such as, with lower alkanesulfonic acid, such as methanesulfonic acid, trifluoromethanesulfonic acid etc. can form mesylate, fluoroform sulphonate；Tosilate, benzene sulfonate can be formed with aryl sulfonic acid, such as benzenesulfonic acid or p-methyl benzenesulfonic acid etc.；With organic carboxyl acid, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid etc. can form corresponding salt；Glutamate, Glu or aspartate can be formed with aminoacid, such as glutamic acid or aspartic acid.With mineral acid, such as halogen acids (such as Fluohydric acid., hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulphuric acid or phosphoric acid etc. also can form corresponding salt.
Second object of the present invention is to provide a kind of pharmaceutical composition, described pharmaceutical composition comprises at least one active component and one or more pharmaceutically acceptable carrier or excipient, described active component can be in the solvate of the BTK inhibitor compound of the present invention, the optical isomer of described compound, described compound or the most acceptable salt of its optical isomer, described compound or its optical isomer any one or the most multiple.
Described carrier includes the conventional thinner of pharmaceutical field, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant etc., it may also be necessary to add flavouring agent, sweeting agent etc..Medicine of the present invention can make tablet, powder, granule, capsule, the various ways such as oral liquid and injecting drug use, and the medicine of above-mentioned each dosage form all can be prepared according to the conventional method of pharmaceutical field.
On the other hand, the present invention is to provide disease, obstacle or the disease using the compound described in logical formula I disclosed herein～logical formula (III) and optical isomer thereof or its pharmaceutically acceptable salt or solvate to benefit from the suppression of bruton's tyrosine kinase (Btk) activity to suppress bruton's tyrosine kinase (Btk) activity or treatment.
In further aspect, it provided herein that by giving the compositions of a kind of at least one compound containing therapeutically effective amount of therapist in need thus the method suppressing the bruton's tyrosine kinase activity of described curee, the structural formula of wherein said compound is logical formula (I)～logical formula (III).In some embodiments, curee's suffering from autoimmune disease in need, such as inflammatory bowel, arthritis, lupus, rheumatoid arthritis, psoriasis arthropathica, osteoarthritis, Still disease (Still ' s disease), adolescent arthritis, diabetes, myasthenia gravis, chronic lymphocytic thyroiditis (Hashimoto ' s thyroiditis), Order thyroiditis (Ord ' s thyroiditis), Graves' disease (Graves ' disease), rheumatoid arthritis syndrome (nullgren’s syndrome)、Multiple sclerosis、Guillain-Barre syndrome (Guillain-Barr é syndrome)、Acute disseminated encephalomyelitis、Bronzed disease (Addison ' s disease)、Opsoclonus-myoclonic syndrome、Mandatory spondylitis、Antiphospholipid antibody syndrome、Aplastic anemia、Autoimmune hepatitis、Celiac disease (coeliac disease)、Goodpasture's syndrome (Goodpasture ' s syndrome)、Idiopathic thrombocytopenic purpura、Optic neuritis、Scleroderma、Primary biliary cirrhosis、Reiter syndrome (Reiter ' s syndrome)、Aortic arch syndrome (Takayasu ' s arteritis)、Temporal arteritis、Warm type autoimmune hemolytic anemia、Wegner granulomatosis (Wegener ' s granulomatosis)、Psoriasis、Alopecia universalis、Behcet disease (Disease), confirmed fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvodynia.
In further embodiment, curee in need suffers from cancer.In one embodiment, described cancer is B cell proliferative disease, such as diffusivity large B cell lymphoid tumor, follicular lymphoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, B cell PL, lymphoplasmacytic lymphoma/macroglobulinemia Waldenstron (Mmacroglobulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmocytoma, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, mantle cell lymphoma, vertical diaphragm (thymus) large B cell lymphoid tumor, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma (Burkitt lymphoma)/leukemia or lymphomatoid granulomatosis.
The present invention also provides for the compound or pharmaceutically acceptable salt thereof of the present invention application in preparing BTK inhibitor, the particularly application in preparation treatment cell proliferative diseases.Described cell proliferative diseases includes cancer.In other words, the present invention also provide for the compound described in logical formula I～logical formula (III) and optical isomer thereof or its pharmaceutically acceptable salt or solvate individually or and other drug application in treatment proliferative diseases (such as cancer) is used in combination.Can and the antineoplastic agent that be used in combination of compound or pharmaceutically acceptable salt thereof provided by the present invention include but and at least one following kind non-limiting: mitotic inhibitor (such as vinblastine, vindesine and vinorelbine)；Tubulin decomposing inhibitor (such as taxol)；Alkylating reagent (such as cisplatin, carboplatin and cyclophosphamide)；Antimetabolite (such as 5-fluorouracil, ftorafur, methotrexate, cytosine arabinoside and hydroxyurea)；Can be inserted into antibiotic (such as A Leisu, mitomycin and bleomycin A5)；Enzyme (such as asparagine enzyme)；Topoisomerase inhibitors (as relied on primary glycosides and camptothecine)；Biological response modifier (such as interferon).
Present invention also offers the logical formula I of preparation and the method for pharmaceutically acceptable derivant thereof, synthesize with the synthetic route shown in following scheme:
As Upper instituteShow, compound 1 (prepared by the method for reference WO2012158795) and R1B(OH)2At potassium phosphate, palladium catalyst and in the presence of suitably solvent or mixed solvent are such as dioxane/water; back flow reaction 24 hours; the compound 2 obtained is in the presence of triphenyl phosphorus, DIAD and suitable solvent are such as THF; reacting with the 3-hydroxy piperidine of Boc protection and obtain compound 3, key intermediate 4 is prepared in hydrolysis the most in acid condition.In the presence of this key intermediate DCC and suitable solvent such as DCM, with substitutional crylic acid fragment condensation reaction, obtain logical formula (I) compound.
Inventor experiments prove that, the compounds of this invention has antiproliferative inhibitory action to tumor cell lines such as A549, SGC7901, MCF-7, PC-9IR, HL-60, can be applicable in the medicine of the relevant solid tumor for the treatment of human or animal's cell proliferative or leukemia.
Inventor experiments prove that, the compounds of this invention has preferable pharmacokinetic property, can be applicable to the relevant solid tumor of oral medication human or animal's cell proliferative or leukemia or suffering from autoimmune disease.
Inventor experiments prove that, the compounds of this invention has the response characteristic of dibit point.
Detailed description of the invention
The exploitativeness of the present invention is described below by embodiment, it will be understood by those of skill in the art that the teaching according to prior art, corresponding technical characteristic modified or replaces, still falling within the scope of protection of present invention.
The preparation of embodiment 1. key intermediate 4a
The synthesis of step 1. 3-(6-phenoxypyridines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2a)
By iodo-for 3-1H-pyrazolo [3; 4-d] pyrimidine-4-amine (compound 1) (2.61g; 10mmol), during 4-phenoxypyridines boric acid (3.83g, 18mmol) and potassium phosphate (5.375g, 25mmol) are sequentially added into single neck bottle; add 1; 4-dioxane (40mL) and water (10mL), under nitrogen protection, add triphenyl phosphorus palladium (1.76g; 1.5mmol), back flow reaction 24h.React complete and be cooled to room temperature, it is stirred overnight, separate out yellow mercury oxide, sucking filtration, washing (50ml*3), obtains yellow solid 2.25g, for 3-(6-phenoxypyridines-3-base)-1H-pyrazolo [3 after being dried 24 hours, 4-d] pyrimidine-4-amine (compound 2a), productivity 67%.
The synthesis of step 2. 3-(4-amino-3-(6-phenoxypyridines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3a)
By 3-(6-phenoxypyridines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2a) (2.12g, 7mmol), 3-hydroxy piperidine-1-t-butyl formate (1.55g, 7.7mmol), triphenyl phosphorus (2.75g, 10.5mmol) with azodiisobutyronitrile (2.12g, 10.5mmol) it is dissolved in THF (250ml), room temperature reaction 12h (the monitoring reaction of TLC thin layer chromatography is the most complete).After completion of the reaction, decompression and solvent recovery.Adding 100 ethyl acetate in residue reactant mixture, extract organic layer 3 times with 100ml*3 saturated sodium carbonate solution, merge organic facies, after saturated sodium-chloride washes 1 time, anhydrous sodium sulfate is dried.Decompression and solvent recovery obtains brown solid 1.40g, productivity 40%.The synthesis of step 3.3-(6-phenoxypyridines-3-base)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine hydrochlorate (compound 4a)
By 3-(4-amino-3-(6-phenoxypyridines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3a) (0.97g, 2mmol) it is dissolved in 15ml dioxane, dropping 10ml 2N HCl, stirred overnight at room temperature.The crude product recrystallizing methanol that decompression and solvent recovery obtains, obtains off-white color solid 4a (0.71g, productivity 80%, [M+H]=424.2).
The preparation of embodiment 2. key intermediate 4b
The synthesis of step 1. 3-(6-(2-fluorophenoxy) pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2b)
Synthesis step reference example 1 step 1. synthetic method being similar to compound 2a, prepares compound 2h (2.31g, productivity 68%) from 4-(4-chlorophenoxy) pyridine boronic acid (4.46g, 18mmol).
The synthesis of step 2. 3-(4-amino-3-(6-(2-fluorophenoxy) pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3b)
Synthesis step reference example 1 step 2. synthetic method being similar to compound 3a prepares compound 3b (1.40g, productivity 40%).
The synthesis of step 3. 3-(6-(2-fluorophenoxy) pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine hydrochlorate (compound 4b)
Synthesis step reference example 1 step 3. synthetic method being similar to compound 4a prepares compound 4b (0.67g, productivity 77%, [M+H]=442.2).
The preparation of embodiment 3. key intermediate 4c
The synthesis of step 1. 3-(6-(4-fluorophenoxy) pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2c)
Synthesis step reference example 1 step 1. synthetic method being similar to compound 2a, prepares compound 2c (2.32g, productivity 68%) from 4-(4-chlorophenoxy) pyridine boronic acid (4.46g, 18mmol).
The synthesis of step 2. 3-(4-amino-3-(6-(4-fluorophenoxy) pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3c)
Synthesis step reference example 1 step 2. synthetic method being similar to compound 3a prepares compound 3i (1.32g, productivity 38%).
The synthesis of step 3. 3-(6-(4-fluorophenoxy) pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine hydrochlorate (compound 4c)
Synthesis step reference example 1 step 3. synthetic method being similar to compound 4a prepares compound 4c (0.68g, productivity 78%, [M+H]=442.2).
The preparation (compound 5-1) of embodiment 4. 1-(3-(4-amino-3-(6-phenoxypyridines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-bromopropyl-2-alkene-1-ketone
4a (548mg, 1.3mmol), 2-bromopropene acid (195mg, 1.3mmol) is dissolved in 5ml dichloromethane, dichloromethane (5ml) solution of room temperature dropping DCC (267mg, 1.3mmol), back flow reaction 4 hours.After reaction terminates, being cooled to room temperature, sucking filtration, after filtrate concentrates, column chromatography for separation (petroleum ether: ethyl acetate: triethylamine=2:1:0.1) obtains white solid 202mg, productivity 30%, [M+H]=520.1.1H-NMR(δ,CDCl3-d6): 8.50 (d, 1H, J=2.0Hz, ArH), 8.35 (s, 1H, ArH), 8.03 (dd, 1H, J1=8.4Hz, J2=2.4Hz, ArH), 7.42 (td, 2H, J1=7.6Hz, J2=2.0Hz, ArH), 7.23 (t, 1H, J=7.6Hz, ArH), 7.18 (dd, 2H, J1=8.4Hz, J2=2.0Hz, ArH), 7.08 (d, 1H, J=8.4Hz, ArH), 6.04 (s, 2H ,-NH2), 5.19 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.10 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.05 (d, 1H ,-C=CH2),4.91(m,1H,piperidine),4.63(m,0.5H,piperidine),4.45(m,0.5H,piperidine),4.12(m,0.5H,piperidine),3.75(m,0.5H,piperidine),3.43(m,0.5H,piperidine),3.17(m,0.5H,piperidine),2.85(m,0.5H,piperidine),2.77(m,0.5H,piperidine),2.30(m,2H,piperidine),1.73(m,2H,piperidine)。
The preparation (compound 5-2) of embodiment 5. 1-(3-(4-amino-3-(6-phenoxypyridines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-chloropropyl-2-alkene-1-ketone
Synthesis step reference example 4. synthetic method being similar to compound 5-1 prepares compound 5-2 (214mg, productivity 35%, [M+H]=476.2).1H-NMR(δ,CDCl3-d6): 8.51 (d, 1H, J=2.0Hz, ArH), 8.36 (s, 1H, ArH), 8.05 (dd, 1H, J1=8.0Hz, J2=2.0Hz, ArH), 7.44 (td, 2H, J1=7.6Hz, J2=2.0Hz, ArH), 7.24 (t, 1H, J=7.6Hz, ArH), 7.20 (dd, 2H, J1=8.4Hz, J2=2.0Hz, ArH), 7.11 (d, 1H, J=8.4Hz, ArH), 5.98 (s, 2H ,-NH2), 5.21 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.11 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.06 (d, 1H ,-C=CH2),4.92(m,1H,piperidine),4.63(m,0.5H,piperidine),4.43(m,0.5H,piperidine),4.11(m,0.5H,piperidine),3.74(m,0.5H,piperidine),3.42(m,0.5H,piperidine),3.17(m,0.5H,piperidine),2.82(m,0.5H,piperidine),2.75(m,0.5H,piperidine),2.31(m,2H,piperidine),1.73(m,2H,piperidine)。
The preparation (compound 5-3) of embodiment 6. 1-(3-(4-amino-3-(6-(2-fluorophenoxy) pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-bromopropyl-2-alkene-1-ketone
Synthesis step reference example 4. synthetic method being similar to compound 5-1 prepares compound 5-3 (227mg, productivity 29%, [M+H]=538.1).1H-NMR(δ,CDCl3-d6): 8.51 (d, 1H, J=2.0Hz, ArH), 8.39 (s, 1H, ArH), 8.06 (dd, 1H, J1=8.4Hz, J2=2.0Hz, ArH), 7.37 (dd, 2H, J1=8.4Hz, J2=7.2Hz, ArH), 7.17 (d, 1H, J=8.4Hz, ArH), 6.94 (m, 3H, ArH), 6.00 (s, 2H ,-NH2), 5.21 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.11 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.03 (d, 1H ,-C=CH2),4.92(m,1H,piperidine),4.60(m,0.5H,piperidine),4.42(m,0.5H,piperidine),4.11(m,0.5H,piperidine),3.72(m,0.5H,piperidine),3.43(m,0.5H,piperidine),3.13(m,0.5H,piperidine),2.82(m,0.5H,piperidine),2.70(m,0.5H,piperidine),2.31(m,2H,piperidine),1.75(m,2H,piperidine)。
The preparation (compound 5-4) of embodiment 7. 1-(3-(4-amino-3-(6-(2-fluorophenoxy) pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-chloropropyl-2-alkene-1-ketone
Synthesis step reference example 4. synthetic method being similar to compound 5-1 prepares compound 5-4 (201mg, productivity 31%, [M+H]=494.1).1H-NMR(δ,CDCl3-d6): 8.52 (d, 1H, J=2.0Hz, ArH), 8.39 (s, 1H, ArH), 8.05 (dd, 1H, J1=8.4Hz, J2=2.0Hz, ArH), 7.37 (dd, 2H, J1=8.4Hz, J2=7.6Hz, ArH), 7.15 (d, 1H, J=8.4Hz, ArH), 6.94 (m, 3H, ArH), 5.92 (s, 2H ,-NH2), 5.21 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.12 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.06 (d, 1H ,-C=CH2),4.91(m,1H,piperidine),4.63(m,0.5H,piperidine),4.41(m,0.5H,piperidine),4.11(m,0.5H,piperidine),3.75(m,0.5H,piperidine),3.44(m,0.5H,piperidine),3.16(m,0.5H,piperidine),2.81(m,0.5H,piperidine),2.75(m,0.5H,piperidine),2.32(m,2H,piperidine),1.74(m,2H,piperidine)。
The preparation (compound 5-5) of embodiment 8. 1-(3-(4-amino-3-(6-(4-fluorophenoxy) pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-bromopropyl-2-alkene-1-ketone
Synthesis step reference example 4. synthetic method being similar to compound 5-1 prepares compound 5-5 (234mg, productivity 30%, [M+H]=538.1).1H-NMR(δ,CDCl3-d6): 8.41 (d, 1H, J=2.0Hz, ArH), 8.28 (s, 1H, ArH), 7.96 (dd, 1H, J1=8.8Hz, J2=2.4Hz, ArH), 7.01 (m, 5H, ArH), 5.84 (s, 2H ,-NH2), 5.29 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.13 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.03 (d, 1H ,-C=CH2),4.92(m,1H,piperidine),4.61(m,0.5H,piperidine),4.44(m,0.5H,piperidine),4.12(m,0.5H,piperidine),3.74(m,0.5H,piperidine),3.41(m,0.5H,piperidine),3.13(m,0.5H,piperidine),2.82(m,0.5H,piperidine),2.68(m,0.5H,piperidine),2.32(m,2H,piperidine),1.75(m,2H,piperidine)。
The preparation (compound 5-6) of embodiment 9. 1-(3-(4-amino-3-(6-(4-fluorophenoxy) pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-chloropropyl-2-alkene-1-ketone
Synthesis step reference example 4. synthetic method being similar to compound 5-1 prepares compound 5-6 (205mg, productivity 31%, [M+H]=494.1).1H-NMR(δ,CDCl3-d6): 8.41 (d, 1H, J=2.0Hz, ArH), 8.28 (s, 1H, ArH), 7.97 (dd, 1H, J1=8.4Hz, J2=2.0Hz, ArH), 7.01 (m, 5H, ArH), 5.92 (s, 2H ,-NH2), 5.21 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.12 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.06 (d, 1H ,-C=CH2),4.99(m,1H,piperidine),4.65(m,0.5H,piperidine),4.41(m,0.5H,piperidine),4.17(m,0.5H,piperidine),3.75(m,0.5H,piperidine),3.43(m,0.5H,piperidine),3.16(m,0.5H,piperidine),2.83(m,0.5H,piperidine),2.71(m,0.5H,piperidine),2.33(m,2H,piperidine),1.74(m,2H,piperidine)。
The preparation (compound 5-7) of embodiment 10. 1-(3-(4-amino-3-(6-phenoxypyridines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-fluoropropyl-2-alkene-1-ketone
Synthesis step reference example 4. synthetic method being similar to compound 5-1 prepares compound 5-7 (195mg, productivity 33%, [M+H]=460.2).1H-NMR(δ,CDCl3-d6): 8.51 (d, 1H, J=2.0Hz, ArH), 8.36 (s, 1H, ArH), 8.05 (dd, 1H, J1=8.0Hz, J2=2.4Hz, ArH), 7.43 (td, 2H, J1=7.6Hz, J2=2.0Hz, ArH), 7.26 (t, 1H, J=8.0Hz, ArH), 7.21 (dd, 2H, J1=8.4Hz, J2=2.0Hz, ArH), 7.12 (d, 1H, J=8.4Hz, ArH), 5.99 (s, 2H ,-NH2), 5.21 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.11 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.06 (d, 1H ,-C=CH2),4.92(m,1H,piperidine),4.65(m,0.5H,piperidine),4.39(m,0.5H,piperidine),4.12(m,0.5H,piperidine),3.72(m,0.5H,piperidine),3.42(m,0.5H,piperidine),3.17(m,0.5H,piperidine),2.83(m,0.5H,piperidine),2.76(m,0.5H,piperidine),2.32(m,2H,piperidine),1.77(m,2H,piperidine)。
Embodiment 11. external Btk kinase inhibiting activity and anti tumor activity in vitro test
The external Btk kinase inhibiting activity assay method of the compounds of this invention:
Medicine is dissolved in DMSO the storing solution making 10mM, and the test concentrations medicinal liquid being diluted to 50x is standby, test concentrations with 3 by gradient dilution, respectively 25nM, 8.33nM, 2.78nM, 0.93nM, 0.31nM, 0.10nM.In 96 orifice plates, add 10 μ L 50x medicine reserve liquids, add 90 μ L 1x kinase buffer liquid, on the oscillator concussion 10 minutes.Take 5 μ L from the 96 each holes of orifice plate and be transferred to 384 orifice plates, in 384 orifice plates, set 2 multiple holes.Kinase reaction: prepare 2.5x kinase buffer liquid: added by enzyme in 1x kinases basis buffer.Prepare 2.5x small peptide solution: small peptide and the ATP of FAM labelling are added in 1x kinases basis buffer.Added with in 5 μ L medicinal liquid 384 orifice plates, add 10 μ L 2.5x kinase buffer liquid, incubated at room 10 minutes.In 384 orifice plates, add 10 μ L 2.5x small peptide solution, hatch 1 hour for 28 DEG C.Add 25 μ L stop buffer stopped reaction.Reading, and the suppression ratio that computerized compound is to enzyme, the Fitting Calculation goes out the kinase whose IC of BTK50。
Select different solid tumors and leukemia cell line that synthesized compound carried out the mensuration of anti tumor activity in vitro:
Cell strain: human lung carcinoma cell (A549), human breast cancer cell (MCF7), gastric carcinoma cells (SGC7901), acute promyelocytic leukemia cell (HL60), human lung carcinoma cell gefitinib mdr cell (PC9-IR).
Culture medium: A549:RPMI 1640+ hyclone
MCF7:DMEM+ hyclone
SGC7901:RPMI 1640+ new-born calf serum
HL60:RPMI 1640+ hyclone
PC9-IR:DMEM+ hyclone
Method for preparation of drug: medicine is dissolved in DMSO the storing solution making 10mM, and dilution obtains 5 variable concentrations (test concentrations 100x) by a certain percentage.
Tumor cell In vitro culture:
By five selected strain tumor cell A549, MCF7, SGC7901, HL60, PC9-IR, in 37 DEG C, 5%CO2Cell culture incubator is hatched, passes on when cell density grows to 70～90% (passing on after attached cell Duck ' s EDTA digestion), required for experiment later.
Tumor cell A549, MCF7, SGC7901, HL60, PC9-IR, plant into 4000/200 μ L/ holes, in 37 DEG C, 5%CO on 96 orifice plates2Overnight incubation in cell culture incubator.Every hole adds compound 2 μ L, and final concentration of 50 μMs, 10 μMs, 2 μMs, 0.4 μM, 0.08 μM common in 37 DEG C, 5%CO2Cell culture incubator is hatched 72 hours, with DMSO (2%) as matched group.After 72 hours, add 20 μ L CCK-8 solution, be placed in 37 DEG C, 5%CO2In cell culture incubator 4 hours.The hole of cell is not added as blank with having added respective amount cell culture fluid and CCK-8 solution.Measuring absorbance (OD value) by microplate reader at 450nm, the data obtained is used for calculating IC50。
The computing formula of cell inhibitory rate is: cell inhibitory rate %=[(matched group OD value-blank group OD value)-(medication group OD value-blank group OD value)]/(compared with control cells OD value-blank group OD value) × 100%, tries to achieve half-inhibition concentration (IC by CalcuSyn computed in software50)。
Table 1Part of compounds is to BTK kinase inhibiting activity and tumor cell in vitro proliferation inhibition activity
FromIn tableData, it can be seen that majority of compounds all has obvious inhibitory activity to BTK, compared with HZ-003, are declined slightly.But, on a cellular level, compound 5-1～5-6 tested all shows the tumor cell proliferation inhibition activity more potent than positive control, also shows higher or suitable tumor cell proliferation inhibition activity compared with HZ-003.Compared with replacing Buddhist nun with her cloth, the solid tumor cell activity of compound 5-1～5-6 is higher (A549, SGC-7901, MCF-7), and same to blood tumor cell (HL-60).Particularly in human lung carcinoma cell (A549), compound 5-1 improves 10 times than her cloth for Buddhist nun's activity, improves 5 times than HZ-003.Meanwhile, all compounds also show that potent tumor cell proliferation inhibition activity in PC9-IR (gefitinib persister).Therefore, the involved in the present invention BTK inhibitor that can be used as has wide antitumor application prospect.
Embodiment 12. solubility test
Weigh the test-compound 100mg being ground into fine powder, respectively at 25 DEG C ± 2 DEG C in a certain amount of solvent (1ml, 3ml, 10ml, 100ml), every strength shaking in 5 minutes 30 seconds；Observe 30 minutes interior dissolving situations, as without visible solute, be considered as being completely dissolved.
Experimental result shows, HZ-003 still has part undissolved when 100ml solvent, with reference to the definition of Chinese Pharmacopoeia, belongs to soluble,very slightly.And compound 5-1 is completely dissolved when 100ml solvent, there is fraction undissolved when 10ml, belong to slightly soluble, significantly improve than HZ-003.Illustrate that the introducing of aromatic rings nitrogen-atoms significantly improves the dissolubility of compound.
The sign of embodiment 13. external dibit point irreversible inhibitor character:
First, after using compound 5-1 pretreatment restructuring Btk, with the culture medium repeated washing without inhibitor, its activity will not recover (see for example J.B.Smaill etc., J.Med.Chem.1999,42,1803).Secondly, mass spectrum is passed through, it was observed that the ratio of the molecular weight of the covalent complex between main mass spectra peak correspondence compound 5-3 and Btk is 1:1 (compound 4:518, dalton, Btk kinases binding domain of recombinating: 33487；Complex predictive value is 34005, and measured value is 34005).
Secondly, after using compound 5-1 and cysteine to incubate bath altogether 3 hours, detect through HPLC-MS, find that majority of compounds 5-1 is changed into by the product of two cysteine additions that (predicted molecular weight is: 682), actual molecular weight is (682), experiment proves, the compound tested has by the ability of bimolecular compounds containing thiol groups addition, although it is suitable for Buddhist nun that this also illustrates her cloth of this compounds Btk kinase inhibiting activity in vitro and positive drug, but her cloth can be substantially better than in cell aspect and replace Buddhist nun.
Embodiment 14. is administered orally pharmacokinetic studies
Replacing Buddhist nun as reference with her cloth, investigated compound 5-1 pharmacokinetic property in rat body respectively, concrete grammar is as follows: with SD rat as laboratory animal, gastric infusion 20mg/kg, tail vein Bolos intravenous administration 5mg/kg.The tail venous blood sampling time point of gastric infusion is 0.17,0.33,0.5,1,1.5,2,4,6,8,12,24 hour；It is 0.05,0.1,0.17,0.5,1,2,4,6,8,12,24 hour that intravenously administrable takes blood time point.Take whole blood 0.3ml, take blood plasma 0.1ml after being centrifuged and use LC-MS to be analyzed.Result shows, the oral administration biaavailability of compound 5-1 is respectively 19%, and her cloth is 12% for the bioavailability of Buddhist nun, and therefore compound 5-1 stability in vivo relatively her cloth has had for Buddhist nun and significantly significantly improves.After its reason may is that the α position of acrylamide introduces halogen introducing, on the premise of not affecting drug absorption so that the metabolic rate of double bond is by a certain degree of suppression, and then improves blood drug level and improve bioavailability.
Embodiment 15: use compound 5-1 treatment class to divide wet arthritis
In the mouse model of rheumatoid arthritis, have rated the in vivo efficacy of compound 5-1, in Balb/c mice, by giving anti-collagen antibody and lipopolysaccharide-induced arthritis (Nandakumar etc., Am.J.Pathol.2003,163:1827-1837).Concrete grammar was as follows: at the 0th day, injected the Chemico mAb mixture of 100mg/kg anti-II collagen type, at the 1st day, peritoneal injection 1.25mg/kg lipopolysaccharide in female Balb/c mouse vein.At the 2nd day to 12 days, by the compound 5-1 of 10mg/kg, every day oral administration 1 time.Result shows, compound 5-1 has obvious internal anti-class and divides the effect of wet arthritis, specifically, the inflammatory cell infiltration that occurs in model group, synovial hyperplasia, inflammatory granulation tissue are formed, the phenomenon such as slough appearance after compound 5-1 treats be improved significantly.
Claims (9)
1. a bruton's tyrosine kinase inhibitor, it is characterised in that it has the knot of formula I
Structure:
And optical isomer or its pharmaceutically acceptable salt or solvate, wherein: Ra, Rb, Rc
It is independently selected from H, halogen ,-CF3、-CN、-NO2、OH、NH2、-L-C1-C6Alkyl,
-L-C1-C6Thiazolinyl, heteroaryl substituted or non-substituted for-L-or-L-substituted or non-substituted
Aryl, wherein L is key, O, S ,-S (=O) ,-S (=O)2、NH、C(O)、CH2、-NHC(O)O、
-NHC (O) or-C (O) NH, X are selected from fluorine, chlorine and bromine, Y1,Y2Selected from C, N, Y1,Y2Extremely
Rare one is selected from N.
2. a bruton's tyrosine kinase inhibitor, it is characterised in that it has formula II's
Structure:
And optical isomer or its pharmaceutically acceptable salt or solvate, wherein: each
Rd is H, halogen ,-CF independently3、-CN、-NO2、-OH、C1-C3Alkoxyl,
Or-NH2, X is selected from fluorine, chlorine and bromine, Y1,Y2Selected from C, N, Y1,Y2At least one is selected from
N。
3. a bruton's tyrosine kinase inhibitor, it is characterised in that it has general formula III
Structure:
And optical isomer or its pharmaceutically acceptable salt or solvate, wherein: X selected from fluorine,
Chlorine and bromine, Y1,Y2Selected from C, N, Y1,Y2At least one is selected from N.
4. a pharmaceutical composition, described pharmaceutical composition comprise at least one active component with
And one or more pharmaceutically acceptable carrier or excipient, described active component is such as right
Require in 1 to 3 the bruton's tyrosine kinase inhibitor compound described in any one, described
The optical isomer of compound, described compound or its optical isomer are the most acceptable
In the solvate of salt, described compound or its optical isomer any one or the most
Kind.
5. the bruton's tyrosine kinase suppression as described in any one in claims 1 to 3
Immunomodulator compounds and optical isomer thereof or its pharmaceutically acceptable salt or solvate are in preparation
Treat the medicine of the disease, obstacle or the disease that benefit from the suppression of bruton's tyrosine kinase activity
Application in thing.
6. the bruton's tyrosine kinase suppression as described in any one in claims 1 to 3
Immunomodulator compounds and optical isomer thereof or its pharmaceutically acceptable salt or solvate are in preparation
Individually or with other drug application in the medicine for the treatment of cell proliferative diseases is used in combination.
7. the bruton's tyrosine kinase suppression as described in any one in claims 1 to 3
Immunomodulator compounds and optical isomer thereof or its pharmaceutically acceptable salt or solvate are in preparation
Individually or with other drug application in the medicine for the treatment of cancer is used in combination.
8. the bruton's tyrosine kinase suppression as described in any one in claims 1 to 3
Immunomodulator compounds and optical isomer thereof or its pharmaceutically acceptable salt or solvate are in preparation
Individually or with other drug application in the medicine for the treatment of autoimmune disease is used in combination.
9. the bruton's tyrosine kinase suppression as described in any one in claims 1 to 3
Immunomodulator compounds and optical isomer thereof or its pharmaceutically acceptable salt or solvate are in preparation
Individually or with other drug application in the medicine for the treatment of lupus erythematosus is used in combination.
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| CN112142745B (en) * | 2019-06-27 | 2023-03-21 | 杭州和正医药有限公司 | Casein kinase 1 epsilon inhibitor, pharmaceutical composition and application thereof |
| CN110606848A (en) * | 2019-08-27 | 2019-12-24 | 药雅科技(上海)有限公司 | 5-azaindole derivative Bruton's tyrosine kinase inhibitor and preparation method and application thereof |
| WO2023088477A1 (en) * | 2021-11-22 | 2023-05-25 | 杭州和正医药有限公司 | Multifunctional compound capable of degrading btk kinase, and composition and use |
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