CN104447730A - Oxazolidinone compounds and application thereof to drugs - Google Patents

Oxazolidinone compounds and application thereof to drugs Download PDF

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Publication number
CN104447730A
CN104447730A CN201410740292.2A CN201410740292A CN104447730A CN 104447730 A CN104447730 A CN 104447730A CN 201410740292 A CN201410740292 A CN 201410740292A CN 104447730 A CN104447730 A CN 104447730A
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compound
methyl
acid
salt
purposes
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CN104447730B (en
Inventor
郑金付
文亮
张瑾
吴守涛
袁小凤
林润锋
王晓军
左应林
张英俊
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

Abstract

The invention relates to oxazolidinone compounds and an application thereof to preparation of drugs for preventing and treating thromboembolic diseases and in particular relates to a compound shown in a general formula (I) or stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound. All the variables are defined in the specification. The invention also relates to an application of the compound shown in the general formula (I) or the stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound as drugs and in particular relates to an application of the substances as drugs for preventing and treating thromboembolic diseases.

Description

Oxazolidinone compounds and the application in medicine thereof
Technical field
The invention belongs to pharmaceutical field, be specifically related to a kind of Xin oxazolidinone compounds, pharmaceutical composition, and as preparing the purposes of medicine, particularly as purposes and the purposes being used for the treatment of thromboembolic disorders of the medicine for the preparation of factor Xa inhibitor.
Background technology
The main practical function of Xa factor of activation is by producing zymoplasm to the limited proteolysis of zymoplasm, and Xa factor is in occupation of central position in the final general path of blood coagulation, and it in connection with inherent with external activate mechanism.Zymoplasm produces the final serine protease in the path of fibrin clot.By forming Prothrombin Complex Concent-(Xa factor, factor Ⅴ, Ca 2+and phosphatide) amplify the generation of zymoplasm by its precursor.An Xa factor molecule can produce 138 prothrombin molecule (Elodi, a., Varadi, K.:Optimization ofconditions for the catalytic effect of the factor IXa – factor VIII complex:Probable role of the complex in theamplification of blood coagulation.Thromb.Res.1979,15,617-629), so suppress in the interference in blood coagulation system Xa factor may be more effective than making thrombin inactivation.
Therefore, effective and special Xa factor inhibitor is needed to be used as potential valuable therapeutical agent to treat thromboembolic disorders.The present invention relates to new Xa factor inhibitor, preferably there is the pharmacological characteristics of improvement, more preferably there is higher Xa factor inhibit activities and better selectivity, and/or preferably there is the characteristic of following advantage and improvement, but be not limited to, pharmacy characteristic is (as solubleness, perviousness and the adaptability to Sustained-release formulations), volume requirements (as lower dosage and/or dosage once a day), reduce with the factor (as clearance rate and/or volume of distribution) of the haemoconcentration of peak valley sign, increase the factor of active agent concentration (as protein binding, volume of distribution), reduce the factor (as cytochrome P 450 enzymes suppresses or induction) of the tendency of clinical medicine interphase interaction, reduce the factor of the possibility of adverse side effect (as the pharmacology selectivity outside serine protease, possible chemistry or metabolic reaction, and limited CNS perviousness) and improve production cost or feasibility factor (as synthesis difficulty, the number of chiral centre, the simplicity of chemical stability and operation).
Summary of the invention
The invention provides Yi Zhong oxazolidinone compounds, or its pharmaceutical composition, can effectively treat the thrombotic disease relevant to supressor Xa.
On the one hand, the present invention relates to Yi Zhong oxazolidinone compounds, have such as formula the compound shown in (I), or the steric isomer of formula (I) compound, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein, Q is O or-CH 2-;
R is following minor structure:
condition is Q when being O, and R is not
Wherein each X 1be-CH independently 2-or-C (=O)-;
Each Y is-CH independently 2-,-O-or-NR 4-, wherein R 4for hydrogen, methyl or ethyl;
Each m is 0 or 1 independently;
X is hydrogen, fluorine, chlorine, bromine or iodine;
R 2for C 1-3alkyl or C 1-3alkoxyl group;
R 3for hydrogen, C 1-3alkyl or C 1-3alkoxyl group;
Each n 1and n 2be 1,2 or 3 independently; With
N is 0,1,2 or 3.
In some embodiments,
R 2for methyl, methoxyl group, oxyethyl group or positive propoxy; With
R 3for hydrogen, methyl, methoxyl group, oxyethyl group or positive propoxy.
The present invention relates to following one of them compound or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug,
On the one hand, present invention also offers a kind of pharmaceutical composition containing compound of the present invention, this pharmaceutical composition contains compound of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
On the other hand, the present invention relates to described compound or the described pharmaceutical composition purposes in the medicine of preparation, prevention, process or treatment thrombotic disease.
In certain embodiments, purposes of the present invention, wherein said thrombotic disease is myocardial infarction, stenocardia, to block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis again.
In certain embodiments, purposes of the present invention is described compound or the described pharmaceutical composition purposes for the preparation of the medicine for the treatment of disseminated inravascular coagulation (DIC).
In further embodiments, purposes of the present invention is described compound or the described pharmaceutical composition purposes for the preparation of the medicine of supressor Xa.
The present invention relates to the preparation of the compound that (I) comprises, the method for abstraction and purification on the other hand.
The present invention comprises the application of the compounds of this invention and pharmacy acceptable salt thereof, for the production of pharmaceutical prod treatment patient thrombotic disease, comprises the disease that those are described in the invention.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula (I) and the pharmaceutically acceptable carrier of at least one, vehicle, thinner, assistant agent, the effective therapeutic dose needed for vectorial combination.The present invention comprises the disease effectively suppressing osteoporosis equally, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises the representative compound of use formula (I) is treated patient.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.Term " pharmaceutically acceptable " comprises material or composition must be applicable to chemistry or toxicology, relevant with the Mammals be used for the treatment of with other components of composition preparation.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxysuccinic acid, Lactic acid Citric Acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or their combination.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide, ammonium, N +(R 14) 4salt and alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, N +(R 14) 4salt, as R 14h, C 1-4alkyl, C 6-10aryl, C 6-10aryl C 1-4alkyl etc., and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.Also suitable, nontoxic ammonium is comprised, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Circumstantial letter of the present invention
Definition and general terms
Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.
Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.
Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can with reference to " Organic Chemistry ", ThomasSorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley & Sons, description in New York:2007, its full content is incorporated to herein by reference.
Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, such as, also refer to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.
Term used in the present invention " patient " refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.
At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.
The term " alkyl " that the present invention uses comprises the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkyl can independently optionally replace by one or more substituting group described in the invention.Some of them embodiment is, alkyl group contains 1-10 carbon atom, other embodiment is, alkyl group contains 1-8 carbon atom, and other embodiment is, alkyl group contains 1-6 carbon atom, other embodiment is, alkyl group contains 1-4 carbon atom, and other embodiment is, alkyl group contains 1-3 carbon atom.Alkyl group further example comprises, but is not limited to, methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), 2-methyl-propyl or isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), 1-methyl-propyl or sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3) etc.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom.The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH 3), oxyethyl group (EtO ,-OCH 2cH 3), 1-propoxy-(n-PrO, n-propoxy-,-OCH 2cH 2cH 3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH 3) 2) etc.
Term " halogen " or " halogen atom " refer to F, Cl, Br or I.
Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of theA.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphates andPhosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary ofChemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry ofOrganic Compounds ", John Wiley & Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, enantiomer, atropisomer, and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
" steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer, etc.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can be transformed mutually by low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) comprises the change by proton shifting, as the isomerization of keto-enol and imine-enamine.Valence (valency) tautomer comprises the change reassembling into bonding electron.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66:1-19, described in 1977..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, malate, 2 hydroxy propanoic acid salt, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Time term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
In addition, compound disclosed by the invention, comprise their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, DMSO, etc.).Compound is come into the open in the present invention can with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of non-solvation.
Any structural formula that the present invention provides is also intended to represent these compounds not by the form of the form of isotopic enrichment and isotopic enrichment.The compound of isotopic enrichment has the structure of the general formula description that the present invention provides, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number.The Exemplary isotopes can introduced in the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as 2h, 3h, 11c, 13c, 14c, 15n, 17o, 18o, 18f, 31p, 32p, 35s, 36cl and 125i.
On the other hand, such as, wherein there is radio isotope in the compound that the present invention that compound of the present invention comprises isotopic enrichment defines, as 3h, 14c and 18those compounds of F, or wherein there is non radioactive isotope, as 2h and 13c.The compound of such isotopic enrichment can be used for metabolism research and (uses 14c), reaction kinetics research (uses such as 2h or 3h), detect or imaging technique, as positron emission tomography (PET) or the SPECT (single photon emission computed tomography) (SPECT) comprising medicine or substrate tissue measure of spread, or can be used in the radiotherapy of patient. 18the compound of F enrichment is desirable especially for PET or SPECT research.Use suitable isotope labeling reagent to substitute original used unmarked reagent described by embodiment in the routine techniques that shown in the formula (I) of isotopic enrichment, compound can be familiar with by those skilled in the art or the present invention and preparation process to prepare.
In addition, particularly deuterium is (that is, for higher isotope 2h or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index improves brings.Should be appreciated that the deuterium in the present invention is seen as the substituting group of formula (I) compound.The concentration of such higher isotope particularly deuterium can be defined by the isotopic enrichment factor.Term used in the present invention " the isotopic enrichment factor " refers to specified ratio between isotopic isotopic abundance and natural abundance.If the substituting group of the compounds of this invention is designated as deuterium, this compound has at least 3500 (each deuterium at D atom place 52.5% of specifying mixes) to each D atom of specifying, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), the isotopic enrichment factor of at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).It can be the such as D that isotropic substance replaces that the pharmaceutically useful solvate of the present invention comprises wherein recrystallisation solvent 2o, acetone-d 6, DMSO-d 6those solvates.
The compounds of this invention and pharmaceutical composition, preparation and purposes
According to another aspect, the feature of pharmaceutical composition of the present invention comprises the compound shown in formula (I), the compound listed by the present invention, or the compound of embodiment 1-7, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, patient's thrombotic disease can be treated or be alleviated to the amount of compound or effectively as Xa factor inhibitor.
There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can directly or indirectly according to other any adducts or derivatives of needing administration of patient, the compound described by other aspects of the present invention, its meta-bolites or his residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, assistant agent further, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As with described by Publication about Document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, LippincottWilliams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Except carrier medium and the inconsistent scope of compound of the present invention of any routine, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycol compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleate and Ethyl Lauroyl acid esters, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, isotonic salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.
The compounds of this invention can be applied with the form of oral preparation, as tablet, and capsule (wherein each comprises the formula of sustained release or time controlled released), pill, pulvis, granula, elixir, tincture, suspension agent, syrup, and emulsifying agent.They also can with intravenously (bolus or transfusion), intraperitoneal, and subcutaneous or intramuscular form is used, and the dosage form of all uses is all known by the those of ordinary skill of pharmaceutical field.They can be used separately, but generally select to use together with a kind of pharmaceutical carriers by based on selected method of application and the pharmacy practice of standard.
The dosage regimen of the compounds of this invention by different with known various factors, as the characteristics of pharmacokinetics of particular agent and pattern thereof and route of administration; The race of recipient, age, sex, healthy state, medical conditions and body weight; The nature and extent of symptom; The kind of parallel treatment; The frequency for the treatment of; The approach of dispenser, the kidney of patient and liver function, and the effect that hope reaches.A doctor or animal doctor can make decision and the medicine being with effective amount prevents, offsets or stop the development of thromboembolic disorders.
According to general governing principle, in order to reach the effect of specifying, each activeconstituents used day oral dosage scope be about 0.001 between 1000mg/kg body weight, preferably, between about 0.01 to 100mg/kg body weight.And, most preferably, between about 1.0 to 20mg/kg body weight/day.Use for intravenous, in the infusion process of conventional rate most preferred dosage range be about 1 to about 10mg/kg body weight/minute.The compounds of this invention can to use once a day, or can with every day at twice, use for three times or four times.
Compound of the present invention can use through the local of suitable nasal carrier and use with intranasal form, or uses with cutaneous routes through the subsides of skin medicine by using.When using with the form of transdermal delivery system, the dosage used during whole medication is continuous print instead of interval.
Typically, this compound and the suitable pharmaceutical diluents selected according to the form used and conventional pharmacy practice, vehicle, or carrier (referring to pharmaceutical carriers at this) is mixed to be used, and method of application can be oral tablet, capsule, elixir, syrup etc.
Such as, use for tablet or capsules per os, active medicine component can combine, as lactose with a kind of oral, atoxic, pharmaceutically acceptable inert carrier, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Si Liaodengji dicalcium phosphate feed grade, calcium sulfate, N.F,USP MANNITOL, sorbyl alcohol etc.; For Orally administered in liquid form, oral drug components can with any oral, atoxic, pharmaceutically acceptable inert carrier combine, as ethanol, glycerine, water etc.And, when needs or required time, suitable tackiness agent, slipping agent, decomposing agents and tinting material also can join in mixture.Suitable tackiness agent comprises starch, gelatin, natural sugar as glucose or beta lactose, corn sweetener, natural gum that is natural and synthesis as gum arabic, tragacanth, or sodiun alginate, carboxymethyl cellulose, polyethylene glycol, wax etc.The lubricant applied in these formulations comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc.Decomposition agent includes, but not limited to starch, methylcellulose gum, agar, wilkinite, xanthan gum, etc.
The compounds of this invention also can be used with the form of liposomal delivery system, as the vesica of little individual layer, and the vesica of large individual layer and multilamellar vesicle.Liposome can be formed by different phosphatide, as cholesterol, and stearylamine, or phosphatidylcholine.
The compounds of this invention also with the polymkeric substance coupling of solubility, this polymer is as the pharmaceutical carriers of target.Such polymer comprises polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl methacrylate amine-phenol, poly-hydroxyethyl l-asparagine phenol, or with polyethylene oxide-polylysine that palmitoyl residues replaces.And, the compounds of this invention can with a class Biodegradable polymeric coupling, for completing controllable drug release, such as, poly(lactic acid), polyglycolic acid, the multipolymer of poly(lactic acid) and polyglycolic acid, poly epsilon caprolactone lactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate, and the crosslinked or amphipathic blocking-up multipolymer of hydrogel.
Be suitable for the per unit dosage of the formulation (pharmaceutical composition) used, the activeconstituents of about 1mg to about 100mg can be contained.In these pharmaceutical compositions, the weight of activeconstituents generally will account for about 0.5-95% of the gross weight of composition.
Gelatine capsule can contain activeconstituents and powder carrier, as lactose, and starch, derivatived cellulose, Magnesium Stearate, stearic acid, etc.Similar thinner can be used to make compressed tablets.The product of Tablet and Capsula as sustainable release can be manufactured to be provided in the medicine of continuous release in for some time.The tablet of compression can add sugar-coat or wrap thin film to cover any offending taste and to make tablet and air exclusion, or adds that the bag of enteric solubility is optionally decomposed by gastrointestinal disturbances road.
Orally administered liquid dosage form can containing tinting material and food flavouring to improve the acceptance of patient.
Usually, water, a kind of suitable oil, salt solution, the dextrose (glucose) of hydration, and relevant sugar soln and glycol (as propylene glycol or polyoxyethylene glycol) are the Suitable carriers of parenteral solution.Without the water-soluble salt of solution preferably containing activeconstituents that enteron aisle is used, suitable stablizer, and buffer substances that may be necessary.Antioxidant is suitable stablizer, and as sodium bisulfite, S-WAT, or vitamins C, both also can combinationally use separately and also can use citric acid and its salt and EDETATE SODIUM salt.In addition, parenteral solution also contains sanitas, as geramine, and methyl-or propyl group-p-Hydroxybenzoate, and chlorobutanol.
Wherein compound of the present invention and other anti-freezing agent combination, such as, for every kg patient body weight, a kind of per daily dose can be the compound of the formula (I) of about 0.1 to 100mg and second antithrombotics of about 1 to 7.5mg.For a kind of Tabules, compound of the present invention can be generally that each dose unit has about 5 to 10mg, and the amount of the second anti-agglutinant is that each dose unit has approximately from 1 to 5mg.Wherein, other anti-freezing reagent specifically comprises, but be not limited to, Eliquis, razaxaban, Yi Dushaban, shellfish Qu Shaban, dabigatran, bemiparin, Enoxaparin Sodium, Tinzaparin sodium, Danaparoid sodium, piperylene sodium, nadroparin calcium, Ardeparin Sodium, Parnaparin Sodium etc.
According to general governing principle, the compounds of this invention and a kind of antiplatelet agent combination are used, general per daily dose can be that per kilogram patient body weight about 0.01 arrives the compound of the formula (I) of 25mg and the antiplatelet reagent of about 50 to 150mg, and preferably approximately 0.1 arrives the compound of the formula (I) of 1mg and the antiplatelet reagent of about 1 to 3mg.When compound and the thrombolytics combined administration of formula (I), general per daily dose can be the compound of per kilogram patient body weight about 0.1 to the formula (I) of 1mg, and under thrombolytics existent condition, compared with general dosage when using separately with thrombolytics, when thrombolytics is used together with the compound of formula (I), the dosage of thrombolytics can reduce about 70-80%.
When two or more aforesaid second therapeutical agents are used together with the compound of formula (I), usually, additional or the collaborative effect of therapeutical agent when considering co-administered, the amount of each component in typical per daily dose and typical formulation, relative to usual dosage when using separately, can decline to some extent.
Especially, when providing as a single dose unit, between the activeconstituents that there is combination, there is the possibility of chemical reaction.Due to this reason, when the compound of formula (I) and the second therapeutical agent are in a single dose unit during united, their compound method will make the minimize physical contact between activeconstituents (namely be, reduce), although active ingredient combinations is in a single dose unit.Such as, a kind of activeconstituents can be enteric coating bag quilt.By enteric coating bag by a kind of activeconstituents, likely not only make the contact between the activeconstituents of associating minimize, but also a kind of release in the gastrointestinal tract likely controlled in these compositions is not so that the one of these components discharge and discharge in small intestine under one's belt.It is further that activeconstituents a kind of also can superscribe the material affecting its sustained release in the gastrointestinal tract and can be used for the physical contact reduced between the activeconstituents of associating, the component of sustained release also can extraly with enteric coating bag by so that this composition only discharges in enteron aisle.Another method is also had to relate to the formula of associating product, a kind of polymer coating of lasting and/or enteric release of one of them component, and another component also uses polymer as a kind of HYDROXY PROPYL METHYLCELLULOSE (HPMC) of low viscosity rank or other suitable material bag quilt known in the field, to reach the object of further separate active ingredients.The reaction of polymer coating pair and other component defines a kind of obstruction additionally.
Once understanding present disclosure, these and other make the minimized method of contact between the component of associating product of the present invention be clearly for those skilled in the art, no matter they are used with single formulation or use with the form be separated, but be in the identical time or use in an identical manner.
The compound that the present invention relates to or its pharmaceutical salts or its hydrate can be effective to prevent, process, treat or alleviate patient's thrombotic disease, particularly effectively can treat myocardial infarction, stenocardia, block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis.
The general synthetic method of this compound
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, N,N-dimethylacetamide and sherwood oil are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3or DMSO-d 6for solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS being equipped with G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
Time (min) A(CH 3CN，0.1％HCOOH) B(H 2O，0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is evaluated by Agilent 1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
CDC13 deuterochloroform
DMSO dimethyl sulfoxide (DMSO)
DMSO-d 6deuterated dimethyl sulfoxide
CuI cuprous iodide
CH 3nH 2methylamine
EtOH ethanol
G gram
Mg milligram
Mol mole
Mmol mmole
H hour
ML milliliter
FXa factor Xa
HATU 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester
Mol, mole
MM mmole
μM micromole
Pos.ion positive ion
Neg.ion negative ion
ESI electron spray ionisation
M/z mass-charge ratio
PT plasma prothrombin time
The partial thromboplastin time of APTT activation
Synthetic schemes 1:
The method that target product 6a can be described by synthetic schemes 1 prepares, wherein X, X 1, Y and m have implication as described in the present invention.
Compound 1a and raw material 2a, at cuprous iodide, under part (as N, N'-dimethyl-ethylenediamine) and alkali (as salt of wormwood) exist, carries out linked reaction through high temperature in a solvent, obtains intermediate 3a; Intermediate 3a is under methylamine effect, and deprotection in ethanol, generates intermediate 4a; Intermediate 4a and sour 5a carries out condensation reaction and obtains target product 6a.
Synthetic schemes 2:
The method that target product 6b can be described by synthetic schemes 2 prepares, wherein X, X 1, Y and m have implication as described in the present invention.
Compound 1b and raw material 2a, at cuprous iodide, under part (as N, N'-dimethyl-ethylenediamine) and alkali (as salt of wormwood) exist, carries out linked reaction through high temperature in a solvent, obtains intermediate 3b; Intermediate 3b is under methylamine effect, and deprotection in ethanol, generates intermediate 4b; Intermediate 4b and sour 5a carries out condensation reaction and obtains target product 6b.
Embodiment
The following examples can the present invention will be further described, but these embodiments should as the restriction to scope of the present invention.
Embodiment 1:(R) the chloro-N-of-5-((2-oxo-3-(3-((2-oxo-piperidine-1-base) methyl) phenyl) oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
Step 1:1-(3-bromobenzyl) piperidines-2-ketone
Potassium hydroxide (3.36g, 60mmol) is dissolved in DMSO (10mL), at room temperature stirs 15 minutes.Add 2-piperidone (4.0g, 12mmol), tetrabutylammonium iodide (740mg, 2.0mmol) and 3-bromobenzyl bromine (2.5g, 10mmol), at room temperature stir 4 hours.Add water (20mL) cancellation reaction, extract by ethyl acetate (30mL × 3).Merge organic phase, saturated aqueous common salt (50mL) washs, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography (petrol ether/ethyl acetate (v/v)=1/1), obtains white solid (2.0g, 75.0%).
MS(ESI,pos.ion)m/z:268.1(M+1)。
Step 2:(S)-2-((2-oxo-3-(3-((2-oxo-piperidine-1-base) methyl) phenyl) oxazolidine-5-base) methyl) isoindoline-1,3-diketone
Under nitrogen protection; 1-(3-bromobenzyl) piperidines-2-ketone (4.45g is added successively in two mouthfuls of round-bottomed flasks of 50mL; 16.7mmol), (R)-2-((2-Yang Dai oxazolidine-5-base) methyl) isoindoline-1; 3-diketone (4.64g; 20mmol), salt of wormwood (6.91g; 50.1mmol), cuprous iodide (0.636g, 3.34mmol), N 1, N 2-dimethyl ethane-1,2-diamines (0.5mL, 3.34mmol) and Isosorbide-5-Nitrae-dioxane (20mL), be heated to 120 DEG C and stir 12 hours.Be chilled to room temperature, extract by ethyl acetate (30mL × 3).Merge organic phase, use water (20mL × 2), saturated aqueous common salt (40mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains white solid (6.2g, 86%).
MS(ESI,pos.ion)m/z:434.2(M+1).
Step 3:(S)-5-(amino methyl)-3-(3-((2-oxo-piperidine-1-base) methyl) phenyl) oxazolidine-2-ketone
By methylamine (40% aqueous solution, 8.0mL) join (S)-2-((2-oxo-3-(3-((2-oxo-piperidine-1-base) methyl) phenyl) oxazolidine-5-base) methyl) isoindoline-1,3-diketone (430mg, in ethanol (20mL) solution 1.4mmol), be heated to return stirring 1.5 hours.Pressure reducing and steaming solvent, thick product directly throws next step.
Step 4:(R) the chloro-N-of-5-((2-oxo-3-(3-((2-oxo-piperidine-1-base) methyl) phenyl) oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
5-chlorothiophene-2-formic acid (0.273g is added successively in two mouthfuls of round-bottomed flasks of 50mL, 1.68mmol), N, N-diisopropylethylamine (0.52mL, 2.8mmol), methylene dichloride (20mL), HATU (0.798g, 2.1mmol) with (S)-5-(amino methyl)-3-(3-((2-oxo-piperidine-1-base) methyl) phenyl) oxazolidine-2-ketone (0.424g, 1.4mmol).At room temperature stir 6 hours, extract with methylene dichloride (30mL × 2).Merge organic phase, use water (20mL × 2), saturated sodium bicarbonate (30mL) solution, saturated aqueous common salt (20mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains white solid (0.2g, 32%).
MS(ESI,pos.ion)m/z:448.1(M+1).
1H NMR(600MHz,CDCl 3)δ7.45(s,1H),7.39–7.33(m,2H),7.31(t,J＝7.8Hz,1H),7.02(d,J＝7.4Hz,1H),6.88(d,J＝3.9Hz,2H),4.87–4.82(m,1H),4.61(d,J＝14.9Hz,1H),4.57(d,J＝14.8Hz,1H),4.09(t,J＝8.7Hz,1H),3.89–3.80(m,2H),3.73–3.68(m,1H),3.24(t,J＝5.4Hz,2H),2.55–2.46(m,2H),1.80(s,4H).
Embodiment 2:(R) the chloro-N-of-5-((3-(the fluoro-5-of 3-((3-oxo-morpholine) methyl) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
The bromo-5-fluorophenyl of step 1:(3-) methyl alcohol
At 0 DEG C, in tetrahydrofuran (THF) (20mL) solution of the bromo-5-fluorobenzoic acid (4.38g, 20.0mmol) of 3-, slowly drip borine tetrahydrofuran complex tetrahydrofuran solution (30mL, 30.0mmol) of 1M.Stirring is continued 1.5 hours, then in stirred overnight at room temperature at 0 DEG C.At room temperature slowly add methyl alcohol wherein until without gas effusion cancellation.Pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=10/1), obtains weak yellow liquid (3.9g, 95%).
MS(ESI,pos.ion)m/z:186.90(M-17)
The bromo-3-of step 2:1-(brooethyl)-5-fluorobenzene
At 0 DEG C, in anhydrous methylene chloride (50mL) solution of (the bromo-5-fluorophenyl of 3-) methyl alcohol (3.9g, 19mmol), add phosphorus tribromide (3.6mL, 38mmol).Rise to stirred overnight at room temperature.Add water (40mL), extract with methylene dichloride (60mL × 3).Merge organic phase, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=40/1), obtains colorless oil (4.7g, 92%).
MS(EI)m/z::267.9(M).
Step 3:4-(the bromo-5-fluorophenyl of 3-) morpholine-3-ketone
At 0 DEG C, to the bromo-3-of 1-(brooethyl)-5-fluorobenzene (4.7g, 18mmol), morpholine-3-ketone (1.8g, 18mmol) with tetrabutylammonium iodide (320mg, the sodium hydride (1.4g, 35mmol) of 60% is added in tetrahydrofuran (THF) (50.0mL) solution 0.88mmol).At 0 DEG C, continue stirring 1 hour, rise to stirring at room temperature 4 hours.Add water (50mL), with ethyl acetate (60mL × 3) extraction, merge organic phase, with saturated aqueous common salt (40mL) washing, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=4/1), obtains pale yellow oil (1.50g, 30%).
MS(ESI,pos.ion)m/z:288.00(M+1).
Step 4:(R)-2-((3-(the fluoro-5-of 3-((3-oxo-morpholine) methyl) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) isoindoline-1,3-diketone
4-(the bromo-5-fluorophenyl of 3-) morpholine-3-ketone (1.5g is added successively in tube sealing, 5.2mmol), (R)-2-((2-Yang Dai oxazolidine-5-base) isoindoline-1,3-diketone (1.3g, 5.2mmol), N, N'-dimethyl-ethylenediamine (180mg, 2.1mmol), cuprous iodide (200mg, 1.05mmol), salt of wormwood (2.2g, 16mmol) He 1,4-dioxane (20mL), under nitrogen atmosphere, be heated to 120 DEG C stir 8 hours.Filter, filtrate decompression boils off solvent, and thick product, through column chromatography purification (methylene chloride/methanol (v/v)=100/1), obtains white solid (1.08g, 46%).
MS(ESI,pos.ion)m/z:454.10(M+1).
Step 5:(R)-4-(3-(5-(amino methyl)-2-Yang Dai oxazolidine-3-base)-5-fluorophenyl) morpholine-3-ketone
To (R)-2-((3-(the fluoro-5-of 3-((3-oxo-morpholine) methyl) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) isoindoline-1, the aqueous methylamine solution (3mL) of 40% is added in ethanol (30mL) solution of 3-diketone (1.08g, 2.38mmol).Be heated to 95 DEG C stir 1.5 hours, be chilled to room temperature, pressure reducing and steaming solvent, thick product is directly used in next step reaction without processing further.
Step 6:(R) the chloro-N-of-5-((3-(the fluoro-5-of 3-((3-oxo-morpholine) methyl) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
To (R)-4-(3-(5-(amino methyl)-2-Yang Dai oxazolidine-3-base)-5-fluorophenyl) morpholine-3-ketone (769mg, 2.38mmol) with 5-chlorothiophene-2-formic acid (464mg, HATU (1.36g is added in methylene dichloride (40mL) solution 2.86mmol), 3.57mmol) and N, N-diisopropylethylamine (829 μ L, 4.76mmol).Stirring at room temperature 6 hours.Pressure reducing and steaming solvent, adds methylene dichloride (50mL), and organic phase uses saturated sodium bicarbonate solution (30mL) to wash successively, and saturated aqueous common salt (30mL) washs, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtains faint yellow solid (290mg, 26%).
MS(ESI,pos.ion)m/z:468.05(M+1)；
1H NMR(400MHz,DMSO-d 6)δ8.96(t,J＝5.7Hz,1H),7.68(d,J＝4.0Hz,1H),7.39(d,J＝11.4Hz,1H),7.25(s,1H),7.19(d,J＝4.0Hz,1H),6.83(d,J＝9.0Hz,1H),4.90-4.78(m,1H),4.55(s,2H),4.17(t,J＝9.0Hz,1H),4.12(s,2H),3.88-3.79(m,3H),3.60(t,J＝5.5Hz,2H),3.27(t,J＝5.1Hz,2H).
The chloro-N-of embodiment 3:5-((5-oxo-1-(4-(3-oxo-morpholine) phenyl) pyrrolidin-3-yl) methyl) thiophene-2-carboxamide derivatives
Step 1:4-(methylol) pyrrolidin-2-one
At 0 DEG C, 5-pyrrolidone-3-methyl-formiate (5g, 34.931mmol) is dissolved in dry Virahol (80mL), add sodium borohydride (4.72g, 122.3mmol), stir after 2 hours at 0 DEG C, move to room temperature for overnight.Add methyl alcohol (20mL), pressure reducing and steaming solvent, thick product, through column chromatography purification (ethyl acetate/methanol (v/v)=10/1), obtains white solid (4.0g, 99.5%).
MS(ESI,pos.ion)m/z:116.1(M+1).
Step 2:2-((5-oxo-pyrrolidine-3-base) methyl) isoindoline-1,3-diketone
Triphenylphosphine (1.914g is added successively in two mouthfuls of round-bottomed flasks of 100mL, 7.30mmol), phthalic imidine (1.073g, 7.296mmol), tetrahydrofuran (THF) (40mL), 4-(methylol) pyrrolidin-2-one (0.70g, 6.08mmol), after being chilled to 0 DEG C, add diisopropyl azodiformate (1.475g, 7.296mmol, 1.437mL), mixture stirs after 1 hour and moves to stirred overnight at room temperature at 0 DEG C.Pressure reducing and steaming solvent, thick product, through column chromatography purification (ethyl acetate), obtains titled compound as white solid (1.16g, 78.1%).
MS(ESI,pos.ion)m/z:245.2(M+1).
Step 3:2-((5-oxo-1-(4-(3-oxo-morpholine) phenyl) pyrrolidin-3-yl) methyl) isoindoline-1,3-diketone
Under nitrogen protection; 2-((5-oxo-pyrrolidine-3-base) methyl) isoindoline-1 is added successively in the sealed can of 50mL; 3-diketone (0.55g; 2.25mmol), 4-(4-iodophenyl) morpholine-3-ketone (1.09g; 3.60mmol), salt of wormwood (0.943g; 6.76mmol), cuprous iodide (0.129g, 0.676mmol), N 1, N 2-dimethyl ethane-1,2-diamines (0.07mL, 0.676mmol) and Isosorbide-5-Nitrae-dioxane (20mL), be heated to 125 DEG C and stir 12 hours.Be chilled to room temperature, extract by ethyl acetate (30mL × 3).Merge organic phase, use water (20mL × 2), saturated aqueous common salt (40mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains titled compound as white solid (0.7g, 70%).
MS(ESI,pos.ion)m/z:420.1(M+1).
Step 4:4-(4-(4-(amino methyl)-2-oxo-pyrrolidine-1-base) phenyl) morpholine-3-ketone
By methylamine (40% aqueous solution, 5.0mL) join 2-((5-oxo-1-(4-(3-oxo-morpholine) phenyl) pyrrolidin-3-yl) methyl) isoindoline-1,3-diketone (0.7g, in ethanol (20mL) solution 2.0mmol), be heated to 95 DEG C and stir 1.5 hours.Pressure reducing and steaming solvent, thick product directly throws next step.
The chloro-N-of step 5:5-((5-oxo-1-(4-(3-oxo-morpholine) phenyl) pyrrolidin-3-yl) methyl) thiophene-2-carboxamide derivatives
2-chlorothiophene-5-formic acid (0.488g is added successively in two mouthfuls of round-bottomed flasks of 100mL, 3.0mmol), N, N-diisopropylethylamine (0.99mL, 6.0mmol), methylene dichloride (50mL), HATU (1.529g, 3.9mmol) with 4-(4-(4-(amino methyl)-2-oxo-pyrrolidine-1-base) phenyl) morpholine-3-ketone (0.386g, 1.33mmol).At room temperature stir and spend the night, extract with methylene dichloride (30mL × 2).Merge organic phase, use water (20mL × 2), saturated sodium bicarbonate (30mL) solution, saturated aqueous common salt (20mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains titled compound as white solid (0.5g, 40%).
MS(ESI,pos.ion)m/z:434.1(M+1).
1H NMR(600MHz,CDCl 3)δ7.61(d,J＝8.7Hz,2H),7.36(d,J＝3.8Hz,1H),7.33(t,J＝5.8Hz,1H),7.28(d,J＝8.4Hz,2H),6.89(d,J＝3.8Hz,1H),4.35(s,2H),4.06(t,J＝4.9Hz,2H),3.88–3.82(m,1H),3.78–3.72(m,2H),3.58(dd,J＝9.7,4.4Hz,1H),3.43–3.36(m,1H),3.30(dt,J＝13.7,6.8Hz,1H),2.75–2.65(m,2H),2.29(dd,J＝16.2,4.7Hz,1H).
Embodiment 4:(S, Z) the chloro-N-of-5-((3-(4-(cyclopentyl (methoxyimino) methyl) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
Step 1: cyclopentyl (4-nitrophenyl) methyl alcohol
At nitrogen atmosphere and-78 DEG C, in anhydrous tetrahydro furan (20mL) solution of 4-nitrobenzaldehyde (2g, 13.23mmol), drip cyclopentyl magnesium chloride diethyl ether solution (12.4mL, 24.8mmol) of 2M.Rise to stirring at room temperature 3 hours.Then add saturated ammonium chloride (20mL) cancellation, aqueous phase ethyl acetate (10mL × 3) extraction, merges organic phase, with saturated aqueous common salt (20mL) washing, and anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification, obtains (640mg, 21.8%).
MS(ESI,pos.ion)m/z:222(M+1).
Step 2: cyclopentyl (4-nitrophenyl) ketone
Water and the concentrated sulfuric acid solution of chromium trioxide is slowly added in the acetone soln of the cyclopentyl be chilled to (4-nitrophenyl) methyl alcohol (640mg, 2.89mmol).Stir after 1 hour at 4 DEG C, add water dissolution, filter the salt that dechromises, filtrate chloroform extraction.Pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=2/1), obtains white solid (538mg, 85%).
MS(ESI,pos.ion)m/z:220(M+1).
Step 3:(4-aminophenyl) (cyclopentyl) ketone
In water (5mL) solution of iron (1g, 17.9mmol), slowly add hydrochloric acid (1mL), be heated to 65 DEG C and stir 15 minutes.Incline and solvent, add methyl alcohol (10mL) solution of cyclopentyl (4-nitrophenyl) ketone (538mg, 2.45mmol) wherein, with hcl acidifying to pH 2-3, be heated to 65 DEG C and stir 2 hours.Be chilled to room temperature, add triethylamine (2mL), filter, filtrate decompression boils off solvent.Thick product, through column chromatography purification, obtains yellow solid (260mg, 56.0%).
MS(ESI,pos.ion)m/z:190(M+1).
Step 4:(4-(pentamethylene formyl radical) phenyl) Urethylane.
DIPEA (500 μ L, 3.1mmol) is slowly added in methylene dichloride (10mL) solution of (4-aminophenyl) (cyclopentyl) ketone (260mg, 1.36mmol).After stirring at room temperature 15 minutes, slowly drip methyl-chloroformate (130 μ L, 1.65mmol) wherein.After dripping, then stir 1 hour, suction filtration, solid with methylene chloride washs, and thick product is through column chromatography purification, and obtaining title compound is white solid (270mg, 79.5%)
MS(ESI,pos.ion)m/z:248(M+1).
Step 5:(Z)-(4-(pentamethylene base (methoxyimino) methyl) phenyl) Urethylane
(4-(pentamethylene formyl radical) phenyl) Urethylane (270mg is added successively in round-bottomed flask; 1.09mmol), methoxyl group amine salt hydrochloride (100mg; 1.20mmol), sodium sulfate (200mg; 1.41mmol), pyridine (0.5mL) and methyl alcohol (10mL), react completely to TLC monitoring in stirring at room temperature.Pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains title (162mg, 53.7%).
MS(ESI,pos.ion)m/z:277(M+1).
Step 6:(S, Z) the chloro-N-of-5-((3-(4-(cyclopentyl (methoxyimino) methyl) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
At nitrogen atmosphere and-78 DEG C, to (Z)-(4-(pentamethylene base (methoxyimino) methyl) phenyl) Urethylane (160mg, the hexane solution (84 μ L, 1.34mmol) of the n-Butyl Lithium of 1.6M is dripped in anhydrous tetrahydro furan (10mL) solution 0.579mmol).At-78 DEG C, continue stirring after 1.5 hours, drip tetrahydrofuran (THF) (5mL) solution of (R)-5-chloro-N-(oxyethane-2-ylmethyl) thiophene-2-carboxamide derivatives (189mg, 0.868mmol) wherein.At-78 DEG C, continue stirring after 2 hours, rise to stirred overnight at room temperature.Add saturated ammonium chloride (20mL) cancellation, with ethyl acetate (10mL × 3) extraction, merge organic phase, with saturated aqueous common salt (20mL) washing, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product is through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), and obtaining title compound is white solid (16mg, 6.0%).
MS(ESI,pos.ion)m/z:462(M+1)；
1HNMR(400MHz,CDCl 3)δ7.66-7.64(d,J＝8Hz,2H),7.60-7.58(d,J＝8Hz,1H),7.47-7.45(d,J＝8Hz,1H),7.16-7.13(dd,J＝6Hz,1H),6.88-6.86(d,J＝8Hz,1H),6.22(m,1H),4.78-4.77(m,1H),4.54-4.51(m,,1H),4.36-4.35(m,,1H),3.94(s,1H)3.92–3.87(m,1H),3.78(s,1H),3.48-3.43(m,1H),1.64-1.62(m,1H),1.61-1.59(m,8H).
Embodiment 5:(S) the chloro-N-of-5-((3-(4-(3-methoxyl group trimethylene oxide-3-base) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
Step 1:3-(4-nitro) oxa-ring fourth-3-alcohol
At-78 DEG C, in anhydrous tetrahydro furan (120mL) solution of the iodo-4-oil of mirbane (10g, 40.16mmol) of 1-, add the hexane solution (27.6mL, 44.18mmol) of 1.6M n-Butyl Lithium, stir 10 minutes.Slowly dripping anhydrous tetrahydro furan (10mL) solution of 3-oxetanone (2.88g, 40mmol) wherein, stirring 10 minutes, rising to room temperature.Add water (40mL), aqueous phase ethyl acetate (30mL × 3) extracts.Merge organic phase, with saturated aqueous common salt (40mL) washing, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product is through column chromatography purification, and obtaining title compound is white solid (1.1g, 12.8%)
MS(ESI,pos.ion)m/z:196.0(M+1).
Step 2:3-methoxyl group-3-(4-nitrophenyl) trimethylene oxide
At-5 DEG C, in tetrahydrofuran (THF) (20mL) solution of 3-(4-nitro) oxa-ring fourth-3-alcohol (2g, 10.25mmol), add the sodium hydride (740mg, 18.4mmol) of 60%.At-5 DEG C, continue stirring 1 hour, then add methyl iodide (750 μ L, 12.3mmol).Rise to stirred overnight at room temperature.Add water (30mL), aqueous phase ethyl acetate (20mL × 3) extracts.Merge organic phase, with saturated aqueous common salt (40mL) washing, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification, obtains white solid (1.75g, 82%).
MS(ESI,pos.ion)m/z:210.0(M+1).
Step 3:4-(3-methoxyl group trimethylene oxide-3-base) ammonia
Palladium/the carbon (500mg) of 10% is added in methyl alcohol (30mL) solution of 3-methoxyl group-3-(4-nitrophenyl) trimethylene oxide (1.75g, 8.37mmol).At H 2stir under atmosphere and spend the night.Filter, filtrate decompression boils off solvent, and obtaining title compound is white solid (1.3g, 87%)
MS(ESI,pos.ion)m/z:180.0(M+1).
Step 4:(4-(3-methoxyl group trimethylene oxide-3-base) phenyl) Urethylane
DIPEA (1.3g, 10.04mmol) is slowly added in methylene dichloride (10mL) solution of 4-(3-methoxyl group trimethylene oxide-3-base) ammonia (1.5g, 8.37mmol).After stirring at room temperature 15 minutes, slowly drip methyl-chloroformate (900mg, 10.4mmol) wherein.After dripping, then stir 1 hour, suction filtration, solid with methylene chloride washs, and thick product is through column chromatography purification, and obtaining title compound is white solid (1.18g, 56.2%).
Step 5:(R) the chloro-N-of-5-(oxyethane-2-ylmethyl) thiophene-2-carboxamide derivatives
The sodium hydride (160mg, 4.0mmol) of 60% is added, DMF (3mL) and 5-chlorothiophene-2-methane amide (400mg, 2.25mmol) in round-bottomed flask.Be heated to 60 DEG C be stirred to without gas generation, be chilled to room temperature, add (R)-2-(chloromethyl) oxyethane (300 μ L, 3.7mmol) wherein.Stirring at room temperature 12 hours.Add saturated ammonium chloride solution (2mL) cancellation, then add water (30mL), extract by ethyl acetate (20mL × 3).Merge organic phase, with saturated aqueous common salt (40mL) washing, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product is through column chromatography purification, and obtaining title compound is white solid (82mg, 14%).
1H NMR(400MHz,CDCl 3)δ7.37-7.36(d,2H),6.90-6.89(d,2H),4.85-4.78(m,1H),4.09-4.03(m,1H),3.87-3.70(m,3H),1.99(bar,1H)；
MS(ESI,pos.ion)m/z:218.0(M+1).
Step 6:(S) the chloro-N-of-5-((3-(4-(3-methoxyl group trimethylene oxide-3-base) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
At nitrogen atmosphere and-78 DEG C, to (4-(3-methoxyl group trimethylene oxide-3-base) phenyl) Urethylane (80mg, the hexane solution (0.42mL, 0.66mmol) of the n-Butyl Lithium of 1.6M is dripped in anhydrous tetrahydro furan (10mL) solution 0.33mmol).At-78 DEG C, continue stirring after 1.5 hours, drip tetrahydrofuran (THF) (5mL) solution of (R)-5-chloro-N-(oxyethane-2-ylmethyl) thiophene-2-carboxamide derivatives (81mg, 0.37mmol) wherein.At-78 DEG C, continue stirring after 2 hours, rise to stirred overnight at room temperature.Add saturated ammonium chloride (20mL) cancellation, with ethyl acetate (10mL × 3) extraction, merge organic phase, with saturated aqueous common salt (20mL) washing, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains titled compound as white solid (15mg, 10.5%).
MS(ESI,pos.ion)m/z:423.1(M+1)；
1H NMR(400MHz,CDCl 3)δ7.41-7.35(m,5H),6.93(bar,1H)；6.89-6.88(d,2H),4.96-4.95(m,1H)；4.93-4.91(d,2H),4.81-4.79(d,2H)；4.48-4.44(dd,1H),4.28-4.24(dd,1H),4.16-4.10(q,1H),3.89-3.83(q,1H),3.10(s,3H).
Embodiment 6:(S, E) the chloro-N-of-5-((3-(4-(3-(cyanoimino) morpholinyl) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
Step 1:4-(4-iodophenyl) morpholinyl-3-thioketones
In toluene (300mL) solution of 4-(4-iodophenyl) morpholinyl-3-ketone (9.7g, 32mmol), add lawesson reagent (6.5g, 16mmol), be heated to 100 DEG C and stir 3 hours.Be chilled to room temperature, extract by ethyl acetate (100mL × 2).Merge organic phase, use water (50mL × 2), saturated aqueous common salt (50mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (sherwood oil/methylene dichloride (v/v)=1/1), obtains titled compound as white solid (9.1g, 89%).
MS(ESI,pos.ion)m/z:320.0(M+1).
Step 2:4-(4-iodophenyl)-5-(methylthio group)-3,6-dihydro-2H-1,4-oxazine-4-iodide
Methyl iodide (16.5g, 116mmol) is added in acetonitrile (50mL) solution of 4-(4-iodophenyl) morpholinyl-3-thioketones (9.26g, 29.0mmol).At room temperature stir 2 hours.Pressure reducing and steaming solvent, thick product directly throws next step.
Step 3:(E)-N-(4-(4-iodophenyl) morpholinyl-3-subunit) cyanamide
4-(4-iodophenyl)-5-(methylthio group)-3 is added successively in the sealed can of 250mL, 6-dihydro-2H-1,4-oxazine-4-iodide (13.4g, 29.0mmol), acetonitrile (150mL), cyanamide (9.75g, 232mmol) with triethylamine (11.7g, 116mmol).Be heated to 85 DEG C stir 15 hours.Filter, filter cake acetonitrile wash, filtrate decompression boils off solvent, and thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains titled compound as white solid (7.2g, 76%).
MS(ESI,pos.ion)m/z:328.0(M+1).
Step 4:(R, E)-N-(4-(4-(5-(azido-methyl)-2-Yang Dai oxazolidine-3-base) phenyl) morpholinyl-3-subunit) cyanamide
Under nitrogen protection; (R)-5-(azido-methyl) oxazolidine-2-ketone (1.56g is added successively in the sealed can of 50mL; 11.0mmol), (E)-N-(4-(4-iodophenyl) morpholinyl-3-subunit) cyanamide (3.6g; 11.0mmol), salt of wormwood (4.56g; 33.0mmol), cuprous iodide (419mg, 2.2mmol), N 1, N 2-dimethyl ethane-1,2-diamines (388mg, 4.4mmol) and Isosorbide-5-Nitrae-dioxane (50mL), be heated to 120 DEG C and stir 4 hours.Be chilled to room temperature, extract by ethyl acetate (50mL × 3).Merge organic phase, use water (50mL × 2), saturated aqueous common salt (40mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/6), obtains titled compound as white solid (0.9g, 20%).
MS(ESI,pos.ion)m/z:342.15(M+1).
Step 5:(S, E)-N-(4-(4-(5-(amino methyl)-2-Yang Dai oxazolidine-3-base) phenyl) morpholine-3-subunit) cyanamide
By (R, E)-N-(4-(4-(5-(azido-methyl)-2-Yang Dai oxazolidine-3-base) phenyl) morpholinyl-3-subunit) cyanamide (0.09g, 0.26mmol) with triphenylphosphine (138mg, 0.526mmol) be dissolved in the mixing solutions of tetrahydrofuran (THF)/water (v/v)=10/1 (22mL), at room temperature stir 10 hours.Extract by ethyl acetate (30mL × 3).Merge organic phase, use water (20mL × 2), saturated aqueous common salt (40mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtains colorless oil title compound (83mg, 100%).
MS(ESI,pos.ion)m/z:316.2(M+1).
Step 6:(S, E) the chloro-N-of-5-((3-(4-(3-(cyanoimino) morpholinyl) phenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
2-chlorothiophene-5-formic acid (0.496g is added successively in two mouthfuls of round-bottomed flasks of 50mL, 3.05mmol), N, N-diisopropylethylamine (1.74mL, 10.2mmol), methylene dichloride (30mL), HATU (1.45g, 3.81mmol).At room temperature stir after 1 hour and add (S, E)-N-(4-(4-(5-(amino methyl)-2-Yang Dai oxazolidine-3-base) phenyl) morpholine-3-imino-) cyanamide (0.803g, 2.55mmol).At room temperature stir 6 hours, extract with methylene dichloride (30mL × 2).Merge organic phase, use water (20mL × 2), saturated aqueous common salt (20mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtains compound as white solid (0.078g, 6.7%).
MS(ESI,pos.ion)m/z:460.0(M+1)；
1H NMR(600MHz,DMSO-d 6)δ8.98(t,J＝5.7Hz,1H),7.69(d,J＝4.0Hz,1H),7.62(d,J＝8.9Hz,2H),7.41(d,J＝8.9Hz,2H),7.20(d,J＝4.0Hz,1H),4.86(td,J＝11.2,5.8Hz,1H),4.73(s,2H),4.21(t,J＝8.9Hz,1H),4.04(t,J＝5.0Hz,2H),3.87(dd,J＝9.0,6.1Hz,1H),3.71(t,J＝4.9Hz,2H),3.62(dd,J＝14.4,8.2Hz,2H).
Embodiment 7:(S) the chloro-N-of-5-((3-(4-(1,1-dioxothiochromane-6-base) phenyl)-2-oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
Step 1:(R)-2-(2-hydroxyl-3-((4-iodophenyl) is amino) propyl group) isoindoline-1,3-ketone
(S)-2-(oxyethane-2-ylmethyl) isoindoline-1 is added successively in round-bottomed flask, 3-diketone (2.0g, 9.84mmol), 4-Iodoaniline (2.2g, 10.0mmol), ethanol (90mL) and water (10mL), be heated to 100 DEG C and stir 12 hours.Product is settled out from solution.Precipitation suction filtration, filter cake washed with diethylether, vacuum-drying.Merge mother liquor, pressure reducing and steaming solvent, (S)-2-(oxyethane-2-ylmethyl) isoindoline-1 is added again in residue, 3-diketone (1.0g, 4.92mmol), ethanol (90mL) and water (10mL), gained mixture is heated to 100 DEG C and stirs 12 hours.Refilter, filter cake washed with diethylether, vacuum-drying.That merge and dry filter cake is title compound is white solid (3.6g, 84.9%).
1H NMR(CDCl 3,400MHz)δ7.85-7.88(m,2H),7.38-7.77(m,2H),7.41(d,J＝8.8Hz,2H),6.48(d,J＝8.8Hz,2H),4.11-4.16(m,1H),3.90(d,J＝5.0Hz,2H),3.13-3.27(m,2H).
Step 2:(S)-2-((3-(4-iodophenyl)-2-Yang Dai oxazolidine-5-base) methyl) isoindoline-1,3-diketone
N is added, N in tetrahydrofuran (THF) (90mL) solution of (R)-2-(2-hydroxyl-3-((4-iodophenyl) is amino) propyl group) isoindoline-1,3-ketone (3.4g, 8.05mmol) 'the DMAP of-carbonyl dimidazoles (2.6g, 16.0mmol) and catalytic amount.Be heated to 60 DEG C stir 12 hours, then add N, N '-carbonyl dimidazoles (2.6g, 16.0mmol), stirs 12 hours again at 60 DEG C.Precipitation suction filtration, tetrahydrofuran (THF) washs, vacuum-drying.Merge mother liquor, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=2/1), obtains white solid (3.0g, 83.1%).
1H NMR(CDCl 3,400MHz)δ7.87-7.89(m,2H),7.52-7.77(m,2H),7.66(d,J＝8.8Hz,2H),7.30(d,J＝8.8Hz,2H),4.96-5.00(m,1H),4.07-4.17(m,2H),3.87-4.00(m,2H).
Step 3:(S)-5-(amino methyl)-3-(4-iodophenyl) oxazolidine-2-ketone
To (S)-2-((3-(4-iodophenyl)-2-Yang Dai oxazolidine-5-base) methyl) isoindoline-1, the aqueous methylamine solution (3.5mL) of 40% is added in ethanol (80mL) solution of 3-diketone (1.6g, 3.57mmol).Be heated to 95 DEG C stir 1 hour, pressure reducing and steaming solvent.The non-purifying of thick product is directly used in next step reaction.
Step 4:(S) the chloro-N-of-5-((3-(4-iodophenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
(S)-5-(amino methyl)-3-(4-iodophenyl) oxazolidine-2-ketone (1.10g is added successively in round-bottomed flask, 3.46mmol), 5-chlorothiophene-2-formic acid (800mg, 4.92mmol), HATU (2.9g, 7.63mmol), diisopropylethylamine (1.7mL, 10.3mmol) with DMF (15mL).Stirring at room temperature 3 hours.Add water (30mL), with ethyl acetate (30mL × 3) extraction, merge organic phase, use water (30mL × 2) washing, saturated aqueous common salt (50mL) washing successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains white solid (1.5g, 93.8%).
1H NMR(CDCl 3,400MHz)δ8.02(s,1H),7.66(d,J＝8.8Hz,2H),7.30(d,J＝4.0Hz,1H),7.28(d,J＝8.8Hz,2H),6.90(d,J＝4.0Hz,1H),6.60(t,J＝6.0Hz,1H),4.82-4.89(m,1H),4.08(t,J＝8.8Hz,1H),3.71-3.92(m,3H).
Step 5:(S) the chloro-N-of-5-((3-(4-(1,1-dioxothiochromane-6-base) phenyl)-2-oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives
The chloro-N-of (S)-5-((3-(4-iodophenyl)-2-Yang Dai oxazolidine-5-base) methyl) thiophene-2-carboxamide derivatives (231mg is added successively in round-bottomed flask, 0.499mmol), 6-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxy boron pentane-2-base) thiochroman 1, 1-dioxide (192mg, 0.623mmol), sodium carbonate (64mg, 0.604mmol), tetra-triphenylphosphine palladium (116mg, 0.0932mmol), toluene (16mL), ethanol (4mL) and water (1mL), under nitrogen atmosphere, be heated to 100 DEG C stir 16 hours.Add water (20mL), with ethyl acetate (20mL × 3).Merge organic phase, with saturated aqueous common salt (40mL) washing, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains white solid (26mg, 10.1%).
1H NMR(400MHz,DMSO-d 6)δ8.98(t,J＝5.6Hz,1H),7.83(d,J＝8.4Hz,1H),7.73-7.78(m,3H),7.65-7.69(m,4H),7.19(d,J＝4.0Hz,1H),4.83-4.90(m,1H),4.23(t,J＝8.8Hz,1H),3.89(dd,J＝6.0,9.2Hz,1H),3.49-3.53(m,2H),3.08(t,J＝6.0Hz,2H),2.31-2.37(m,2H)；
MS(ESI,pos.ion)m/z:517.2(M+1).
Active testing example
Anticoagulation effect in vitro is tested
The clotting time of compounds extend rabbit plasma
1. the preparation of each concentration compound
Get each compound working fluid (100mM) of 4 μ L, be diluted to the working fluid of each concentration with methyl-sulphoxide liquid.
2. the preparation of plasma sample
Get some rabbits, auricular vein injects 3% pentobarbital solution (30mg/kg) anesthesia, with the vacuum test tube aorta abdominalis blood sampling containing 3.8% Sodium Citrate 0.2mL to 2mL, collect multitube, turn upside down mixing for several times, leave standstill 10min, in the centrifugal 10min of 3000rpm, draw each pipe blood plasma, all blood plasma is mixed to same centrifuge tube, 1.6mL often pipe packing, it is for subsequent use to insert rapidly-80 DEG C of Refrigerator stores.
3. application of sample and mensuration clotting time PT and APTT
Get out 1.5mL EP manage, often pipe adds 180 μ L plasma specimens; In each pipe blood specimen, add the medicine of 4 μ L respective concentration respectively, control group adds 4 μ L dimethyl sulfoxide solutions, and concussion mixing, hatches 5min for 37 DEG C; PT and APTT is measured with Sysmex CA1500 Automatic coagulometer; Draw amount effect curve, matching is carried out to curve, calculate the concentration (CT of the test compounds that the clotting time of sening as an envoy to doubles thus 2).
Compound is to the restraining effect of people FXa activity and anticoagulation effect in vitro
A：1.00nM-10nM；B：10.01nM-50nM；C：50.01nM-1.00μM；D：1.01μM-20.00μM
Conclusion: this series compound has good factor Xa inhibit activities, has the effect extending the clotting time simultaneously.
The solubleness test of compound
In 15mL tapered tube, add water (10mL), vibration limit, limit adds sample, until sample stops dissolving, and 37 DEG C of water bath with thermostatic control jolting 24h, jolting speed 40rpm.After jolting terminates, sample is filtered through water system millipore filtration (0.45 μm, Φ 13mm), discard just filtrate, precision pipettes subsequent filtrate (500 μ L), adds diluent acetonitrile-water (500 μ L, v/v=60/40), the two mixing, obtains need testing solution.
Get need testing solution (40 μ L), adopt HPLC to detect, by one point external standard method calculation sample concentration:
Numbering Compound solubility (mg/mL)
Embodiment 1 0.26
Embodiment 2 0.48
Embodiment 3 0.60
Embodiment 4 0.11
Embodiment 5 0.15
Embodiment 6 0.32
Embodiment 7 0.16
Conclusion: this series compound has good solubleness.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.

Claims (8)

1. a compound, have such as formula the compound shown in (I), or the steric isomer of formula (I) compound, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein, Q is O or-CH 2-;
R is following minor structure:
condition is Q when being O, and R is not
Wherein each X 1be-CH independently 2-or-C (=O)-;
Each Y is-CH independently 2-,-O-or-NR 4-, wherein R 4for hydrogen, methyl or ethyl;
Each m is 0 or 1 independently;
X is hydrogen, fluorine, chlorine, bromine or iodine;
R 2for C 1-3alkyl or C 1-3alkoxyl group;
R 3for hydrogen, C 1-3alkyl or C 1-3alkoxyl group;
Each n 1and n 2be 1,2 or 3 independently; With
N is 0,1,2 or 3.
2. compound as claimed in claim 1, wherein
R 2for methyl, methoxyl group, oxyethyl group or positive propoxy; With
R 3for hydrogen, methyl, methoxyl group, oxyethyl group or positive propoxy.
3. the compound according to any one of claim 1-2, comprise following one of them structure or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug,
4. a pharmaceutical composition, comprises the compound described in any one of claim 1-3, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combine arbitrarily.
5. the compound described in an any one of claim 1-3 or pharmaceutical composition according to claim 4 are preparing the purposes prevented, process, treat or alleviate in the medicine of patient's thrombotic disease.
6. purposes according to claim 5, wherein said thrombotic disease is myocardial infarction, stenocardia, to block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis again.
7. purposes according to claim 6, described purposes is for the compound described in any one of claim 1-3 or pharmaceutical composition according to claim 4 are for the preparation of the purposes of the medicine for the treatment of disseminated inravascular coagulation (DIC).
8. purposes according to claim 6, described purposes is for compound described in any one of claim 1-3 or pharmaceutical composition according to claim 4 are for the preparation of the purposes of the medicine of supressor Xa.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801572A (en) * 2016-05-12 2016-07-27 山东罗欣药业集团股份有限公司 Preparation method of rivaroxaban

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009103A1 (en) * 1991-11-01 1993-05-13 The Upjohn Company Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents
CN101248067A (en) * 2005-06-27 2008-08-20 菲尔若国际公司 Oxazolidinone derivatives and use thereof as antibiotics
CN101325957A (en) * 2005-10-10 2008-12-17 拜耳医药保健股份公司 Microangiopathy treatment and prevention
CN101610767A (en) * 2006-11-02 2009-12-23 拜耳先灵制药股份公司 The combination treatment of the oxazolidinones that is substituted

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009103A1 (en) * 1991-11-01 1993-05-13 The Upjohn Company Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents
CN101248067A (en) * 2005-06-27 2008-08-20 菲尔若国际公司 Oxazolidinone derivatives and use thereof as antibiotics
CN101325957A (en) * 2005-10-10 2008-12-17 拜耳医药保健股份公司 Microangiopathy treatment and prevention
CN101610767A (en) * 2006-11-02 2009-12-23 拜耳先灵制药股份公司 The combination treatment of the oxazolidinones that is substituted

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUSANNE ROEHRIG ET AL.: "Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (BAY 59-7939):An Oral,Direct Factor Xa Inhibitor", 《J.MED.CHEM.》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801572A (en) * 2016-05-12 2016-07-27 山东罗欣药业集团股份有限公司 Preparation method of rivaroxaban
CN105801572B (en) * 2016-05-12 2018-11-06 山东罗欣药业集团恒欣药业有限公司 A kind of preparation method of razaxaban

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