CN104892527A - Optical isomers used as tyrosine kinase inhibitors - Google Patents

Abstract

The invention belongs to the technical field of medicine, and particularly relates to optical isomers represented by the formula (II) and the formula (III) and used as tyrosine kinase inhibitors, and pharmaceutically acceptable salts thereof. The invention also relates to preparation methods of the optical isomers, pharmaceutical preparations containing the optical isomers, and the optical isomers playing important roles in preparation of drugs for prevention and/or treatment of B cell related leukemia (such as B cell chronic lymphocytic cancer, non-hodgkin lymphoma and the like), inflammatory and autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus and the like).

Description

As the optical isomer of tyrosine kinase inhibitor

1, technical field

The invention belongs to medical art, be specifically related to the optical isomer as tyrosine kinase inhibitor and pharmacy acceptable salt thereof, the preparation method of described isomer, pharmaceutical preparation containing described isomer, and described isomer is for the preparation of preventing and/or treating the relevant leukemia (such as B cell chronic lymphocytic cancer, non-Hodgkin lymphoma) of B cell, plays an important role in inflammatory and autoimmune disorder (such as rheumatoid arthritis, systemic lupus erythematous etc.).

2, background technology

One of maximum family of protein kinase composition people fermentoid, and regulate many different intracellular signaling processes (T.Hunter, Cell198750:823-829) by adding on phosphate group to protein.Especially, tyrosine kinases phosphorylate protein is at the phenol moieties of tyrosine residues.Family tyrosine kinase comprises the member controlling Growth of Cells, migration and differentiation.Abnormal kinase activity has related to many human diseasess, comprises cancer, autoimmune disease and inflammatory diseases.Because protein kinase belongs to the key regulator of cell signaling, they provide the target regulating cell function with small molecule kinase inhibitors, and therefore become good medicinal design target.Except the treatment of kinase mediated lysis, the selectivity of kinase activity and effective inhibitor also can be used for studying cell signaling processes and identifying that other has the cell target of therapeutic potential.

Good evidence is there is about the keying action of B cell in the pathogenesis of autoimmunization and/or inflammatory diseases.Inflammatory diseases such as the rheumatoid arthritis caused for autoantibody as Rituxan based on the therapeutical agent of protein consuming B cell is effective (Rastetter etc., Annu Rev Med200455:477).Therefore, the inhibitor of the protein kinase played a role in B cell activation should be for the disease pathology of B cell mediation therapeutical agent as useful in autoantibody generates.

Control the response of a series of B cell by the intracellular signaling of B-cell receptor (BCR), comprise propagation and break up to ripe antibody-producting cell.BCR is the crucial point of adjustment of B cell activity and the intracellular signaling of exception can cause the B cell proliferation of imbalance and the formation of pathogenic autoantibodies, and it causes various autoimmune disease and/or inflammatory diseases.Bu Ludun (Bruton ' s) tyrosine protein kinase (Btk) be at the film near-end of the BCR kinases relevant with the non-BCR in immediately downstream.The shortage of Btk has shown blocking-up BCR intracellular signaling, and therefore the suppression of Btk can be effective methods for the treatment of of the lysis blocking B cell mediation.

Btk is the member of Tyrosylprotein kinase Tec family, and display is early stage B cell is formed and mature B cell activates and survives key regulator (Khan etc., Immunity19953:283; Ellmeier etc., J.Exp.Med.2000192:1611).The Btk sudden change of people causes the chain gamma-globulin of illness X to lack mass formed by blood stasis (XLA) Immunol.Rev.2005203:200 such as () Lindvall.These patients are immunocompromised hosts, and it is ripe to show impaired B cell, the immunoglobulin (Ig) of reduction and periphery b cell level, the immunne response not relying on T cell of minimizing and at the post-stimulatory calciokinesis weakened of BCR.

Evidence about the effect of Btk in autoimmune disease and inflammatory diseases is provided by Btk-deficient mice model.In the clinical front mouse model of systemic lupus erythematous (SLE), the remarkable improvement of Btk deficient mice display progression of disease.In addition, Btk-deficient mice has resistance (Jansson and Holmdahl Clin.Exp.Immunol.199394:459) to Collagen-Induced Arthritis.Prove Btk inhibitor dose-dependently effect in arthritis mouse model (Z.Pan etc., Chem.Med Chem.20072:58).

Btk may relate to the cell expressing of lysis in addition except B cell.Such as Btk shows the threshing (J.Biol.Chem.2005280:40261 such as Iwaki) of impaired antigen induction by mastocyte that is mast cell-expressed and Btk defective type derived from bone marrow.This display Btk may be used for the reaction for the treatment of pathologic mast cells as transformation reactions and asthma.In addition, wherein lack the monocyte from XLA patient of Btk activity and show TNF α generation J Exp Med2003197:1603 such as () Horwood reduced after stimulation.Therefore, the inflammation that TNF is alpha mediated can be regulated by small molecules Btk inhibitor.In addition, the Btk reported plays a role (IsIam and Smith Immunol.Rev.2000178:49) in apoptosis, and therefore Btk inhibitor will be effectively J.Exp.Med.2005201:1837 such as () Feldhahn for some B cell lymphoma for the treatment of and leukemia.

The Dasatinib of listing in 2006 is Mutiple Targets inhibitor, has comparatively high inhibition effect, be used for the treatment of chronic lymphocytic leukemia to Btk; In addition 2013 is also Mutiple Targets inhibitor by the Ibrutinib (PCI-32765) of FDA approval listing, is non-reversibility, is used for the treatment of lymphoma, leukemia and autoimmune disease to Btk restraining effect.

At present not yet selectively Btk inhibitor listing, the fastest medicine of research is that CC-292(is also known as AVL-292), entering the clinical II phase in by the end of October, 2013 studies, and it, as irreversible Selective depression Btk, is used for the treatment of rheumatoid arthritis.

After chiral drug refers to and introduces chiral centre in drug molecular structure, a pair that the obtains enantiomer with mirror image in kind each other.The physico-chemical property basic simlarity of these enantiomers is only opticity difference to some extent, is named as R-type (dextrorotation) or S-type (left-handed), racemize respectively.The chiral drug of clinical application, except natural and semisynthetic drug, the medicine containing chirality of synthetic still supplies medicine based on racemize, accounts for more than 87% of whole synthesis of chiral medicine.And going deep into along with study of pharmacy work since nearly 20 years, show the stereoselective difference of drug enantiomer, made them different from the avidity of each acceptor and cause the huge difference of pharmacological action.High enantiomorph active in chiral drug is called excellent enantiomorph by people, and active enantiomorph that is low or non-activity is called bad enantiomorph.In many cases, bad isomer does not only have drug effect, but also the drug effect of the excellent enantiomorph of meeting partial offset, sometimes even also serious toxic side effects can be produced, show the complicacy of drug effect difference, also the therapeutic index and its raceme that determine single enantiomer have quite poor different, DL-(+-as the well-known) curative effect of syntomycin is only D(-) half of paraxin; Larger than D-isomer 100 times of the pharmaceutical activity of Proprasylyte L-isomer.

The optical isomer of chiral drug has different pharmacodynamics, pharmacokinetics and toxicologic properties." chirality " technology of utilization, composition that is inoperative in medicine or toxic side effect can be rejected by people effectively, and produce the homochiral medicine with single oriented structure, thus make pharmaceutical cpd purer, when disease therapy, curative effect is faster, the course for the treatment of is shorter.Therefore, research one of important directions having become international new drug research at present of chiral drug, has also had many examples of many successful.Chiral technology has been widely applied in the exploitation of digestive system, cardiovascular diseases, cancer drug.

Present invention applicant has applied for a series of tyrosine kinase inhibitor; wherein compound N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (I) shows good activity; this compound is raceme; it has asymmetric center, there is optical isomer.Consider that in prior art, a lot of chiral mixture medicine exists the toxic side effect, the potential problems such as reduction drug effect and quality control difficulties etc. that easily produce the unknown, and optically pure steric isomer relative to chiral mixture have safer, toxic side effect is little, stability is better and the easier advantage of quality control, and optically pure steric isomer also has the advantage in pharmacodynamics, pharmacokinetics and toxicology.Therefore, exploitation is efficient, safety and the single stereoisomers of good stability, and the quality control in producing follow-up medicament research and development and Marketed drugs is significant.

3, summary of the invention

With exploitation, the present invention has that the excellent exploitation preventing and/or treating leukemia, inflammatory and/or the autoimmune disorder that B cell is correlated with is efficient simultaneously, safety and the single stereoisomers medicine of good stability for target, found the optical isomer as tyrosine kinase inhibitor.

Concrete technical scheme, provides optical isomer and the pharmacy acceptable salt thereof of the compound shown in formula I, is selected from formula II, (III) and pharmacy acceptable salt thereof:

Its name is called: N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide,

N-(3-(2-(4-(2-methoxyethoxy)phenylamino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl)acryla mide；

Its name is called: (R)-N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide,

(R)-N-(3-(2-(4-(2-methoxyethoxy)phenylamino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl)acr ylamide；

Its name is called: (S)-N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide,

(S)-N-(3-(2-(4-(2-methoxyethoxy)phenylamino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl)acr ylamide。

The technical scheme of the application relates to the preparation method of described formula II, (III) optical isomer, it is characterized in that chiral separation or chiral induction N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (formula I compound) obtain formula II or (III) optical isomer of single configuration.

In one embodiment, the invention still further relates to formula II, (III) preparation method of optical isomer, chromatographic column chiral separation N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (formula I compound) is utilized to obtain formula II or (III) optical isomer of single configuration, condition comprises: adopt HPLC method, use preparation liquid phase (HPLC) and chiral column to formula I compound separation, collect its respective components, rotary evaporation is except desolventizing, obtain sterling formula II or (III) optical isomer of optical isomer.

In one embodiment, the invention still further relates to formula II, (III) another preparation method of optical isomer, it is characterized in that adding chiral reagent rear oxidation N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide, chiral induction N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (formula I compound) produces formula II or (III) optical isomer of single configuration.Its reaction scheme is as follows:

Method comprises:

(1) metatitanic acid four isopropyl ester and chiral reagent are dissolved in methyl alcohol and water mixed solution, under stirring, add water and N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide;

(2), after stirring, add oxygenant, room temperature reaction spends the night;

(3) add water, with dichloromethane extraction, dry, column chromatography obtains product.

Wherein, chiral reagent is selected from D-(-)-DET or L-(+)-DET; Oxygenant is selected from tertbutyl peroxide (TBHP) or hydrogen oxide isopropyl benzene (CHP).

Technical scheme of the present invention also relates to described formula II, its pharmacy acceptable salt of (III) optical isomer, is selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, citric acid, tartrate, oxysuccinic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or arginine.

Technical scheme of the present invention also relates to described formula II and/or (III) optical isomer and pharmacy acceptable salt thereof, also comprises the second therapeutical agent being selected from antineoplastic agent, immunosuppressor and/or antiphlogiston.

Technical scheme of the present invention also relates to the pharmaceutical preparation of described formula II and/or (III) optical isomer, its pharmacy acceptable salt and one or more pharmaceutical carriers, is pharmaceutically acceptable arbitrary formulation.

Technical scheme of the present invention also relates to profit and requires that the formula II described in 1 and/or (III) optical isomer and pharmacy acceptable salt thereof are for the preparation of preventing and/or treating B cell relevant leukemia, inflammatory and/or autoimmune disorder.

Detailed Description Of The Invention

" chiral separation (Chiral resolution) " of the present invention, also known as optical resolution (Optical resolution) or racemate resolution, for in stereochemistry, become the method for two different mirror image isomerism things in order to separation of racemic compound.

The main method of chiral separation has:

(1) crystallization Split Method

Seed crystallization: also claim preferential crystallization method., in the saturated of thermotropism or oversaturated racemize solution, add a kind of crystal seed of pure optical activity isomer, create asymmetric environment.Be cooled to certain temperature.At this moment the excessive a little isomer identical with crystal seed will preferential crystallization out.After elimination crystal, in remaining mother liquor, add the hot saturated solution that water and raceme are made again, then be cooled to certain temperature.At this moment another isomer superfluous a little will crystallize out.Theoretically, if raw material can form the racemic modification of aggregate, so said process is carried out repeatedly just a pair enantiomorph to be converted into pure optical isomer.

(2) chemical method

Chemical method: the physics of a pair enantiomer, identical with the chemical property that achiral reagent reacts, therefore general separation method cannot be split out.Chemical resolution method is the mixture going to process this D-acid and L-acid with a pure optical activity isomer D-alkali, reacts derivatize respectively, forms a pair diastereomer: D-acid-D-alkali and L-acid-D-alkali with it.Diastereomer is separated easily via common physical method such as fractionation crystallization.After isolating diastereomer, as long as pure D-acid and L-acid just can be obtained respectively by strong acid treatment.

Chemical resolution method is applicable to containing easy reactive group, and reaction after also regenerating easily go out the molecule of original enantiomeric compounds.Modal easy reactive group is acid and alkaline group, this is because acid-base reaction is very easy, the salt ratio generated is easier to crystallization, and resolving agent is sour, alkali (being generally naturally occurring acid or alkaloid) is cheap and easy to get maybe can conveniently reclaim, also pure than being easier to obtained optically-active.Conventional acid resolving agent has: (+)-tartrate, (+)-dextrocamphoric acid, (+)-camphor-10-sulfonic acid, L-(-)-oxysuccinic acid etc.; Conventional basic resolving agent has: (-)-vauqueline, (-)-brucine, D-(-)-ephedrine, (+) or (-)-α-phenylethylamine etc.

(3) enzymolysis process

Enzymolysis process: enzymatic reaction is that High level of stereoselectivity is single-minded to substrate, this character can be used for making a certain isomer in racemic modification participate in enzymatic reaction, be consumed as another material, and another isomer is unaffected, but character is obviously different from the material formed after consumption, make utilization general physical separation method that the fractionation of two enantiomorphs is become possibility.This method is best suited for amino acid whose fractionation.Compared with chemical method, have many advantages: have High level of stereoselectivity specificity, product polarimetry purity is very high; Side reaction is few, and productive rate is high, and product separation is purified simple; Mostly carry out in a mild condition, pH value is how close neutrality also, little to equipment corrosion; Enzyme is nontoxic, easily by environment degradable.But also have some shortcomings, mainly can zymin kind limited, and the preservation condition of enzyme is harsher, and price is also costly.

(4) column chromatography

Column chromatography: the sorbent material utilizing light to live, makes two enantiomorphs and chiral derivatization agent form two diastereomeric adsorptives (direct method).These two adsorptives are different by the degree of adsorbing, and can distinguish wash-out out.

In addition chiral separation is also had also to comprise polymeric film Split Method, Extraction resolution method, electrophoresis Split Method etc.

" chiral induction " of the present invention (chiral induction), also asymmetric induction (asymmetric induction) is cried, it is stereochemistry noun, refer under the effect of the reagent of a rich chirality, chemical reagent, catalytic materials or environment, the product in a chemical reaction to the greatest extent in a certain enantiomer or diastereomer more than another kind.Asymmetric induction is an important element of asymmetric synthesis, refers to the configuration utilizing the unsymmetrical factors in substrate molecule (chiral centre) to remove to induce new asymmetric atom (chiral atom), makes the steric isomer of generation inequality.In addition, the Stereoselective reaction utilizing chiral solvent, chiral auxiliary(reagent), chiral reagent, chiral catalyst etc. to occur, also belongs to chiral induction.

Above-claimed cpd of the present invention can adopt the method that describes in following flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to following methods.Optical isomer compound of the present invention can pass through the conventional chiral drug preparation method such as chromatographic separation, asymmetric oxidation, fractionation and obtain.

For simplicity, the present invention uses well-known abbreviation to represent number of chemical compound, includes but not limited to

DMF:N, dinethylformamide; THF: tetrahydrofuran (THF); DIEA:N, N-diisopropylethylamine;

BINAP:2,2 '-bis-diphenyl phosphine-1,1 '-dinaphthalene; Two diphenyl phosphine-9, the 9-dimethyl xanthene of Xantphos:4,5-;

TBHP: tertbutyl peroxide; CHP: hydrogen oxide isopropyl benzene; D-(-)-DET:D-(-)-diethyl tartrate; L-(+)-DET:L-(+)-diethyl tartrate etc.

Method one: utilize chromatographic column chiral separation N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (formula I compound) to obtain formula II or (III) optical isomer of single configuration; condition comprises: adopt HPLC method; use preparation liquid phase (HPLC) and the chiral isomer separation of chiral column; collect its respective components; rotary evaporation, except desolventizing, obtains the sterling of optical isomer.

Method two: add chiral reagent rear oxidation N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide, chiral induction N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (formula I compound) produces formula II or (III) optical isomer of single configuration.

Reaction scheme:

Reactions steps:

By metatitanic acid four isopropyl ester and chiral reagent (as D-(-)-DET, L-(+)-DET) be dissolved in methyl alcohol and water mixed solution, add water and N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide under stirring, after stirring 10min, add oxygenant (TBHP, CHP), room temperature reaction spends the night, and adds water, with dichloromethane extraction, drying, column chromatography obtains product.

Wherein, chiral shift reagent includes but are not limited to D-(-)-DET, L-(+)-DET; Oxygenant includes but are not limited to tertbutyl peroxide (TBHP), hydrogen oxide isopropyl benzene (CHP).

Clinically, formula II of the present invention, (III) optical isomer can in a free form or its pharmacy acceptable salt form use.The aobvious alkalescence of formula II of the present invention, (III) optical isomer, can form acid salt with mineral acid or organic acid.Example hydrochloric acid salt, hydrofluoride, hydrobromate, hydriodate, vitriol, trifluoroacetate, benzene sulfonate, mesylate, fluoroform sulphonate, esilate, carbonate, nitrate, phosphoric acid salt, phosphite, maleate, tartrate, Citrate trianion, acetate, benzoate, fumarate, oxalate, gluconate, hydroxyl acetate, isethionate, lactic acid salt, Lactobionate, malate, succinate, tosilate, glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.

Formula II of the present invention, (III) optical isomer and pharmacy acceptable salt thereof can form pharmaceutical composition with one or more pharmaceutical carriers.Described pharmaceutical composition can make the conventional formulation used clinically, the mode such as oral or administered parenterally can be applied to the patient needing this treatment.As tablet, particle, capsule, powder, injection, inhalation, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, eye drops, nasal cavity drop, sprays, preparation capable of permeating skin etc.These preparations can pass through ordinary method, add pharmaceutical carrier such as vehicle, tamanori, moistening agent, disintegrating agent, thickening material etc. and are prepared from.

Formula II of the present invention, (III) optical isomer and pharmacy acceptable salt thereof have good BTK kinase inhibitory activity, are the medicines better with excellent antitumor action and treating autoimmune diseases effect.Formula II of the present invention, (III) compound or its pharmacy acceptable salt treat the relevant leukemia (such as B cell chronic lymphocytic cancer, non-Hodgkin lymphoma) of B cell in preparation simultaneously, and play an important role in autoimmune disorder (such as rheumatoid arthritis, systemic lupus erythematous etc.).

Formula II of the present invention, (III) optical isomer and pharmacy acceptable salt thereof are a kind of kinase inhibitor, particularly Btk inhibitor.These inhibitor may be used for the disease of one or more response kinase inhibition for the treatment of in Mammals, comprise the disease of the suppression of response Btk suppression and/or B cell proliferation.Do not wish to be bound by any specific theory, believe that the interaction of the compounds of this invention and Btk causes the suppression of Btk activity, and therefore obtain these compound pharmaceutical application.Therefore, the present invention includes the Mammals of the suppression being used for the treatment of and there is response Btk activity and/or the disease suppressing B cell proliferation, the method of such as people, the method comprises: the chemical entities that at least one to the Mammals effective dosage with such disease provides in this article.Experimentally such as by measuring the haemoconcentration of compound, or in theory by calculating bioavailability, effective concentration can be determined.Except Btk, also may include but not limited to by other kinases affected, other Tyrosylprotein kinase and serine/threonine kinase.

Kinases is controlling elementary cell process as played significant effect in the intracellular signaling path of propagation, differentiation and dead (apoptosis).Abnormal kinase activity has implied that, in various disease, described disease comprises kinds cancer, autoimmunization and/or inflammatory diseases and acute inflammatory response.The versatility effect of kinases in key cells intracellular signaling path provides the remarkable chance of the novel drugs identifying target kinases and intracellular signaling path.

An embodiment comprises the method that treatment has the patient of the acute inflammatory response of the suppression of autoimmunization and/or inflammatory diseases or response Btk activity and/or B cell proliferation.

The autoimmunization that can affect according to compound of the present invention and composition and/or inflammatory diseases is used to include but not limited to: psoriatic, transformation reactions, regional enteritis, irritable bowel syndrome, sjogren disease, the hyperacute rejection of tissue graft rejection reaction and transplant organ, asthma, systemic lupus erythematous (with relevant glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-be correlated with other vasculitis), autoimmune haemolytic and thrombocytopenic symptom, Gourde(G) Paasche syndrome (with relevant glomerulonephritis and pulmonary apoplexy), atherosclerosis, rheumatoid arthritis, chronic idiopathic thrombocytopenic purpura (ITP), Addison disease, Parkinson's disease, alzheimer's disease, diabetes, septic shock and myasthenia gravis.

What comprise herein is methods for the treatment of, wherein by least one chemical entities that provides herein and antiphlogiston combination medicine-feeding.Antiphlogiston includes but not limited to: NSAID, non-specific and COX-2 specificity cyclooxygenase-2 inhibitors, gold compound, cortical steroid, methotrexate, tumour necrosis factor (TNF) receptor antagonist, immunosuppressor and methotrexate.

The example of NSAID includes but not limited to, Ibuprofen BP/EP, flurbiprofen, Naproxen Base and naproxen sodium, diclofenac, the combination of diclofenac sodium and Misoprostol, sulindac, benzene daybreak propionic acid, diflunisal, piroxicam, indomethacin, R-ETODOLAC, fenoprofen calcium, Ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium and Oxychloroquine.The example of NSAID also comprises COX-2 specific inhibitor as celecoxib, valdecoxib, Lu meter Kao former times and/or L-791456.

In some embodiments, antiphlogiston is salicylate or salt.Salicylate or salt include but not limited to acetylsalicylic acid or Asprin, sodium salicylate and choline salicylate and magnesium salicylate.

Antiphlogiston can also be cortical steroid.Such as, cortical steroid can be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone phosphate disodium, or prednisone.

In further embodiment, antiphlogiston is gold compound, as Sodium Aurothiomalate or auranofin.

The present invention also comprise wherein antiphlogiston be metabolic poison as dihydrofolate reductase inhibitor, if methotrexate or dihydroorotate salt dehydrogenase inhibitor are as the embodiment of leflunomide.

It is anti-monoclonal antibody (as according to storehouse pearl monoclonal antibody or training gram pearl monoclonal antibody) that other embodiment of the present invention relates to wherein at least one anti-inflammatory compound, TNF antagonist is as the combination of etanercept (entanercept) or infliximab, and described infliximab is a kind of anti-TNF alpha monoclonal antibody.

Other embodiment of the present invention relate to wherein at least one active drug be immunosuppressant compounds as being selected from methotrexate, leflunomide, cyclosporin A, tacrolimus, the combination of the immunosuppressant compounds in azathioprine and mycophenolate mofetile.

B cell and the B cell precursor of expressing Btk have implied in the pathology that B cell is pernicious, B cell is pernicious includes but not limited to B cell lymphoma, lymphoma (comprising Huo Qijin and non-Hodgkin lymphoma), hairy cell lymphoma, multiple myeloma, chronic with acute myelogene leukemia with chronic with acute Lymphocytic leukemia.

Show that Btk is the inhibitor of the dead inducement signal conducting composite (DISC) of Fas/APO-1 (CD-95) in B-system lymphoidocyte.The destiny of leukemia/lymphoma cell may be the balance (Vassilev etc. between the reverse proapoptosis effect of the caspase activated by DISC and the upstream anti-apoptotic regulation mechanism comprising Btk and/or its substrate, J.Biol.Chem.1998,274,1646-1656).

Also find that Btk inhibitor can be used as chemical sensitizer, therefore may be used for combining with other chemotherapeutic drug, the medicine of described chemotherapeutic drug particularly cell death inducing, as antineoplastic agent, immunosuppressor etc.The example of other chemotherapeutic drug that can combinationally use with chemical sensitization inhibitor includes but are not limited to topoisomerase I inhibitor (as camptothecine or Hycamtin), Topoisomerase II inhibitors (as daunomycin and Etoposide), alkylating agent is (as endoxan, melphalan and BCNU), (such as antibody is as anti-CD20 antibodies for the medicament (as PTX and vinealeucoblastine(VLB)) of tubulin guiding and biotechnological formulation, IDEC8, immunotoxin and cytokine).

Btk activity has expressed the bcr-abl fusion gene caused by the transposition of chromosome dyad 9 and 22 leukemia to some is relevant.This exception is observed usually in chronic myelogenous leukemia.Btk is in essence by bcr-abl tyrosine phosphorylation, and this initiation prevents apoptotic downstream survival signaling (N.Feldhahn etc., J.Exp.Med.2005,201 (11), 1837-1852) in bcr-abl cell.

The compounds of this invention, compared with immediate prior art, has the following advantages:

(1) formula II of the present invention, (III) optical isomer and pharmacy acceptable salt thereof have good BTK kinase inhibitory activity, good selectivity, and side effect is little;

(2) formula II of the present invention, (III) optical isomer and pharmacy acceptable salt thereof demonstrate good biologically stable, and effect is more lasting, and bioavailability is high;

(3) the compounds of this invention preparation technology is simple, and medicine purity is high, steady quality, is easy to carry out large-scale commercial production.

Set forth the compounds of this invention beneficial effect further below by way of pharmacological evaluation, but this should be interpreted as the compounds of this invention only has following beneficial effect.

the pharmacological activity test of test example the compounds of this invention

in Vitro Anti bruton's tyrosine kinase (BTK) determination of activity of I the compounds of this invention

Trial-product:

Contrast medicine:

N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide; self-control, its structure formula I and preparation method are shown in preparation embodiment.

The compounds of this invention:

Self-control, its chemical name and structure formula II, (III) and preparation method are shown in the preparation embodiment of each compound.

Experimental technique:

Representative implication of abridging in following experiment is as follows:

ATP: Triphosaden; BTK: bruton's tyrosine kinase; Mg: milligram; ML: milliliter; μ g: microgram;

_{μ l}: microlitre; MM: mmole often rises; EDTA: ethylenediamine tetraacetic acid (EDTA); DMSO: dimethyl sulfoxide (DMSO).

1. test materials

HTRFR KinEASE ^tM– TK: purchased from Cisbio, lot number 62TK0PEB; BTK: purchased from Carna, Cat.No.08-080; ATP: purchased from Sigma, Cat.No.A7699, CAS No.34369-07-8; MgCl ₂: purchased from Sigma, CAS No.7786-30-3, Lot.No.101M8701V; DMSO: purchased from Sigma, CAS No.67-68-5, Lot.No.STBC0365V; 96 orifice plates: purchased from Thermo, Cat.No.249944, Lot.No.1057825; 384 orifice plates: purchased from Greiner, Cat.No.784075, Lot.No.E1112 Φ 6Y.

2. test preparation of reagents

1. 1 × Kinase buffer(5mM MgCl ₂, 1mM DTT, 50nM SEB); 2. that DTT stoste sterilized water for injection is diluted to 100mM is for subsequent use as storing solution for DTT; 3. the storing solution of ATP sterilized water for injection preparation 5mM is for subsequent use; 4. 10mM compound solution: the compound stock solution that compound dissolution is mixed with 10mM by employing 100%DMSO is for subsequent use.

3. the enzyme reaction stage

1. the compound solution 100%DMSO of 10mM is diluted 20 times, a series of 3 times of dilutions are carried out after redilution 2 times, totally 10 concentration gradients, then use 1 × kinase buffer using the solution dilution 100 times of each concentration as test compound concentration, 4 μ L/ holes.2. 5 × enzyme solution is prepared: enzyme is added 1 × kinase buffer, 2 μ L/ holes.3. 30min is hatched under 25 DEG C of conditions.4. 5 × TK Substrate-biotin is prepared: added by TK Substrate-biotin in 1 × kinase buffer, 2 μ L/ holes; 5. 5 × ATP is prepared: added by ATP in 1 × kinase base buffer, 2 μ L/ holes; 6. under 25 DEG C of conditions, 40min is hatched.

4. the detection reaction stage

1. 4 × Streptavidin-XL665 is prepared: added by Streptavidin-XL665 in Detection buffer, 5 μ L/ holes.2. every hole adds 5 μ L TK Antibody-Cryptate again.3. 60min is hatched under 25 DEG C of conditions.

5. digital independent

After the detection reaction stage completes, detect the fluorescent value of sample at 615nm and 665nm place respectively by microplate reader.

6. fitting of a curve draws IC ₅₀

Ratio=(665nm fluorescent value/615nm fluorescent value) × 10 ⁴

$Z^{\′}=1-3\×\frac{\mathrm{STDEV}\left(\mathrm{Positive}\right)+\mathrm{STDEV}\left(\mathrm{negative}\right)}{\mathrm{AVERAGE}\left(\mathrm{Positive}\right)-\mathrm{AVERAGE}\left(\mathrm{negative}\right)}$

Adopt GraphPad5.0 software to carry out curve fitting, fit equation is Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * HillSlope)), draws IC ₅₀value.

Experiment conclusion:

In sum, the compounds of this invention has stronger inhibit activities to BTK kinases, better than control compounds.

the In Vitro Anti cytology determination of activity of II the compounds of this invention

The compounds of this invention: self-control, its chemical name and structural formula and preparation method are shown in the preparation embodiment of each compound.

1. laboratory apparatus

Envision2104 reads plate instrument, PerkinElmer, (U.S.); CO ₂incubator, SANYO. (Japan); Inverted microscope, XDS-1B, Chongqing broadcasting and TV. (Chongqing, China); PH counts, Mettler Toledo Five easy. (China); MACS separator (Miltenyi, the U.S.); FACSCalibur (BD, the U.S.).

2. cell

At 37 DEG C, in 5%CO2 incubator, use the foetal calf serum of the ultralow immunoglobulin (Ig) containing 10%, penicillin/streptomycin, 5mM HEPES, the RPMI1640 culture medium culturing Balb/c mouse primary splenic B cells of 50 μMs of beta-mercaptoethanols.Substratum purchased from American GIBCO.

3. mouse

Male, the Balb/c mouse in 6-8 week.

4. reagent and compound are prepared

(1) CellTiter-Glo (CTG) (article No.: G7572, Promega), is stored in-20 DEG C by CTG damping fluid and CTG substrate, recommends to prepare CTG reagent with following method:

Melt CTG damping fluid before using and balance to room temperature, conveniently, it is good and in room temperature preservation by more than 48 hours that CTG damping fluid can melt before use.The CTG substrate of freeze-drying is equilibrated to room temperature, and the damping fluid getting 100ml, in the amber bottle that substrate is housed, just obtains CTG reagent.Mixing is until obtain homogeneous solution gently, and substrate should melt completely in one minute, and packing also preserves CTG reagent for a long time in-20 DEG C of refrigerators.

(2) b cell separating kit (number of ordering: 130-090-862, Miltenyi)

(3) PE anti-biotin antibody (article No.: 409003, Biolegend)

(4) PE/cy7anti-mouse CD45R/B220antibody (article No.: 103221, Biolegend)

(5) Cell strainer (article No.: 352340, BD Falcon)

(6) AffiniPure F (ab') ₂fragment goat anti mouse IgM, μ chain specific (article No.: 115-006-020, Jackson)

(7) test compounds is prepared

Preparation test compounds liquid storage: compound powder is dissolved in DMSO, to 10mM concentration.

. preparation test compounds gradient dilution solution: first, get test compounds liquid storage DMSO3 times of continuous gradient dilution of 10mM, totally 10 concentration.The compound getting the DMSO dilution of 10 μ L is more respectively added in 90 μ L Compound Dilution Buffer, the compound containing 10%DMSO dilution getting 10 μ L is more respectively added in 90 μ L Compound Dilution Buffer, compound maximum concentration is 10 μMs, and DMSO concentration is 0.1%, totally 10 concentration gradients.

5. experimental technique

(1) Balb/c mouse B cell is separated:

Get Balb/c mouse spleen, smash to pieces in MACS damping fluid, obtain single cell suspension with the Nylon cell screen filtration of 40 μm.

4 DEG C, by the cell suspension that obtains at 400g centrifugal five minutes, remove supernatant, add the erythrocyte cracked liquid of 1ml under room temperature and resuspended cell mass lightly.After two minutes, add the MACS damping fluid of precooling.With the cell screen filtration cell suspensions of 40 μm in a new centrifuge tube.4 DEG C, 400g carrys out collecting cell in centrifugal 5 minutes.

Before adding magnetic bead, with MACS damping fluid, cell density is adjusted to 10 ⁷individual cell/40 μ l.Every 10 ⁷the biotinylated mixtures of antibodies of 10 μ l is added in individual cell.20 minutes are hatched on ice, every 10 after mixing ⁷add the magnetic bead of the MACS damping fluid of 30 μ l and the antibiotin of 20 μ l in individual cell and hatch 20 minutes on ice.The MACS damping fluid re-suspended cell of centrifugal rear use 500 μ l.The MACS sorting post of precooling is placed in MACS sorter, cell suspension is added in MACS sorting post.Collect the cell of the non-binding antibody flowed down.

By the cell of flow cytometry before PE anti-biotin antibody and CD45R (B220) antibody test grouping system and after sorting.

(2) cytotoxicity experiment and IC ₅₀measure

With the mouse B cell of blood counting chamber counting fresh separated, expect that blue staining detection Cell viability should more than 98% by a word used in place name.

With substratum, cell density is adjusted to every milliliter 3.89 × 10 ⁵individual cell. get 90 μ l cell suspensions in 96 orifice plates with multichannel pipettor, obtaining final cell density is 3.5 × 10 ⁴individual cell per well.

Form storage liquid with DMSO dissolved dilution test compound and positive compound, add a series of compound solutions of 10 μ l preparations to (each concentration of each compound does 3 repetitions) in 96 orifice plates.At 37 DEG C, 5%CO ₂hatch 30 minutes in incubator, and then add 50 μ l B cell stimulation mixed solutions, the final concentration stimulating anti-Igm in mixed solution is 10 μ g/ml.

By cell plate at 37 DEG C, 5%CO ₂detect by the method for CTG after continuing to hatch 72 hours in incubator.

Melt CTG reagent and balance to room temperature, being transferred in 96 orifice plates with multichannel pipettor, 50 μ lCTG reagent/holes, the quick oscillator of microwell plate shaking after 2 minutes and place 10 minutes in the dark, detecting luminescence with Envision and read value.

6. data analysis

The data obtained can be analyzed with Excel2007 and GraphPad Prism5.0 software, in order to calculate IC ₅₀, return fitting data by utilizing non-linear S curve and draw a dose-effect curve, GraphPad Prism5.0 software can provide IC automatically ₅₀value.

The following formula of cell survival rate calculates: V _sample/ V2 _{solvent control}× 100%, V _samplebe compound treatment hole read value, V2 _{solvent control}the mean value that value is read in solvent control hole (V2).

7. experimental result:

The compounds of this invention is to the IC of the inhibit activities of Balb/c mouse B cell cell in vitro ₅₀﹤ 0.5 μM.

Experiment conclusion: in sum, the compounds of this invention all has stronger restraining effect to Balb/c mouse B cell propagation.

iII the compounds of this invention is to rat spleen cells BTK enzyme occupation rate determination experiment

The amount of BTK is taken in order to measure not combined thing in cell or tissue lysate, use ELISA scheme, it utilizes a kind of the not combined thing of combination to take the biotinylated probe compound of BTK, assessing compound is under different concns, to the occupation rate situation of BTK enzyme in splenocyte, calculate %BTK occupation rate (BTK Occupancy).

1, experiment material

Little mouse-anti BTK antibody (Becton Dickinson); Goat anti-mouse HRP antibody (Becton Dickinson); Cell pyrolysis liquid (Cell Signaling); Bruton's tyrosine kinase (BTK) (Carna); 96 orifice plates (Thermo) of Streptavidin bag quilt; Rat lymphocyte separating kit (LTS1083PK, Tianjin Hao ocean biological products science and technology limited Company); Microplate reader (victor4, PE); Whizzer (5804R, Eppendorf); Microscope (CX31RTSF, Olympus); MACS sorter (midiMACS separation unit, MACS).

2, experimental procedure

(1) preparation of reagents

Probe compound solution (Probe): take sample compound 1mg, compound concentration is the storing solution of 1mM, dilutes during use with sample diluting liquid; Sample diluting liquid (Sample diluents): containing the PBS of 1% bovine serum albumin and 0.1%Tween-20; Washings (Washing solution): containing the PBS of 0.05%Tween-20.

(2) the unicellular preparation of Rats Spleen

The PBS wash buffer of spleen 1mL (is cut an osculum in one end of spleen, inject 1ml precooling PBS with syringe at the spleen the other end to rinse), then the aseptic filter screen of 200 order is transferred to, shred with operating scissors, grind with syringe again, notice that grinding limit, limit adds the PBS wash buffer of precooling, amount to the PBS wash buffer with 5ml.4 DEG C, the centrifugal 3min of 400g, removes supernatant, adds 20ml cell washing solution PBS, 4 DEG C, 600Rpm, centrifugal 10min, washs 3 times.

(3) compound and cytosis

After cell counting, with PBS, cell concn is diluted to 3 × 107Cells/ml, 90 μ l/ holes.Add compound 10 μ l/ hole, hatch 1h for 37 DEG C.20 DEG C, the centrifugal 20min of 400g, discards supernatant.

(4) lysing cell

Proteinase inhibitor PMSF is joined in cell pyrolysis liquid (cell lysis buffer) and (notice that PMSF adds before lysate uses).Lysate is added in the cell of often pipe enrichment and mix, according to the operation of lysate specification sheets, the centrifugal 10min of cracking 5min, 14000g on ice.Get supernatant 100 μ l to add in 96 orifice plates.

(5) BTK determination experiment step

Every hole adds 100ul standard substance or sample mixes with 10 μ l probe compound solution (final concentration is 1 μM), and 1h is hatched in 28 DEG C of concussions.After hatching, get 100 μ l and join (Streptavidin-coatd ELISA plate) on the elisa plate of Streptavidin bag quilt, 1h is hatched in 28 DEG C of concussions.Plate is washed 5 times with washings (Washing sol ution).The mouse anti human BTK antibody (Purified mouse anti-human BTK antibody) (1:1000 doubly dilutes) of 100 μ l purifying is added in every hole.1h is hatched in 28 DEG C of concussions.Plate is washed 5 times with washings.The goat anti-mouse antibody (HRP goat anti-mouse Ig) (1:1000 dilution) that 100 μ l HRP mark is added in every hole.1h is hatched in 28 DEG C of concussions.Wash plate 5 backward every holes with washings and add 100 μ l substrate TMB solution, hatch 15min for 28 DEG C.Every hole adds 50 μ l1M H ₂sO ₄termination reaction.

3, Testing index and detection method

After reaction terminating, detect the OD value at 450nm place.According to OD value, A4 parameter logistic curve in microplate reader is used to calculate the amount of BTK in each sample.

4, data processing and result

* %BTK occupation rate=(control group BTK amount-compound group BTK measures)/control group BTK measures × 100%

* variation coefficient CV=S/ x × 100%

Experiment conclusion:

The BTK occupation rate of the compounds of this invention in rat spleen cells is higher, embodies good drug effect.

4, embodiment

The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.All technology realized based on foregoing of the present invention all belong to scope of the present invention.

embodiment 1N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide preparation

(1) preparation of 3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenylcarbamate

By 3-(the chloro-5-of 2-(methylthio group) pyrimidine-4-yl is amino) phenylcarbamate (0.25g, 0.68mmol) be dissolved in the tertiary amyl alcohol of 10mL, add acetic acid 2 again, 4-(2-methoxy ethoxy) aniline (0.119g, 0.71mmol), react at 85 DEG C of stirring 1h.System be spin-dried for, column chromatography (PE:EA=8:1-2:1) obtains white solid 0.15g, yield 44.1%.

(2) N ⁴-(3-aminophenyl)-N ²the preparation of-(4-(2-methoxy ethoxy) phenyl)-5-(methylthio group) pyrimidine-2,4-diamines

By 3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenylcarbamate (0.14g, 0.28mmol) be dissolved in the DCM of 10mL, logical HCl gas reaction 1h under ice bath, system is spin-dried for, obtain crude product 0.14g, be directly used in next step.

(3) preparation of N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide

Upper step product crude product 0.14g is dissolved in the THF of 10mL, drips DIPEA, until solution ph is 7, drips the THF solution 0.5mL containing acrylate chloride (0.026g, 0.29mmol) at-15 DEG C, under finishing this temperature, react 15min.Drip 5 methyl alcohol, system be spin-dried for, preparation liquid phase purifying (methanol/water=65%) obtains white solid 11mg.Two step yields: 8.7%.

Molecular formula: C ₂₃h ₂₅n ₅o ₃s molecular weight: 451.17 mass spectrums (m/z): 452.2 (M+H) ⁺.

¹H-NMR(CDCl ₃,400MHz)δ(ppm)：8.24(1H,s),8.11(1H,s),8.03(1H,s),7.55-7.47(1H,m),7.45(2H,d),7.32-7.27(1H,m),7.25-7.20(1H,m),7.16-7.04(2H,m),6.93(2H,d),6.46(1H,dd),6.26(1H,dd),5.80(1H,dd),4.12(2H,t),3.76(2H,t),3.46(3H,s),2.28(3H,s).

embodiment 2N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) the preparation of acrylamide

By N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide (0.045g, 0.1mmol) be dissolved in open ports backflow 3h in methyl alcohol, be spin-dried for, the preparation anti-phase purifying of liquid phase (methanol/water=57%) obtains white solid 9mg.Yield: 19.3%.

Molecular formula: C ₂₃h ₂₅n ₅o ₄s molecular weight: 467.16 mass spectrums (m/z): 468.2 (M+H) ⁺

¹H-NMR(DMSO-d ₆,400MHz)δ(ppm)：10.17(1H,s),9.54(2H,s),8.20(1H,s),7.73(1H,s),7.55-7.45(3H,m),7.39(1H,d),7.29(1H,t),6.82-6.73(2H,m),6.42(1H,dd),6.24(1H,dd),5.75(1H,dd),4.00(2H,t),3.62(2H,t),3.29(3H,s),2.95(3H,s).

embodiment 3 (R)-N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide and (S)-N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) third the preparation of alkene acid amides

Method one: utilize chromatographic column chiral separation N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide; adopt HPLC method; use Preparation equipment and the chiral isomer separation of Daicel chiral column of Daicel; collect its respective components, t _r=3.694min, t _r=4.748min.Rotary evaporation, except desolventizing, obtains the sterling of optical isomer.HPLC method separation condition:

Method two: add chiral reagent rear oxidation N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide; chiral induction N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (formula I compound) produces the optical isomer of single configuration

By metatitanic acid four isopropyl ester (1.14g, 4mmol) and D-(-)-DET or L-(+)-DET) (1.65g, 8mmol), be dissolved in 9mL methyl alcohol and 18mL water mixed solution, water 72mg and N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide (1.8g is added under stirring, 4mmol), after stirring 10min, add oxygenant TBHP(0.66g, 65%, 5mmol), room temperature reaction spends the night, add water, with dichloromethane extraction, dry, column chromatography obtains product 0.97g, productive rate 52%.

Claims (10)

1. the optical isomer of the compound shown in formula I and pharmacy acceptable salt thereof, be selected from formula II, (III) optical isomer and pharmacy acceptable salt thereof:

Its name is called: N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide

[N-(3-(2-(4-(2-methoxyethoxy)phenylamino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl)acryla mide]；

Its name is called: (R)-N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide

[(R)-N-(3-(2-(4-(2-methoxyethoxy)phenylamino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl)ac rylamide]；

Its name is called: (S)-N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide

[(S)-N-(3-(2-(4-(2-methoxyethoxy)phenylamino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl)ac rylamide]。

2. the preparation method of formula II as claimed in claim 1, (III) optical isomer, is characterized in that chiral separation or chiral induction N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (formula I compound) obtain formula II or (III) optical isomer of single configuration.

3. formula II according to claim 1, (III) preparation method of optical isomer, it is characterized in that utilizing chromatographic column chiral separation N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (formula I compound) to obtain formula II or (III) optical isomer of single configuration, condition comprises: adopt HPLC method, use preparation liquid phase (HPLC) and chiral column to formula I compound separation, collect its respective components, rotary evaporation is except desolventizing, obtain sterling formula II or (III) optical isomer of optical isomer.

4. the preparation method of formula II according to claim 1, (III) optical isomer; it is characterized in that adding chiral reagent rear oxidation N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide, chiral induction N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylsulfinyl) pyrimidine-4-yl is amino) phenyl) acrylamide (formula I compound) produces formula II or (III) optical isomer of single configuration.Its reaction scheme is as follows:

Method comprises:

(1) metatitanic acid four isopropyl ester and chiral reagent are dissolved in methyl alcohol and water mixed solution, under stirring, add water and N-(3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylthio group) pyrimidine-4-yl is amino) phenyl) acrylamide;

(2), after stirring, add oxygenant, room temperature reaction spends the night;

(3) add water, with dichloromethane extraction, dry, column chromatography obtains product.

5. chiral reagent according to claim 4 is selected from D-(-)-diethyl tartrate, L-(+)-diethyl tartrate.

6. oxygenant according to claim 4 is selected from tertbutyl peroxide (TBHP), hydrogen oxide isopropyl benzene (CHP).

7. formula II according to claim 1, (III) optical isomer and pharmacy acceptable salt thereof, be selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, citric acid, tartrate, oxysuccinic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or arginine.

8. pharmaceutical composition, containing formula II according to claim 1 and/or (III) optical isomer and pharmacy acceptable salt thereof, also comprises the second therapeutical agent being selected from antineoplastic agent, immunosuppressor and/or antiphlogiston.

9. having the right the pharmaceutical preparation of formula II described in requirement 1 and/or (III) optical isomer and pharmacy acceptable salt and one or more pharmaceutical carriers, is pharmaceutically acceptable arbitrary formulation.

10. formula II as claimed in claim 1 and/or (III) optical isomer and pharmacy acceptable salt thereof are for the preparation of preventing and/or treating B cell relevant leukemia, inflammatory and/or autoimmune disorder.