CN105439975A - Heterocyclic substituted styrene compound and application thereof - Google Patents

Heterocyclic substituted styrene compound and application thereof Download PDF

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CN105439975A
CN105439975A CN201510876250.6A CN201510876250A CN105439975A CN 105439975 A CN105439975 A CN 105439975A CN 201510876250 A CN201510876250 A CN 201510876250A CN 105439975 A CN105439975 A CN 105439975A
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bromo
compound
group
yuan
phenyl
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CN105439975B (en
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李剑
黄立新
许叶春
缪丽燕
金慧
张勇
刘秋枫
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
First Affiliated Hospital of Suzhou University
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
First Affiliated Hospital of Suzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to a heterocyclic substituted styrene compound and application thereof. The invention discloses the styrene compound modified through heterocyclic radicals, alkoxy and halogen. The compound is used for testing Syk inhibition activity, results show that the compound has inhibition activity on spleen tyrosine kinase (Syk), part of the compound has strong inhibition activity on Syk, and a structural foundation is laid for further designing and developing novel Syk inhibitor rheumatoid arthritis (RA) treatment medicine.

Description

Heterocyclic substituted styrene compound and uses thereof
The application is the applying date is on December 27th, 2012, and application number is 201210579510.X, and denomination of invention is the divisional application of the patent application of " heterocyclic substituted styrene compound and uses thereof ".
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, be specifically related to heterocyclic substituted styrene compound and its production and use.
Background technology
Rheumatoid arthritis (rheumatoidarthritis, RA) be a kind of common systemic autoimmune disease, basic lesion is chronic synovitis disease, synovial membrane paraplasm, backing layer thicken, pannus is formed and the destruction of cartilage and osseous tissue, finally cause joint deformity and afunction, serious impact is caused on the Health and Living quality of the mankind.The sickness rate of RA in crowd is 0.5% ~ 1.0%, and in recent years in raising trend year by year, China is rheumatismal district occurred frequently especially, has the patient of more than 50,000,000 at present at least.
At present, the treatment to inflammation and sequela is also rested on to the main flow methods for the treatment of of RA both at home and abroad, there is no specific short.Usual employing medicine, physiotherapy and surgical orthopaedic means treatment RA, to control inflammation, correction mechanical or structural abnormal, stop destruction of bone and prevention function of joint forfeiture, its drug treatment be basis.The medicine of RA comprises non-steroidal or steroidal anti-inflammatory medicine, immunomodulator, biotechnological formulation etc.These medicines all can not control destruction of joint completely, can only alleviating pain, alleviate or delay the development of inflammation.
Although modern medicine there is no accurate final conclusion to the definite cause of disease of RA and pathogenesis, but a large amount of molecular biology and immunological investigation find, in the synovial tissue and synovial fluid of RA patient, have the immunocyte (as T cell, B cell, osteoclast and mastocyte, scavenger cell and neutrophil leucocyte) of abnormal increase, immune molecule (cytokine, autoantibody, heat shock protein(HSP) etc.), the generation of the activation of these cells or the release of material and RA and development have close contacting.Thereupon, can a series of target spots of specificity interference RA disease process, as cytokine, recruiting cells associated molecule, immune cell surface antigenic, kinases etc. are also found in succession.Wherein, spleen tyrosine kinase (spleentyrosinekinase, Syk) is regarded as the target of the promising targeted therapy rheumatoid arthritis of most.
Syk belongs to protein tyrosine kinase family, is a kind of non-receptor type protein tyrosine kinase.It is generally expressed in hematopoietic cell, high level expression in B cell, and in other various cell, as low level epithelial cell, inoblast, neurocyte, in liver cell, expression level is lower.Syk is to bone-marrow-derived lymphocyte development and antigen receptor signal conduction, T cell development and antigen receptor signal conducts, Fc receptor signal conducts and the activation of mitotic division activator has very important effect.The autoimmune disorder that immunity receptor such as Fc acceptor and B-cell receptor cause supersensitivity and antibody is very important.After Syk and immunoreceptor tyrosine-based activation motif combine, activation signal passage downstream, finally causes the release of cytokine and lipid medium constantly to increase, as cysteinyl leukotriene and various proteolytic enzyme.These intermediaries just result in the damage of the generation of inflammation, synovial membrane and cartilage.Research shows, Syk inhibitor is probably by blocking the neutrophil leucocyte that is present in synovial membrane and the Fc γ R signal conduction in scavenger cell carrys out ameliorating effect cytosis and directly block these two kinds of approach of B-cell receptor intracellular signaling effect to suppress RA process.In addition, Syk can also regulate and control to be present in the DAP12 acceptor in natural killer cell and osteoclast in signal transducting system downstream, the Glycoprotein VI acceptor in B-cell receptor and thrombocyte, and then immune cell activated.Wherein, Syk is suppressed to carry out the growth of adjusting function scavenger cell by DAP12 acceptor and Fc γ R, suppress the conduction of scavenger cell, stop the release of MMP and reduce the release of various cytokine as IL-6, IL-1 and TNF-α, then stoping the damage of bone, cartilage and synovial membrane.
In sum, the inhibit activities of Syk inhibitor to the medium of these keys and signal transduction pathway and cell lineage fully shows to develop with Syk is that the Syk inhibitor class medicine of target is significant to treatment RA.
Summary of the invention
An object of the present invention is, a kind of heterocyclic substituted styrene compound of novel structure is provided, it is through the test to Syk inhibit activities, result shows: it has inhibit activities (and part of compounds has stronger inhibit activities to Syk) to Syk, has established architecture basics for designing and developing New type of S yk inhibitor class RA medicine from now on further.
Heterocyclic substituted styrene compound of the present invention, it is compound shown in formula I or its pharmaceutically acceptable salt:
In formula I: R 1for C 1~ C 4alkoxyl group; R 2for halogen (F, Cl, Br or I); A is selected from: a kind of in group shown in formula II ~ IV; Ar is 6 yuan of aromatic ring yls or 6 yuan of hetero-aromatic ring bases, or replace 6 yuan of aromatic ring yls or 6 yuan of hetero-aromatic ring bases;
Wherein, R 3for H or C 1~ C 4alkyl; 6 yuan of aromatic ring yls of described replacement or the substituting group of 6 yuan of hetero-aromatic ring bases are selected from: halogen (F, Cl, Br or I), C 1~ C 6alkyl, C 1~ C 6alkoxyl group, carboxyl (-COOH), or ester group (-COOR 4, R 4for C 1~ C 4alkyl) in one or two or more kinds (containing two kinds), substituent number is the integer of 1 ~ 3; Heteroatoms contained by described 6 yuan of hetero-aromatic ring bases is N, O and/or S, and contained heteroatomic number is 1-3; In group shown in formula II ~ IV, curve mark is for replacing position (that is: Ca and Cb, Cc or Cd connect in double bond mode, lower same).
Another object of the present invention is, a kind of pharmaceutical composition is provided, compound shown in described pharmaceutical composition contained I, or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier and/or additive (as pharmaceutically acceptable thinner, tackiness agent and weighting agent etc.).
A further object of the invention is, disclose a kind of purposes of above-mentioned heterocyclic substituted styrene compound and pharmaceutical composition, that is: compound shown in formula I or its pharmaceutically acceptable salt preparing the application in antirheumatic, in other words, the pharmaceutical composition of compound shown in formula I or its pharmaceutically compound shown in acceptable salt and contained I or its pharmaceutically acceptable salt is as the application of spleen tyrosine kinase (spleentyrosinekinase, Syk) inhibitor.
Embodiment
In the present invention's preferred technical scheme, described heterocyclic substituted styrene compound is compound shown in formula I-1 or formula I-2 or its pharmaceutically acceptable salt:
Wherein, R 1, R 2, the definition of A with Ar is with described identical above.
In another preferred technical scheme of the present invention, R 1for C 1~ C 3alkoxyl group; Best R 1for oxyethyl group.
In a further preferred technical solution of the present invention, Ar is phenyl, substituted-phenyl, 6 yuan of hetero-aromatic ring bases, or replaces 6 yuan of hetero-aromatic ring bases;
Wherein, the substituting group of described substituted-phenyl and replacement 6 yuan of hetero-aromatic ring bases is selected from: halogen (F, Cl, Br or I), C 1~ C 6alkyl, C 1~ C 6alkoxyl group, carboxyl (-COOH), or ester group (-COOR 4, R 4for C 1~ C 4alkyl) in one or two or more kinds (containing two kinds), substituent number is the integer of 1 ~ 3; Described 6 yuan of hetero-aromatic ring bases and the heteroatoms replaced contained by 6 yuan of hetero-aromatic ring bases are N, O and/or S, and contained heteroatomic number is 1-3;
Preferred technical scheme is: Ar is phenyl, substituted-phenyl, 6 yuan of hetero-aromatic ring bases, or replaces 6 yuan of hetero-aromatic ring bases;
Wherein, the substituting group of described substituted-phenyl and replacement 6 yuan of hetero-aromatic ring bases is selected from: halogen (F, Cl, Br or I), C 1~ C 3alkyl, C 1~ C 3alkoxyl group, carboxyl (-COOH), or ester group (-COOR 4, R 4for C 1~ C 3alkyl) in one or two or more kinds (containing two kinds), substituent number is the integer of 1 ~ 3; Described 6 yuan of hetero-aromatic ring bases and the heteroatoms replaced contained by 6 yuan of hetero-aromatic ring bases are N, O and/or S, and contained heteroatomic number is 1-3;
Further preferred technical scheme is: Ar is phenyl, the phenyl that halogen (F, Cl, Br or I) replaces, the phenyl that methyl or methoxy replaces, carboxyl (-COOH) or ester group (-COOCH 3) phenyl that replaces or pyridyl;
Wherein, the phenyl that described halogen (F, Cl, Br or I) replaces can be (for chlorine): Chloro-O-Phenyl, a chloro-phenyl-, rubigan, 2,3-dichlorophenyl, 2,4 dichloro benzene base, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,5-trichlorophenyl or 2,3,6-trichlorophenyl etc.;
The phenyl that described methyl or methoxy replaces can be: o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, 3,5-3,5-dimethylphenyl, 3,5-Dimethoxyphenyl, 3,4,5-trimethylphenyl or 3,4,5-trimethoxyphenyl etc.;
Described carboxyl (-COOH) or ester group (-COOCH 3) phenyl that replaces can be: adjacent carboxyl (-COOH) or ester group (-COOCH 3) phenyl, a carboxyl (-COOH) or ester group (-COOCH 3) phenyl or to carboxyl (-COOH) or ester group (-COOCH 3) phenyl etc. is (preferably to carboxyl (-COOH) or ester group (-COOCH 3) phenyl);
Described pyridyl can be: 2-pyridyl, 3-pyridyl or 4-pyridyl (preferred 2-pyridyl).
In addition, the present invention also provides the method for compound shown in a kind of preparation formula I, and concrete synthesis strategy is as follows respectively: described method comprises the steps:
I-1 aand I-2 asynthesis:
In formula, R 5for Cl or Br, R 1, R 2, R 3with the implication of Ar with described identical above.
1) by R 3the ethanolic soln of 1, the 3-propylene diamine replaced slowly drops in the ethanolic soln of dithiocarbonic anhydride, and temperature keeps below 40 DEG C, and the amount of solid separated out in question response flask no longer increases, stopped reaction.Suction filtration, is dissolved in the water filter cake, and react 10 hours under 100 DEG C of conditions, suction filtration, obtains intermediate 5,5-bis-R 3-tetrahydropyrimidine-2 (1H)-thioketones (intermediate V);
2) intermediate V is dissolved in ethanol, is heated to reflux temperature, in reaction system, add bromoacetic acid, react stopped reaction after 6 hours.Suction filtration, a small amount of washing with alcohol of filter cake, will obtain dissolution of solid in 125 grams per milliliter solution of potassium carbonate, with dichloromethane extraction, get organic layer, and dry, suction filtration, obtains intermediate 6,6-bis-R 3-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (intermediate VI).
Another: 1) by 3-R 1-4-hydroxy benzaldehyde is dissolved in acetic acid, in system, drip halogenating agent, and react after 2 hours, stopped reaction, suction filtration, a small amount of acetic acid of filter cake washs, and obtains intermediate 3-R 2-4-hydroxyl-5-R 1-phenyl aldehyde (intermediate VII);
2) be dissolved in DMF by intermediate VII and salt of wormwood, 40 DEG C of reactions after 30 minutes, then add R in reaction system 5the arylmethyl replaced, then reacts 4 hours.After reaction terminates, in flask, add a large amount of water, suction filtration, obtain intermediate 3-R 2-4-virtue methoxyl group-5-R 1-phenyl aldehyde (intermediate VIII).
Another: 1) to be dissolved in acetic acid by 3,4-Dihydroxy benzaldehyde, in system, drip halogenating agent, react after 2 hours, stopped reaction, suction filtration, a small amount of acetic acid of filter cake washs, and obtains intermediate 3-R 2-4,5-dihydroxyl-phenyl aldehyde (intermediate compound I X);
2) be dissolved in DMF by intermediate compound I X and cesium carbonate, 40 DEG C of reactions after 30 minutes, then add halogenated alkyl thing in reaction system, and reaction is spent the night.After reaction terminates, in flask, add a large amount of water, suction filtration, the solid obtained is carried out column chromatography for separation, obtains intermediate 3-R 2-4-R 1-5-hydroxy benzaldehyde (intermediate X);
3) be dissolved in DMF by intermediate X and salt of wormwood, 40 DEG C of reactions after 30 minutes, then add R in reaction system 4the arylmethyl replaced, then reacts 4 hours.After reaction terminates, in flask, add a large amount of water, suction filtration, obtain intermediate 3-virtue methoxyl group-4-R 1-5-R 2-phenyl aldehyde (intermediate X I).
By intermediate VI, intermediate VIII, anhydrous piperidines is dissolved in ethanol, back flow reaction 48 hours.Suction filtration, filter cake ethanol in proper amount is washed, then obtains 2-(3-R through column chromatography 1-4-virtue methoxyl group-5-R 2-α-tolylene)-6,6-bis-R 3-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (I-1 a); Or,
By intermediate VI, intermediate X I, anhydrous piperidines is dissolved in ethanol, back flow reaction 48 hours.Suction filtration, filter cake ethanol in proper amount is washed, then obtains 2-(3-virtue methoxyl group-4-R through column chromatography 1-5-R 2-α-tolylene)-6,6-bis-R 3-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (I-2 a).
I-1 band I-2 bsynthesis:
In formula, R 1, R 2with the implication of Ar with described identical above.
1) maleimide and triphenylphosphine are dissolved in anhydrous propanone, back flow reaction 4 hours, after being cooled to room temperature, suction filtration, filter cake washing with acetone, obtains 3-triphenylphosphine succimide (intermediate X II);
2) be dissolved in methyl alcohol by intermediate X II and intermediate VIII, back flow reaction 6 hours, is cooled to room temperature, suction filtration, and filter cake methanol wash obtains 3-(3-R 1-4-virtue methoxyl group-5-R 2-α-tolylene) Pyrrolidine-2,5-diketone (I-1 b); Or,
Be dissolved in methyl alcohol by intermediate X II and intermediate X I, back flow reaction 6 hours, is cooled to room temperature, suction filtration, filter cake methanol wash, obtains 3-(3-virtue methoxyl group-4-R 1-5-R 2-α-tolylene) Pyrrolidine-2,5-diketone (I-2 b).
I-1 cand I-2 csynthesis:
In formula, R 1, R 2with the implication of Ar with described identical above.
1) be dissolved in acetone by 2-nitrophenols, stirring at room temperature, after 5 minutes, adds salt of wormwood in reaction system, and stirring reaction 15 minutes, then slowly drips ethyl bromoacetate again in reaction system.Drip and finish, temperature is increased to 50 DEG C, reacts 1 hour, stopped reaction, to be cooled to room temperature, suction filtration, filter cake washing with acetone, distills evaporate to dryness by filtrate decompression.Resistates is dissolved in ethyl acetate, washes with water, get ethyl acetate layer, dry, filter, obtain 2-(2-nitro-phenoxy) ethyl acetate (intermediate X III);
2) intermediate X III is dissolved in acetic acid, under 0 DEG C of condition, adds iron powder in batches.2 hours are reacted respectively afterwards under room temperature and reflux conditions.Reaction treats that temperature is cooled to room temperature after stopping, and filter, filter cake acetic acid washs.Filtrate decompression is distilled to acetic acid volume residue 1/4, and add a large amount of water, suction filtration, filter cake washes with water, obtains 2H-benzo [b] [Isosorbide-5-Nitrae] oxazines-3 (4H)-one (intermediate X IV);
3) be added in the Glacial acetic acid acid anhydride of intermediate X IV and triethylamine by intermediate VIII, back flow reaction 9 hours, under room temperature condition, reaction is spent the night.Underpressure distillation part acetic acid, adds q. s. methylene chloride, suction filtration in system, and a small amount of washed with dichloromethane of filter cake, obtains 2-(3-R 1-4-virtue methoxyl group-5-R 2-α-tolylene)-2H-benzo [b] [Isosorbide-5-Nitrae] oxazines-3 (4H)-one (I-1 c); Or,
Be added to by intermediate X I in the Glacial acetic acid acid anhydride of intermediate X IV and triethylamine, back flow reaction 9 hours, under room temperature condition, reaction is spent the night.Underpressure distillation part acetic acid, adds q. s. methylene chloride, suction filtration in system, a small amount of washed with dichloromethane of filter cake, obtains 2-(3-virtue methoxyl group-4-R 1-5-R 2-α-tolylene)-2H-benzo [b] [Isosorbide-5-Nitrae] oxazines-3 (4H)-one (I-2 c).
According to the instruction of above-mentioned preparation method, those of ordinary skill in the art, without the need to creative work, can obtain all compounds that formula I-1 and I-2 comprises.
The present invention will be illustrated further below in an example.These embodiments are only for illustration of the present invention, but the protection domain do not limited the present invention in any way.All parameters in embodiment and remaining explanation unless otherwise indicated, are all for unit with quality (gram).
Embodiment 1
The preparation of 3,4,5,6-tetrahydrochysene-2-pyridinethiol (intermediate V-1).
The ethanolic soln 4 milliliters being dissolved with 1 gram of 1,3-propylene diamine slowly drops to 4 milliliters and is dissolved with in the ethanolic soln of 3.4 milliliters of dithiocarbonic anhydride, and temperature keeps below 40 DEG C, when the amount of solids of the precipitation in question response flask no longer increases, and stopped reaction.Suction filtration, is dissolved in the water filter cake, reacts 10 hours, suction filtration under 100 DEG C of conditions, obtains title compound, 0.97 gram of white solid, yield 62% after drying.
1H-NMR(400MHz,DMSO-d 6)δ:7.84(s,2H),3.09(td,J 1＝5.6Hz,J 2＝2.4Hz,4H),1.75-1.66(m,2H)。
Embodiment 2
The preparation of 6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (intermediate VI-1).
250 milligrams of intermediate V-1 are dissolved in 5 milliliters of ethanol, are heated to reflux temperature, in reaction system, add 448 milligrams of bromoacetic acids, react stopped reaction after 6 hours.Suction filtration, a small amount of washing with alcohol of filter cake, will obtain white solid and be dissolved in 3 milliliter of 125 grams per milliliter solution of potassium carbonate, with dichloromethane extraction, get organic layer, dry, suction filtration, dries and obtains 80 milligrams of white solids (intermediate VI-1), yield 24%.
1H-NMR(400MHz,CDCl 3)δ:3.76(s,2H),3.67(t,J＝5.6Hz,2H),3.55(t,J＝5.6Hz,2H),1.87(dt,J 1＝12.0Hz,J 2＝5.6Hz,2H)。
Embodiment 3
The preparation of the bromo-5-oxyethyl group of 3--4-hydroxy-benzaldehyde (intermediate VII-1).
Be dissolved in by 10 grams of vaniroms in 30 milliliters of acetic acid, in system, drip 3.08 milliliters of bromines, reaction solution fades to yellow, reacts after 2 hours, stopped reaction.Suction filtration, a small amount of acetic acid of filter cake washs, and obtains 7.247 grams of faint yellow solids (intermediate VII-1), yield 49%.
1H-NMR(400MHz,CDCl 3)δ:9.78(s,1H),7.63(s,1H),7.35(s,1H),6.56(s,1H),4.22(q,J＝7.2Hz,2H),1.50(t,J＝7.2Hz,3H)。
Embodiment 4
The preparation of the bromo-4-of 3-(2,4-dichloro-benzyloxy)-5-oxyethyl group-phenyl aldehyde (intermediate VIII-1).
Be dissolved in 10 milliliters of DMFs by 500 milligrams of intermediate VII-1 and 423 milligram salt of wormwood, 40 DEG C of reactions after 30 minutes, then add 283 microlitre 2,4-benzyl dichloride chlorine in reaction system, then react 4 hours.After reaction terminates, add a large amount of water, suction filtration in flask, dry and obtain 781 milligrams of white solids (intermediate VIII-1), yield is 95%.
1H-NMR(400MHz,CDCl 3)δ:9.86(s,1H),7.67(d,J＝1.6Hz,1H),7.40(d,J＝1.6Hz,1H),7.18(s,2H),7.00(s,1H),5.10(s,2H),4.19(q,J＝7.2Hz,2H),2.36(s,6H),1.53(t,J＝6.8Hz,3H)。
Embodiment 5
The preparation of 3-bromo-4,5-dihydroxy-benzaldehyde (intermediate compound I X-1).
Be dissolved in 30 milliliters of acetic acid by 10 gram of 3,4-Dihydroxy benzaldehyde, in system, drip 3.71 milliliters of bromines, reaction solution fades to brown color, reacts after 4 hours, stopped reaction.Suction filtration, a small amount of acetic acid of filter cake washs, and dries and obtains 7.247 grams of faint yellow solids (intermediate compound I X-1), yield 49%.
1H-NMR(400MHz,DMSO-d 6)δ:9.71(s,1H),7.58(s,1H),7.28(s,1H)。
Embodiment 6
The preparation of the bromo-4-oxyethyl group of 3--5-hydroxy benzaldehyde (intermediate X-1).
Be dissolved in 10 milliliters of DMFs by 500 milligrams of intermediate compound I X-1 and 1.13 gram cesium carbonates, 40 DEG C of reactions after 30 minutes, then add 577 microlitre iodoethane in reaction system, and reaction is spent the night.After reaction terminates, in flask, add a large amount of water, suction filtration, obtain brown solid, through column chromatography for separation, obtain 195 milligrams of white solids (intermediate X-1), yield is 35%.
1H-NMR(400MHz,CDCl 3)δ:9.83(s,1H),7.62(d,J＝2.0Hz,1H),7.42(d,J＝2.0Hz,1H),5.98(s,1H),4.24(q,J＝7.2Hz,2H),1.48(t,J＝7.2Hz,3H)。
Embodiment 7
The preparation of the bromo-4-oxyethyl group of 3--5-(2,4-dichloro-benzyloxy)-phenyl aldehyde (intermediate X I-1).
Be dissolved in 10 milliliters of DMFs by 500 milligrams of intermediate X-1 and 423 milligrams of salt of wormwood, 40 DEG C of reactions after 30 minutes, then add 283 microlitre 2,4-benzyl dichloride chlorine in reaction system, then react 4 hours.After reaction terminates, add a large amount of water, suction filtration in flask, dry and obtain 775 milligrams of white solids (intermediate X I-1), yield is 94%.
1H-NMR(400MHz,CDCl 3)δ:9.87(s,1H),7.74(d,J＝2.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.49-7.47(m,2H),7.33(dd,J 1＝8.4Hz,J 2＝2.0Hz,1H),5.22(s,2H),4.24(q,J＝7.2Hz,2H),1.45(t,J＝6.8Hz,3H)。
Embodiment 8
2-[the bromo-4-of 3-(2,4-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene]-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-1 a-1) preparation.
By 100 milligrams of intermediate VI-1,259 milligrams of intermediate VIII-1,47 microliter anhydrous piperidines are dissolved in 10 milliliters of ethanol, back flow reaction 48 hours.Suction filtration, a small amount of washing with alcohol of filter cake, dries and obtains white solid 234 milligrams of (Compound I-1 a-1), yield is 70%.
1H-NMR(400MHz,CDCl 3)δ:7.73(d,J＝8.0Hz,2H),7.43(s,1H),7.34-7.32(m,2H),7.02(s,1H),5.24(s,2H),4.15(q,J＝7.2Hz,2H),3.94(t,J＝4.4Hz,2H),3.81(t,J＝4.4Hz,2H),2.22-2.10(m,2H),1.47(t,J＝6.8Hz,3H)；MS(EI)m/z541.9(M +)。
Embodiment 9
2-[the bromo-4-oxyethyl group of 3--5-(2,4-dichloro-benzyloxy)-α-tolylene]-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-2 a-1) preparation.
Except changing into except intermediate VII-1 by intermediate VIII-1, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain white solid 228 milligrams of (Compound I-2 a-1), yield is 68%.
1H-NMR(400MHz,CDCl 3)δ:7.75-7.72(m,2H),7.43(s,1H),7.36-7.31(m,2H),7.02(s,1H),5.23(s,2H),4.15(q,J＝6.8Hz,2H),3.98-3.87(m,2H),3.82-3.78(m,2H),2.15-2.12(m,2H),1.47(t,J＝6.8Hz,3H)；MS(EI)m/z541.9(M +)。
Embodiment 10
2-[the bromo-4-of 3-(3,4,5-trimethoxy benzyloxy)-5-oxyethyl group-α-tolylene]-6,6-dimethyl-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-1 a-2) preparation.
Except changing 2,4-benzyl dichloride chlorine into 3,4,5-trimethoxy benzyl bromine, 1,3 propylene diamine change into outside 2,2-dimethylpropane-1,3-diamines, and all the other desired raw materials, reagent and preparation method, with embodiment 1,2,3,4 and 8, obtain 126 milligrams of solid (Compound I-1 a-2), yield is 68%.
1H-NMR(400MHz,CDCl 3)δ:7.59(s,1H),7.32(d,J＝2.0Hz,1H),7.03(d,J＝2.0Hz,1H),6.80(s,1H),5.07(s,2H),4.16(q,J＝6.8Hz,2H),3.91(s,6H),3.87(s,3H),3.49(s,1H),3.41(s,2H),1.53(t,J＝6.8Hz,3H),1.08(s,3H)；MS(EI)m/z592.1(M +)。
Embodiment 11
2-[the bromo-4-of 3-(2,4-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene]-6,6-dimethyl-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-1 a-3) preparation.
Except by 1,3 propylene diamine change into outside 2,2-dimethylpropane-1,3-diamines, and all the other desired raw materials, reagent and preparation method, with embodiment 1,2,3,4 and 8, obtain 147 milligrams of solid (Compound I-1 a-3), yield is 75%.
1H-NMR(400MHz,CDCl 3)δ:7.73(d,J＝8.0Hz,2H),7.43(s,1H),7.33(d,J＝5.6Hz,2H),7.02(s,1H),5.23(s,2H),4.15(q,J＝6.8Hz,2H),3.58(s,2H),3.48(s,2H),1.47(t,J＝6.8Hz,3H),1.14(s,6H)；MS(EI)m/z569.9(M +)。
Embodiment 12
2-[the bromo-4-of 3-(3,4,5-trimethoxy benzyloxy)-5-oxyethyl group-α-tolylene]-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-1 a-4) preparation.
Except being changed into by 2,4-benzyl dichloride chlorine outside 3,4,5-trimethoxy benzyl bromine, all the other desired raw materials, reagent and preparation method, with embodiment 1,2,3,4 and 8, obtain 68 milligrams of solid (Compound I-1 a-4), yield is 64%.
1H-NMR(400MHz,CDCl 3)δ:7.53(s,1H),7.26(d,J＝2.0Hz,1H),6.96(d,J＝2.0Hz,1H),6.74(s,2H),5.00(s,2H),4.10(q,J＝7.2Hz,2H),3.85(s,6H),3.81-3.77(m,5H),3.65(t,J＝5.6Hz,2H),1.96-1.91(m,2H),1.47(t,J＝6.8Hz,3H)；MS(EI)m/z564.0(M +)。
Embodiment 13
2-[the bromo-4-of 3-(3,5-benzyloxy-dimethyl)-5-oxyethyl group-α-tolylene]-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-1 a-5) preparation.
Except changing into outside 3,5-dimethylbenzyl bromine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 1,2,3,4 and 8, obtain 52 milligrams of solid (Compound I-1 a-5), yield is 76%.
1H-NMR(400MHz,CDCl 3)δ:7.62(s,1H),7.31(s,1H),7.18(s,2H),7.00(d,J＝1.2Hz,2H),5.03(s,2H),4.15(q,J＝6.8Hz,2H),3.87(t,J＝5.6Hz,2H),3.74(t,J＝5.2Hz,2H),2.36(s,6H),2.09-1.99(m,2H),1.53(t,J＝6.8Hz,3H)；MS(EI)m/z502.0(M +)。
Embodiment 14
2-[the bromo-4-of 3-(3,5-benzyloxy-dimethyl)-5-oxyethyl group-α-tolylene]-6,6-dimethyl-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-1 a-6) preparation.
Except changing 2,4-benzyl dichloride chlorine into 3,5-dimethylbenzyl bromine, 1,3 propylene diamine change into outside 2,2-dimethylpropane-1,3-diamines, and all the other desired raw materials, reagent and preparation method, with embodiment 1,2,3,4 and 8, obtain 61 milligrams of solid (Compound I-1 a-6), yield is 74%.
1H-NMR(400MHz,CDCl 3)δ:7.70(d,J＝1.2Hz,1H),7.32(s,1H),7.18(s,2H),7.01(d,J＝5.6Hz,2H),5.05(s,2H),4.16(q,J＝7.2Hz,2H),3.56(s,2H),3.47(s,2H),2.36(s,6H),1.54(t,J＝6.8Hz,3H),1.12(s,6H)；MS(EI)m/z530.1(M +)。
Embodiment 15
4-{ [the bromo-4-of 2-(3-oxo-3,5,6,7-tetrahydrochysene-2H-thiazole [3,2-a] pyrimidine-2-methylene radical)-6-oxyethyl group] Phenoxymethyl } phenylformic acid (Compound I-1 a-7) preparation.
Except by 2,4-benzyl dichloride chlorine changes into outside 4-bromomethyl-benzoic acid methyl ester, all the other desired raw materials, reagent and preparation method are with embodiment 1,2,3,4 and 8, obtain 58 milligrams of solids (4-{ [the bromo-4-of 2-(3-oxo-3,5,6,7-tetrahydrochysene-2H-thiazole [3,2-a] pyrimidine-2-methylene radical)-6-oxyethyl group] Phenoxymethyl } methyl benzoate), be dissolved in (tetrahydrofuran (THF)/methanol/water=3/3/1, v/v/v)) in totally 6 milliliters of mixing solutionss, add 7 milligrams of sodium hydroxide, 40 DEG C are reacted 6 hours.Stopped reaction, solvent evaporated, adds 1NHCl solution, adjusts pH to 3-4, and adularescent solid is separated out, suction filtration, and washing is dried and obtained 45 milligrams of white solid (Compound I-1 a-7), yield is 81%.
1H-NMR(400MHz,DMSO-d 6)δ:7.95(d,J＝7.6Hz,2H),7.62(s,1H),7.55(d,J＝7.6Hz,2H),7.38(s,1H),7.28(s,1H),5.11(s,2H),4.17(q,J＝6.8Hz,2H),3.72(s,2H),3.56(s,2H),1.91-1.86(m,2H),1.41(t,J＝6.4Hz,3H)；MS(ESI)m/z517.0[M+1] +。
Embodiment 16
2-[the bromo-4-of 3-(pyridine-2-methoxyl group)-5-oxyethyl group-α-tolylene]-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-1 a-8) preparation.
Except changing into outside 2-chloromethylpyridine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 1,2,3,4 and 8, obtain 51 milligrams of solid (Compound I-1 a-8), yield is 62%.
1H-NMR(400MHz,DMSO-d 6)δ:8.54(d,J＝4.4Hz,1H),7.88(td,J 1＝7.6Hz,J 2＝1.2Hz,1H),7.73(d,J＝8.0Hz,1H),7.62(s,1H),7.38-7.34(m,2H),7.29(s,1H),5.15(s,2H),4.15(q,J＝6.8Hz,2H),3.73(t,J＝6.0Hz,2H),3.56(t,J＝5.6Hz,2H),1.91-1.81(m,2H),1.35(t,J＝6.8Hz,3H)；MS(ESI)m/z496.0[M+23] +。
Embodiment 17
2-[the bromo-4-oxyethyl group of 3--5-(2,4-dichloro-benzyloxy)-α-tolylene]-6,6-dimethyl-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-2 a-2) preparation.
Except by 1,3 propylene diamine change into outside 2,2-dimethylpropane-1,3-diamines, and all the other desired raw materials, reagent and preparation method, with embodiment 1,2,5,6,7 and 9, obtain white solid 74 milligrams of (Compound I-2 a-2), yield is 66%.
1H-NMR(400MHz,CDCl 3)δ:7.82-7.75(m,1H),7.73(d,J＝8.0Hz,1H),7.43(s,1H),7.34-7.31(m,2H),7.02(s,1H),5.24(s,2H),4.15(q,J 1＝6.8Hz,2H),3.61(s,2H),3.50(s,2H),1.47(t,J＝6.8Hz,3H),1.16(s,6H)；MS(EI)m/z569.9(M +)。
Embodiment 18
4-{ [the bromo-5-of 2-oxyethyl group-3-(3-oxo-3,5,6,7-tetrahydrochysene-2H-thiazole [3,2-a] pyrimidine-2-methylene radical)] Phenoxymethyl } phenylformic acid (Compound I-2 a-3) preparation.
Except by 2,4-benzyl dichloride chlorine changes into outside 4-bromomethyl-benzoic acid methyl ester, all the other desired raw materials, reagent and preparation method with embodiment 1,2,5,6,7 and 9, obtain 68 milligrams of white solids (4-{ [the bromo-5-of 2-oxyethyl group-3-(3-oxo-3,5,6,7-tetrahydrochysene-2H-thiazole [3,2-a] pyrimidine-2-methylene radical)] Phenoxymethyl } methyl benzoate).Be dissolved in (tetrahydrofuran (THF)/methanol/water=3/3/1, v/v/v) in totally 6 milliliters of mixing solutionss, added 8 milligrams of sodium hydroxide, 40 DEG C of reactions 6 hours.Stopped reaction, solvent evaporated, adds 1NHCl solution, adjusts pH to 3-4, and adularescent solid is separated out, suction filtration, and washing is dried and obtained 46 milligrams of white solid (Compound I-2 a-3), yield is 79%.
1H-NMR(400MHz,DMSO-d 6)δ:7.99(d,J＝8.0Hz,2H),7.68(s,1H),7.61(d,J＝8.0Hz,2H),7.43(s,1H),7.34(s,1H),5.34(s,2H),4.13(q,J＝6.8Hz,2H),3.74(t,J＝4.8Hz,3H),3.59(s,3H),1.92(s,2H),1.32(t,J＝6.8Hz,3H)；MS(ESI)m/z517.0[M+1] +。
Embodiment 19
2-[the bromo-4-oxyethyl group of 3--5-(pyridine-2-methoxyl group) α-tolylene]-6,7-dihydro-2H-thiazole [3,2-a] pyrimidine-3 (5H)-one (Compound I-2 a-4) preparation.
Except changing into outside 2-chloromethylpyridine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 1,2,5,6,7 and 9, obtain 55 milligrams of solid (Compound I-2 a-4), yield is 72%.
1H-NMR(400MHz,DMSO-d 6)δ:8.60(d,J＝4.4Hz,1H),7.87(td,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.57(s,1H),7.53(d,J＝8.0Hz,2H),7.42(d,J＝1.6Hz,1H),7.39-7.35(m,1H),7.29(d,J＝2.0Hz,1H),5.32(s,2H),4.15(q,J＝6.8Hz,2H),3.71(t,J＝6.0Hz,2H),3.55(t,J＝5.6Hz,2H),1.90-1.78(m,2H),1.33(t,J＝6.8Hz,3H)；MS(ESI)m/z474.0[M+1] +。
Embodiment 20
The preparation of 3-triphenylphosphine succimide (intermediate X II-1).
Be dissolved in 10 milliliters of anhydrous propanones by 1 gram of maleimide and 2.7 grams of triphenylphosphines, back flow reaction 4 hours, adularescent precipitation generates.After terminating reaction, question response liquid is cooled to room temperature, suction filtration, filter cake washing with acetone, and dry and obtain white solid 3.4 grams (intermediate X II-1), yield is 92%.
1H-NMR(400MHz,DMSO-d 6)δ:9.69(s,1H),7.67-7.49(m,15H),2.85(s,2H)。
Embodiment 21
3-[the bromo-4-of 3-(2,4-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-1) preparation.
Be dissolved in 10 ml methanol by 200 milligrams of intermediate X II-1 and 225 milligram intermediate VIII-1, back flow reaction 6 hours, adularescent precipitation generates.Be cooled to room temperature, suction filtration, filter cake 3x15 ml methanol washing, obtains 243 milligrams of white solid (Compound I-1 b-1), yield is 90%.
1H-NMR(400MHz,DMSO-d 6)δ:11.48(s,1H),7.71-7.66(m,2H),7.50(dd,J 1＝8.0Hz,J 2＝2.0Hz,1H),7.44(d,J＝1.6Hz,1H),7.33(t,J＝2.0Hz,1H),7.29(d,J＝1.6Hz,1H),5.15(s,2H),4.17(q,J＝6.8Hz,2H),3.71(d,J＝2.4Hz,2H),1.36(t,J＝6.8Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 22
3-[the bromo-4-oxyethyl group of 3--5-(2,4-dichloro-benzyloxy)-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-1) preparation.
Be dissolved in 10 ml methanol by 100 milligrams of intermediate X II-1 and 123 milligram intermediate X I-1, back flow reaction 6 hours, adularescent precipitation generates.Be cooled to room temperature, suction filtration, filter cake 3x15 ml methanol washing, obtains 122 milligrams of white solid (Compound I-2 b-1), yield is 91%.
1H-NMR(400MHz,DMSO-d 6)δ:11.48(s,1H),7.74(d,J＝2.0Hz,1H),7.66(d,J＝8.4Hz,1H),7.53(dd,J 1＝8.4Hz,J 2＝2.0Hz,1H),7.49(s,1H),7.42(s,1H),7.34(s,1H),5.28(s,2H),4.05(q,J＝6.8Hz,2H),3.70(d,J＝2.0Hz,2H),1.26(t,J＝7.2Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 21
3-[the bromo-4-of 3-(2,3-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-2) preparation.
Except changing into outside 2,3-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 3,4,20 and 21, obtain 117 milligrams of white solid (Compound I-1 b-2), yield is 92%.
1H-NMR(400MHz,DMSO-d 6)δ:11.47(s,1H),7.66(dd,J 1＝7.6Hz,J 2＝1.6Hz,2H),7.44(d,J＝6.8Hz,2H),7.33(s,1H),7.29(s,1H),5.21(s,2H),4.16(q,J＝6.4Hz,3H),3.72(d,J＝1.6Hz,2H),1.34(t,J＝6.8Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 22
3-[the bromo-4-of 3-(2,5-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-3) preparation.
Except changing into outside 2,5-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 3,4,20 and 21, obtain 95 milligrams of white solid (Compound I-1 b-3), yield is 88%.
1H-NMR(400MHz,DMSO-d 6)δ:11.48(s,1H),7.60(m,3H),7.46(s,1H),7.34(s,1H),7.30(s,1H),5.08(s,2H),4.18(q,J＝6.8Hz,2H),3.72(d,J＝2.0Hz,2H),1.38(t,J＝6.8Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 23
3-[the bromo-4-of 3-(3,5-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-4) preparation.
Except changing into outside 2,5-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 3,4,20 and 21, obtain 101 milligrams of white solid (Compound I-1 b-4), yield is 85%.
1H-NMR(400MHz,DMSO-d 6)δ:11.48(s,1H),7.77(d,J＝2.4Hz,1H),7.55(d,J＝8.8Hz,1H),7.48(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),7.46(s,1H),7.34(s,1H),7.30(s,1H),5.16(s,2H),4.17(q,J＝6.8Hz,2H),3.72(d,J＝1.6Hz,2H),1.36(t,J＝6.8Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 24
3-[the bromo-4-of 3-(2,3,5-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-5) preparation.
Except changing into outside 2,3,5-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 3,4,20 and 21, obtain 54 milligrams of white solid (Compound I-1 b-5), yield is 79%.
1H-NMR(400MHz,DMSO-d 6)δ:11.48(s,1H),7.89(d,J＝2.4Hz,1H),7.76(d,J＝2.4Hz,1H),7.46(s,1H),7.34(s,1H),7.30(s,1H),5.20(s,2H),4.16(q,J＝6.8Hz,2H),3.72(s,2H),1.33(t,J＝6.8Hz,3H)；MS(ESI)m/z517.8[M+1] +。
Embodiment 25
3-[the bromo-4-of 3-(2,3,6-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-6) preparation.
Except changing into outside 2,3,6-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 3,4,20 and 21, obtain 51 milligrams of white solid (Compound I-1 b-5), yield is 77%.
1H-NMR(400MHz,DMSO-d 6)δ:11.48(s,1H),7.89(d,J＝2.4Hz,1H),7.76(d,J＝2.4Hz,1H),7.46(s,1H),7.34(s,1H),7.29(s,1H),5.20(s,2H),4.16(q,J＝6.8Hz,2H),3.72(s,2H),1.33(t,J＝6.8Hz,3H)；MS(ESI)m/z517.8[M+1] +。
Embodiment 26
3-[the bromo-4-of 3-(3,4-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-7) preparation.
Except changing into outside 3,4-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 3,4,20 and 21, obtain 113 milligrams of white solid (Compound I-1 b-5), yield is 85%.
1H-NMR(400MHz,DMSO-d 6)δ:11.47(s,1H),7.79(d,J＝1.2Hz,1H),7.67(d,J＝8.4Hz,1H),7.49(dd,J 1＝8.4Hz,J 2＝1.6Hz,1H),7.44(s,1H),7.33(s,1H),7.29(s,1H),5.07(s,2H),4.18(q,J＝6.8Hz,2H),3.72(d,J＝2.0Hz,2H),1.39(t,J＝6.8Hz,3H)；MS(ESI)m/z483.9[M+1] +。
Embodiment 27
3-[the bromo-4-of 3-(2,6-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-8) preparation.
Except changing into outside 2,6-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 3,4,20 and 21, obtain 106 milligrams of white solid (Compound I-1 b-8), yield is 88%.
1H-NMR(400MHz,DMSO-d 6)δ:11.47(s,1H),7.51(d,J＝1.6Hz,1H),7.49(s,1H),7.45-7.41(m,1H),7.38(d,J＝2.0Hz,1H),7.32(t,J＝2.4Hz,1H),7.25(d,J＝1.6Hz,1H),5.40(s,2H),4.13(q,J＝6.8Hz,2H),3.70(d,J＝2.4Hz,2H),1.37(t,J＝6.8Hz,2H)；MS(ESI)m/z484.0[M+1] +。
Embodiment 28
3-[the bromo-4-oxyethyl group of 3--5-(2,3-dichloro-benzyloxy)-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-2) preparation.
Except changing into outside 2,3-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 5,6,7,20 and 22, obtain 94 milligrams of white solid (Compound I-2 b-2), yield is 83%.
1H-NMR(400MHz,DMSO-d 6)δ:11.47(s,1H),7.69(dd,J 1＝8.0Hz,J 2＝0.8Hz,1H),7.62(d,J＝8.0Hz,1H),7.50-7.48(m,1H),7.46(s,1H),7.44(d,J＝3.6Hz,1H),7.34(s,1H),5.33(s,2H),4.06(q,J＝7.2Hz,2H),3.69(d,J＝2.0Hz,2H),1.27(t,J＝6.8Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 29
3-[the bromo-4-oxyethyl group of 3--5-(2,5-dichloro-benzyloxy)-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-2 b-3) preparation.
Except changing into outside 2,5-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 5,6,7,20 and 22, obtain 66 milligrams of white solid (Compound I-2 b-3), yield is 78%.
1H-NMR(400MHz,DMSO-d 6)δ:11.48(s,1H),7.74(d,J＝2.4Hz,1H),7.60(d,J＝8.4Hz,1H),7.54-7.48(m,2H),7.45(s,1H),7.35(s,1H),5.27(s,2H),4.06(q,J＝6.8Hz,2H),3.71(d,J＝2.0Hz,2H),1.29(t,J＝6.8Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 30
3-[the bromo-4-oxyethyl group of 3--5-(3,5-dichloro-benzyloxy)-α-tolylene] Pyrrolidine-2,5-diketone (compound 2-1 b-4) preparation.
Except changing into outside 3,5-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 5,6,7,20 and 22, obtain 42 milligrams of white solid (Compound I-2 b-4), yield is 77%.
1H-NMR(400MHz,DMSO-d 6)δ:11.47(s,1H),7.62(s,1H),7.55(s,2H),7.50(s,1H),7.32(d,J＝7.2Hz,2H),5.27(s,2H),4.08(q,J＝6.8Hz,2H),3.67(s,2H),1.32(t,J＝6.8Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 31
3-[the bromo-4-oxyethyl group of 3--5-(2,3,5-dichloro-benzyloxy)-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-2 b-5) preparation.
Except changing into outside 2,3,5-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 5,6,7,20 and 22, obtain 47 milligrams of white solid (Compound I-2 b-5), yield is 82%.
1H-NMR(400MHz,DMSO-d 6)δ:11.49(s,1H),7.93(d,J＝2.4Hz,1H),7.73(d,J＝2.4Hz,1H),7.52(s,1H),7.46(s,1H),7.36(s,1H),5.32(s,2H),4.06(q,J＝7.2Hz,2H),3.72(d,J＝2.0Hz,2H),1.31(t,J＝7.2Hz,3H)；MS(EI)m/z516.9(M +)。
Embodiment 32
3-[the bromo-4-oxyethyl group of 3--5-(2,3,5-dichloro-benzyloxy)-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-2 b-6) preparation.
Except changing into outside 2,3,6-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 5,6,7,20 and 22, obtain 51 milligrams of white solid (Compound I-2 b-6), yield is 87%.
1H-NMR(400MHz,DMSO-d 6)δ:11.48(s,1H),7.81(d,J＝8.8Hz,1H),7.68-7.50(m,5H),7.36(s,1H),5.41(s,2H),3.99(q,J＝7.2Hz,2H),3.77(s,2H),1.18(t,J＝7.2Hz,3H)；MS(EI)m/z516.9(M +)。
Embodiment 33
3-[the bromo-4-oxyethyl group of 3--5-(3,4-dichloro-benzyloxy)-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-2 b-7) preparation.
Except changing into outside 3,4-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 5,6,7,20 and 22, obtain 55 milligrams of white solid (Compound I-2 b-7), yield is 83%.
1H-NMR(400MHz,DMSO-d 6)δ:11.47(s,1H),7.77(d,J＝1.6Hz,1H),7.71(d,J＝8.4Hz,1H),7.52-7.41(m,2H),7.34(s,1H),7.31(s,1H),5.26(s,2H),4.08(q,J＝7.2Hz,2H),3.67(d,J＝2.0Hz,2H),1.31(t,J＝7.2Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 34
3-[the bromo-4-oxyethyl group of 3--5-(2,6-dichloro-benzyloxy)-α-tolylene] Pyrrolidine-2,5-diketone (Compound I-1 b-8) preparation.
Except changing into outside 2,6-benzyl dichloride chlorine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 5,6,7,20 and 22, obtain 56 milligrams of white solid (Compound I-2 b-8), yield is 83%.
1H-NMR(400MHz,DMSO-d 6)δ:11.48(s,1H),7.62(s,1H),7.60(s,1H),7.54-7.49(m,3H),7.36(s,1H),5.36(s,2H),4.00(q,J＝6.8Hz,2H),3.77(d,J＝2.0Hz,2H),1.18(t,J＝6.8Hz,3H)；MS(EI)m/z482.9(M +)。
Embodiment 35
The preparation of 2-(2-nitro Phenoxymethyl) ethyl acetate (intermediate X III-1).
Be dissolved in by 10 grams of 2-nitrophenolss in 25 milliliters of acetone, stirring at room temperature, after 5 minutes, adds 21.5 grams of salt of wormwood in reaction system, stirring reaction 15 minutes, then in reaction system, slowly drips the acetone soln that 5 milliliters are dissolved with 13.2 grams of ethyl bromoacetate again.After dropping terminates, temperature is increased to 50 DEG C, reacts 1 hour, stopped reaction, to be cooled to room temperature.Suction filtration, filter cake washing with acetone, distills evaporate to dryness by filtrate decompression, and resistates is dissolved in 40 milliliters of ethyl acetate, wash with water, get ethyl acetate layer, dry, filter, evaporate to dryness ethyl acetate obtains 15.4 grams of white solids (intermediate X III-1), and yield is 92%.
1H-NMR(400MHz,CDCl 3)δ:7.85(d,J＝8.2Hz,1H),7.50(t,J＝7.8Hz,1H),7.10(d,J＝7.8Hz,2H),4.75(s,2H),4.30-4.20(m,2H),1.30(t,J＝7.2Hz,3H)。
Embodiment 36
The preparation of 2H-benzo [b] [Isosorbide-5-Nitrae] oxazines-3 (4H)-one (intermediate X IV-1).
15.4 grams of intermediate X III-1 are dissolved in 70 milliliters of acetic acid, under 0 DEG C of condition, add 38.4 grams of iron powders in batches.Solution crossfades into black.2 hours are reacted respectively afterwards under room temperature and reflux conditions.Reaction treats that temperature is cooled to room temperature after stopping, and filter, filter cake acetic acid (10mL × 3) washs.Filtrate decompression is distilled to acetic acid volume residue 1/4, and add 75 ml waters, have solid to separate out, suction filtration, filter cake washes with water, and dry to obtain 7.5 grams of pale solids (intermediate X IV-1), yield is 74%.
1H-NMR(400MHz,CDCl 3)δ:9.40(s,1H),6.98(s,3H),6.87(s,1H),4.63(s,2H)。
Embodiment 37
2-[the bromo-4-of 3-(2,4-dichloro-benzyloxy)-5-oxyethyl group-α-tolylene]-2H-benzo [b] [Isosorbide-5-Nitrae] oxazole-3 (4H)-one (Compound I-1 c-1) preparation.
By 596 milligrams of intermediate VIII-1,200 milligrams of intermediate X IV-1 and 280 microlitre triethylamines are dissolved in 3 milliliters of Glacial acetic acid acid anhydrides, N 2protection, back flow reaction 9 hours, under room temperature condition, reaction is spent the night.In system, add q. s. methylene chloride again after underpressure distillation part acetic acid, have insoluble solids to separate out, suction filtration, a small amount of washed with dichloromethane of filter cake, obtain 27 milligrams of white solid (Compound I-1 c-1), yield 4%.
1H-NMR(400MHz,DMSO-d 6)δ:11.19(s,1H),7.72-7.67(m,3H),7.64(s,1H),7.51(dd,J 1＝8.0Hz,J 2＝2.0Hz,1H),7.21-7.13(m,1H),7.07-7.04(m,2H),6.99(dd,J 1＝6.8Hz,J 2＝2.4Hz,1H),6.75(s,1H),5.15(s,2H),4.18(q,J＝6.8Hz,2H),1.39(t,J＝6.8Hz,3H)；MS(ESI)m/z559.9[M+23] +。
Embodiment 37
2-[the bromo-4-oxyethyl group of 3--5-(2,4-dichloro-benzyloxy)-α-tolylene]-2H-benzo [b] [Isosorbide-5-Nitrae] oxazole-3 (4H)-one (Compound I-2 c-1) preparation.
By 596 milligrams of intermediate X I-1,200 milligrams of intermediate X IV-1 and 280 microlitre triethylamines are dissolved in 3 milliliters of Glacial acetic acid acid anhydrides, N 2protection, back flow reaction 9 hours, under room temperature condition, reaction is spent the night.In system, add q. s. methylene chloride again after underpressure distillation part acetic acid, have insoluble solids to separate out, suction filtration, a small amount of washed with dichloromethane of filter cake, obtain 30 milligrams of white solid (Compound I-2 c-1), yield 4%.
1H-NMR(400MHz,DMSO-d 6)δ:11.20(s,1H),7.79-7.74(m,2H),7.72(s,1H),7.67(d,J＝8.4Hz,1H),7.55(dd,J 1＝8.3Hz,J 2＝2.0Hz,1H),7.09-6.96(m,4H),6.75(s,1H),5.30(s,2H),4.07(q,J＝7.2Hz,2H),1.30(t,J＝7.2Hz,3H)；MS(ESI)m/z559.9[M+23] +。
Embodiment 37
4-[the bromo-6-oxyethyl group of 2--4-(3-oxo-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazole-2-methylene radical)-Phenoxymethyl] methyl benzoate (Compound I-1 c-2) preparation.
Except changing into outside bromomethyl-benzoic acid methyl ester by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 3,4,35,36 and 37, obtain 59 milligrams of solid (Compound I-1 c-2), yield is 4%.
1H-NMR(400MHz,DMSO-d 6)δ:11.20(s,1H),8.01(d,J＝3.6Hz,2H),7.70-7.65(m,4H),7.18(s,1H),7.06(d,J＝4.0Hz,2H),7.01(s,1H),6.76(d,J＝4.4Hz,1H),5.14(d,J＝3.6Hz,2H),4.21(m,2H),3.87(d,J＝4.0Hz,3H),1.42(m,3H)；MS(ESI)m/z546.0[M+23] +。
Embodiment 38
4-[the bromo-6-oxyethyl group of 2--4-(3-oxo-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazole-2-methylene radical)-Phenoxymethyl] phenylformic acid (Compound I-1 c-3) preparation.
By 35 milligrams of Compound I-1 c-2 and 5 milligrams of sodium hydroxide are dissolved in (tetrahydrofuran (THF)/methanol/water=3/3/1, v/v/v)) in totally 6 milliliters of mixing solutionss, 40 DEG C are reacted 7 hours, stopped reaction, solvent evaporated, add 1NHCl solution, adjust pH to 3-4, adularescent solid is separated out, suction filtration, washing, dries and obtains 30 milligrams of white solid (Compound I-1 c-3), yield is 90%.
1H-NMR(400MHz,DMSO-d 6)δ:13.00(s,1H),11.19(s,1H),7.98(d,J＝8.0Hz,2H),7.69(d,J＝1.6Hz,1H),7.65-6.63(m,3H),7.21-7.16(m,1H),7.08-7.03(m,2H),7.01-6.97(m,1H),6.75(s,1H),5.13(s,2H),4.20(q,J＝6.8Hz,2H),1.42(t,J＝6.8Hz,3H)；MS(ESI)m/z510.0[M+1] +。
Embodiment 39
2-[the bromo-5-oxyethyl group of 3--4-(pyridine-2-methoxyl group)-α-tolylene]-2H-benzo [b] [Isosorbide-5-Nitrae] oxazole-3 (4H)-one (Compound I-1 c-4) preparation.
Except changing into outside 2-bromo methyl cycloheptapyridine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 3,4,35,36 and 37, obtain 26 milligrams of solid (Compound I-1 c-4), yield is 3%.
1H-NMR(400MHz,DMSO-d 6)δ:11.21(s,1H),8.55(d,J＝4.4Hz,1H),7.89(td,J 1＝8.0Hz,J 2＝1.6Hz,1H),7.75(d,J＝7.6Hz,1H),7.70(d,J＝1.6Hz,1H),7.65(d,J＝1.6Hz,1H),7.39-7.33(m,1H),7.20-7.17(m,1H),7.09-7.02(m,2H),7.02-6.97(m,1H),6.76(s,1H),5.13(s,2H),4.19(q,J＝6.8Hz,2H),1.37(t,J＝6.8Hz,3H)；MS(ESI)m/z467.0[M+1] +。
Embodiment 39
4-[the bromo-5-of 2-oxyethyl group-3-(3-oxo-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazole-2-methylene radical)-Phenoxymethyl] methyl benzoate (Compound I-2 c-2) preparation.
Except changing into outside bromomethyl-benzoic acid methyl ester by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 5,6,7,35,36 and 38, obtain 65 milligrams of solid (Compound I-1 c-2), yield is 4%.
1H-NMR(400MHz,DMSO-d 6)δ:11.22(s,1H),8.03(d,J＝8.2Hz,2H),7.70(d,J＝2.0Hz,1H),7.67-7.64(m,3H),7.09-6.93(m,4H),6.72(s,1H),5.37(s,2H),4.10(q,J＝7.2Hz,2H),3.86(s,3H),1.32(t,J＝7.2Hz,3H)；MS(ESI)m/z546.0[M+23] +。
Embodiment 40
4-[the bromo-5-of 2-oxyethyl group-3-(3-oxo-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazole-2-methylene radical)-Phenoxymethyl] phenylformic acid (Compound I-2 c-3) preparation.
By 40 milligrams of Compound I-2 c-3 and 6 milligrams of sodium hydroxide are dissolved in (tetrahydrofuran (THF)/methanol/water=3/3/1, v/v/v)) in totally 6 milliliters of mixing solutionss, 40 DEG C are reacted 7 hours, stopped reaction, solvent evaporated, add 1NHCl solution, adjust pH to 3-4, adularescent solid is separated out, suction filtration, washing, dries and obtains 35 milligrams of white solid (Compound I-2 c-3), yield is 91%.
1H-NMR(400MHz,DMSO-d 6)δ:13.02(s,1H),11.17(s,1H),8.00(d,J＝8.4Hz,2H),7.69(d,J＝11.2Hz,2H),7.62(d,J＝8.4Hz,2H),7.09-6.93(m,4H),6.72(s,1H),5.37(s,2H),4.10(q,J＝7.2Hz,2H),1.32(t,J＝7.2Hz,3H)；MS(ESI)m/z532.0[M+23] +。
Embodiment 41
2-[the bromo-4-oxyethyl group of 3--5-(pyridine-2-methoxyl group) α-tolylene]-2H-benzo [b] [Isosorbide-5-Nitrae] oxazole-3 (4H)-one (Compound I-2 c-4) preparation.
Except changing into outside 2-bromo methyl cycloheptapyridine by 2,4-benzyl dichloride chlorine, all the other desired raw materials, reagent and preparation method, with embodiment 5,6,7,35,36 and 38, obtain 27 milligrams of solid (Compound I-1 c-4), yield is 4%.
1H-NMR(400MHz,DMSO-d 6)δ:11.17(s,1H),8.60(d,J＝4.4Hz,1H),7.88(td,J 1＝8.0Hz,J 2＝2.0Hz,1H),7.71(d,J＝1.6Hz,1H),7.66(d,J＝1.5Hz,1H),7.54(d,J＝8.0Hz,1H),7.41-7.32(m,1H),7.19-7.11(m,1H),7.10-7.01(m,2H),7.01-6.92(m,1H),6.70(s,1H),5.36(s,2H),4.13(q,J＝7.2Hz,2H),1.34(t,J＝7.2Hz,3H)；MS(ESI)m/z467.0[M+1] +。
Embodiment 42
Compound of the present invention suppresses experiment and the Activity Results of spleen tyrosine kinase (Syk).
To the substituted styrene compound of synthesis, choose spleen tyrosine kinase (Syk), carry out inhibit activities test, (heterocyclic substituted styrene compound is to the inhibit activities data (IC of spleen tyrosine kinase (Syk) for activity data such as table 1 50, nM)) shown in, find that 18 the compounds of this invention have stronger inhibit activities to Syk altogether, wherein half effective inhibition concentration IC 50the active compound of <2 μM has 8, half effective inhibition concentration 2 μMs of <IC 50the active compound of <10 μM has 10.Specifically ask for an interview table 1..
Table 1.
As can be seen from Table 1, the heterocyclic substituted Styryl compounds major part with general structure I of the present invention has very strong Syk inhibit activities, illustrates that compound of the present invention can develop into the rheumatoid arthritis treatment medicine of syk inhibitor class.
The possibility that industry utilizes
Substituted styrene compound molecular structure of the present invention is comparatively simple, preparation technology is succinct, production cost is low, with the closely-related spleen tyrosine kinase of rheumatoid arthritis (Syk) Inhibition test in all demonstrate stronger inhibit activities, being therefore expected to be developed to special efficacy must treat medicine for treating rheumatoid arthritis.

Claims (14)

1. a heterocyclic substituted styrene compound, it is compound shown in formula I or its pharmaceutically acceptable salt:
In formula I: R 1for C 1~ C 4alkoxyl group; R 2for halogen; Ar is 6 yuan of aromatic ring yls or 6 yuan of hetero-aromatic ring bases, or replace 6 yuan of aromatic ring yls or 6 yuan of hetero-aromatic ring bases; A is group shown in formula III or formula IV:
Wherein, 6 yuan of aromatic ring yls of described replacement or the substituting group of 6 yuan of hetero-aromatic ring bases are selected from: halogen, C 1~ C 6alkyl, C 1~ C 6alkoxyl group ,-COOH or-COOR 4in one or two or more kinds, substituent number is the integer of 1 ~ 3;
Heteroatoms contained by described 6 yuan of hetero-aromatic ring bases is N, O and/or S, and contained heteroatomic number is 1-3;
R 4for C 1~ C 4alkyl; In group shown in formula II ~ IV, curve mark is for replacing position.
2. heterocyclic substituted styrene compound as claimed in claim 1, is characterized in that, described heterocyclic substituted styrene compound is compound shown in formula I-1 or formula I-2 or its pharmaceutically acceptable salt:
3. heterocyclic substituted styrene compound as claimed in claim 1 or 2, is characterized in that, wherein R 1for C 1~ C 3alkoxyl group.
4. heterocyclic substituted styrene compound as claimed in claim 3, is characterized in that, wherein R 1for oxyethyl group.
5. heterocyclic substituted styrene compound as claimed in claim 1 or 2, it is characterized in that, wherein Ar is phenyl, substituted-phenyl, 6 yuan of hetero-aromatic ring bases, or replaces 6 yuan of hetero-aromatic ring bases;
Wherein, the substituting group of described substituted-phenyl and replacement 6 yuan of hetero-aromatic ring bases is selected from: halogen, C 1~ C 6alkyl, C 1~ C 6alkoxyl group ,-COOH, or-COOR 4in one or two or more kinds, substituent number is the integer of 1 ~ 3;
Described 6 yuan of hetero-aromatic ring bases and the heteroatoms replaced contained by 6 yuan of hetero-aromatic ring bases are N, O and/or S, and contained heteroatomic number is 1-3; R 4for C 1~ C 4alkyl.
6. heterocyclic substituted styrene compound as claimed in claim 5, it is characterized in that, wherein Ar is phenyl, substituted-phenyl, 6 yuan of hetero-aromatic ring bases, or replaces 6 yuan of hetero-aromatic ring bases;
Wherein, the substituting group of described substituted-phenyl and replacement 6 yuan of hetero-aromatic ring bases is selected from: halogen, C 1~ C 3alkyl, C 1~ C 3alkoxyl group ,-COOH, or ester group-COOR 4in one or two or more kinds, substituent number is the integer of 1 ~ 3;
R 4for C 1~ C 3alkyl.
7. heterocyclic substituted styrene compound as claimed in claim 6, it is characterized in that, wherein Ar is the phenyl of phenyl, halogen substiuted, the phenyl that methyl or methoxy replaces ,-COOH or-COOCH 3the phenyl replaced or pyridyl.
8. heterocyclic substituted styrene compound as claimed in claim 7, it is characterized in that, the phenyl of wherein said halogen substiuted is 2,3-dichlorophenyl, 2,4 dichloro benzene base, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,5-trichlorophenyl or 2,3,6-trichlorophenyl.
9. heterocyclic substituted styrene compound as claimed in claim 7, is characterized in that, the phenyl that wherein said methyl or methoxy replaces is 3,5-3,5-dimethylphenyl or 3,4,5-trimethoxyphenyl.
10. heterocyclic substituted styrene compound as claimed in claim 7, is characterized in that, wherein said-COOH or-COOCH 3the phenyl replaced is: to carboxyl or ester group phenyl, described ester group is-COOCH 3; Described pyridyl is 2-pyridyl.
11. as claim 4, 8, heterocyclic substituted styrene compound described in 9 or 10, it is characterized in that, described heterocyclic substituted styrene compound is: 2-[the bromo-4-oxyethyl group of 3--5-(2, 4-dichloro-benzyloxy)-α-tolylene]-2H-benzo [b] [1, 4] oxazole-3 (4H)-one, 4-[the bromo-6-oxyethyl group of 2--4-(3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazole-2-methylene radical)-Phenoxymethyl] methyl benzoate, 4-[the bromo-6-oxyethyl group of 2--4-(3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazole-2-methylene radical)-Phenoxymethyl] phenylformic acid, 2-[the bromo-5-oxyethyl group of 3--4-(pyridine-2-methoxyl group)-α-tolylene]-2H-benzo [b] [1, 4] oxazole-3 (4H)-one, 4-[the bromo-5-of 2-oxyethyl group-3-(3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazole-2-methylene radical)-Phenoxymethyl] methyl benzoate, 4-[the bromo-5-of 2-oxyethyl group-3-(3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazole-2-methylene radical)-Phenoxymethyl] phenylformic acid, 2-[the bromo-4-oxyethyl group of 3--5-(pyridine-2-methoxyl group) α-tolylene]-2H-benzo [b] [1, 4] oxazole-3 (4H)-one, 2-[the bromo-4-oxyethyl group of 3--5-(2, 4-dichloro-benzyloxy)-α-tolylene]-2H-benzo [b] [1, 4] oxazole-3 (4H)-one, 4-[the bromo-6-oxyethyl group of 2--4-(3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazole-2-methylene radical)-Phenoxymethyl] methyl benzoate, 4-[the bromo-6-oxyethyl group of 2--4-(3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazole-2-methylene radical)-Phenoxymethyl] phenylformic acid, 2-[the bromo-5-oxyethyl group of 3--4-(pyridine-2-methoxyl group)-α-tolylene]-2H-benzo [b] [1, 4] oxazole-3 (4H)-one, 4-[the bromo-5-of 2-oxyethyl group-3-(3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazole-2-methylene radical)-Phenoxymethyl] methyl benzoate, 4-[the bromo-5-of 2-oxyethyl group-3-(3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazole-2-methylene radical)-Phenoxymethyl] phenylformic acid, or 2-[the bromo-4-oxyethyl group of 3--5-(pyridine-2-methoxyl group) α-tolylene]-2H-benzo [b] [1, 4] oxazole-3 (4H)-one.
12. 1 kinds of pharmaceutical compositions, is characterized in that, described pharmaceutical composition comprises heterocyclic substituted styrene compound in claim 1 ~ 11 described in any one and pharmaceutically acceptable carrier and/or additive.
13. are preparing the application in antirheumatic as the heterocyclic substituted styrene compound in claim 1 ~ 11 as described in any one.
14. as claimed in claim 12 pharmaceutical composition preparing the application in spleen tyrosine kinase (spleentyrosinekinase) inhibitor.
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